# ent

id: cord-012682-7goljir4
type: CHEMICAL
entity:
  N terminal residue in Gag adopts a myristoylsequestering conformation 41 42 Moreover the results from screens of the interaction of the host factors with the HIV 1 MA domain showed that heme oxygenase 2 HO


id: cord-012723-2bbd30ud
type: GGP
entity:
  glia derived neurotropic factor Differential pH and capsaicin responses of Griffonia simplicifolia IB4 IB4


id: cord-300445-qzu4gz2d
type: PROTEIN
entity:
  interleukin IL 2 IL 7 granulocyte colony stimulating factor G CSF interferon γinducible protein 10 IP 10 monocyte chemoattractant protein 1 MCP1 macrophage inflammatory protein 1


id: cord-012768-9fvumvdc
type: PROTEIN
entity:
  anti cleaved caspase 9 anti caspase 3 anti cleaved caspase 3 anti cytochrome c Cyt c anti Bim anti FOXO3a antiphospho


id: cord-012768-9fvumvdc
type: PROTEIN
entity:
  forkhead transcription factor FKHRL1 FOXO3a Cystic fibrosis transmembrane conductance regulator CFTR


id: cord-012769-clbqckj2
type: PROTEIN
entity:
  poly ADP ribose polymerase PARP caspase 3 cleaved caspase 3 PI3K p110ɑ p AKT Ser 473 AKT mammalian target


id: cord-013717-e0cai9j3
type: CHEMICAL
entity:
  6 2 4 bis 4 fluorophenyl methylidene piperidin 1 yl ethyl 7 methyl 1 3 thiazolo 3 2 a pyrimidin 5 one


id: cord-013717-e0cai9j3
type: CHEMICAL
entity:
  TEA chloride HEPES taurine S methyl 1 4 dihydro 2 6 dimethyl 3 nitro 4 2 trifluoromethylphenyl pyridine


id: cord-012838-23odny3f
type: PROTEIN
entity:
  ecto 5 nucleotidase NT5E guanidinoacetate N methyltransferase GAMT plateletderived endothelial cell growth factor PD ECGF


id: cord-329011-spiuqngp
type: GGP
entity:
  IFN α recombinant human IFN α1b IFN α2a remdesivir chloroquine favipiravir and lopinavir ritonavir Aluvia


id: cord-012758-18c1rxg8
type: PROTEIN
entity:
  SQSTM1 1 1 000 Cell Signaling Technology 5114 LC3 1 1 000 Sigma L7543 AMPK 1 1 000 Cell Signaling Technology 5831 p AMPK T172 1 1 000 Cell Signaling Technology 50081 p mTOR S2448 1 1000 Cell Signaling Technology 2971 p p70S6 1 1000 Cell Signaling Technology 9205 IL 1β 1 1000 Cell Signaling Technology


id: cord-012802-xm2ftrw2
type: CELL_LINE
entity:
  hepatic carcinoma colon cancer pancreatic cancer etc 6 7 Based on sophoridinic acid with three ring structure


id: cord-012802-xm2ftrw2
type: CELL_LINE
entity:
  MIA Paca 2 human hepatoma cell HepG2 human breast cancer cell MCF 7 human colon carcinoma cells HCT 8


id: cord-012802-xm2ftrw2
type: CELL_LINE
entity:
  HCT116 human breast cancer cell MDA MB 231 human ovarian cancer cell SKOV3 human choriocarcinoma cell JEG3 human colon carcinoma cells HCT116 p53KO


id: cord-012754-yp66g40r
type: ORG
entity:
  the Institutional Animal Care and Use Committee of the Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences Serum


id: cord-012754-yp66g40r
type: CHEMICAL
entity:
  KpnI 309 5 TTTGGTACCCCTCCTTCCAGGTCTCCT CC 3 integrin αv KpnI 16 5 AACCAGATCTAGCTCCTGAGCCTG 3 integrin αv BglII 152 5 GGCCAGATCTACTGTCCACGTCTAGG TTGAAGG 3 Each construct together with pRL TK


id: cord-012791-dyk5mr1q
type: GGP
entity:
  tumor necrosis factor alpha TNF α interleukin 1 beta IL 1β inducible nitric oxide synthase iNOS cyclooxygenase 2 COX 2


id: cord-012778-yr8zuvw9
type: ORG
entity:
  the Sixth Hospital of Peking University Beijing Anding Hospital Guangzhou Psychiatric Hospital West China Hospital of Sichuan University Second Xiangya Hospital First Affiliated Hospital


id: cord-013591-goaokk04
type: GGP
entity:
  derived neurotrophic factor IL 1β interleukin 1β TNF α tumor necrosis factor α CORT corticosterone COX 2 cyclooxygenase 2


id: cord-013567-qnp65w53
type: CHEMICAL
entity:
  sulforhodamine B TCA trichloroacetic acid oligomycin FCCP 2 2 4 trifluoromethoxy phenyl hydrazinylidene


id: cord-012773-wtgk2d68
type: CL
entity:
  motor and nonmotor symptoms A timeline of PD from onset to death has been proposed 17 which not only promotes a comprehensive understanding of the overall disease process but is also a reminder that before a patient shows any PD related clinical symptoms the disease may have progressed severely and possibly irreversibly as a result of neuronal


id: cord-012818-zr4xw3ph
type: CL
entity:
  vascular smooth muscle tissue and myocardial tissue The PPAR signaling pathway is also a regulator with the potential to reverse several key pathological mechanisms of CHD Fig 5 such as vascular wall function foam cell


id: cord-012785-d53k16ow
type: GGP
entity:
  Sin DOI 10 1038 s41401 019 0351 4 sha c1e102df78033e275ef9d1a309f624d6eeb68e34 doc_id 12785 cord_uid d53k16ow Chalcomoracin CMR


id: cord-002006-pwlybr2h
type: DNA
entity:
  primer sets HTNV forward 5 TCTAGTT GTATCCCCATCGACTG 3 HTNV reverse 5 ACATGC GGAATACAATTATGGC 3 human GAPDH forward 5 GGTGGTCCTCTGACTTCAACA 3 human GAPDH reverse 5 GTTGCTGTAGCCAAATTCGTTGT 3 and


id: cord-002006-pwlybr2h
type: DNA
entity:
  mouse GAPDH forward 5 ACCCAGAAGACTGTGGA TGG 3 mouse GAPDH reverse 5 ACACATTGGGGGTAGGA A CA 3 The plasmid pGEM T HTNV pGEM T human GAPDH and pGEM T mouse GAPDH


id: cord-012806-pjehkeh9
type: ORG
entity:
  the Animal Experimentation Ethics Committee Shanghai University of Traditional Chinese Medicine Maintenance


id: cord-012784-c74jr4ga
type: CELL_LINE
entity:
  multiple cell lines 20 21 22 The CMap dataset can help characterize new chemical entities as well as understand their potential molecular mechanisms by using gene


id: cord-012784-c74jr4ga
type: DISEASE
entity:
  liver hepatocellular carcinoma kidney renal papillary cell carcinoma head and neck squamous cell carcinoma


id: cord-012771-3ukffdmq
type: PROTEIN
entity:
  mitochondrial biogenesis peroxisome proliferator activated receptor gammaco activator 1 PGC 1α mitochondrial transcription factor A TFAM


id: cord-012771-3ukffdmq
type: GGP
entity:
  peroxisome proliferator activated receptor gammaco activator 1 PGC 1α mitochondrial transcription factor A TFAM


id: cord-012771-3ukffdmq
type: GGP
entity:
  peroxisome proliferator activated receptors and estrogen receptor related receptors ERRs 18 Mitochondrial transcription factor A


id: cord-012716-t19zmvm6
type: DNA
entity:
  midbrain substantia nigra SN 1 2 1 Methyl 4 phenyl 1 2 3 6 tetrahydropyridine MPTP 6hydroxydopamine 6 OHDA


id: cord-012716-t19zmvm6
type: DNA
entity:
  primer sequences 1 Dicer forward 5 CCTGACAGTGACGGTCCAAAG 3 reverse 5 CATGACTCTTCAACTCAAACT 3 Dicer deletion


id: cord-012716-t19zmvm6
type: PROTEIN
entity:
  goat anti mouse IgG 1 400 Thermo Fisher Scientific USA or Alexa Fluor 594 conjugated goat anti rabbit IgG 1 400 Thermo Fisher Scientific USA


# bib

id: cord-001268-sc0ersky
title: Gene expression profiles of human liver cells mediated by hepatitis B virus X protein
author: Zhang, Wei-ying
date: 2009-04-03
txt: ./txt/cord-001268-sc0ersky.txt
cache: ./cache/cord-001268-sc0ersky.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002275/
doi: 10.1038/aps.2009.22
summary:
  AIM: To demonstrate the gene expression profiles mediated by hepatitis B virus X protein (HBx), we characterized the molecular features of pathogenesis associated with HBx in a human liver cell model. When compared with the gene expression profiles of H7402-X cells [10] , our findings provide new insight into the molecular mechanism of carcinogenesis mediated by HBx in human liver cells. To distinguish the differential expression of genes in normal human liver L-O2 cells and hepatoma cells mediated by HBx, we examined the differential expression profiles in L-O2-X cells by cDNA microarray analysis ( Figure 1 ). HBx was responsible for the upregulation of PCNA and Bcl-2 To further validate the candidate genes in the cDNA microarray and to preliminarily investigate the molecular alterations of proliferating cell nuclear antigen (PCNA) and Bcl-2 in the L-O2-X cell line, we examined the regulation of PCNA and Bcl-2 at the protein level by Western blot analysis.

abstract:
  AIM: To demonstrate the gene expression profiles mediated by hepatitis B virus X protein (HBx), we characterized the molecular features of pathogenesis associated with HBx in a human liver cell model. METHODS: We examined gene expression profiles in L-O2-X cells, an engineered L-O2 cell line that constitutively expresses HBx, relative to L-O2 cells using an Agilent 22 K human 70-mer oligonucleotide microarray representing more than 21,329 unique, well-characterized Homo sapiens genes. Western blot analysis and RNA interference (RNAi) targeting HBx mRNA validated the overexpression of proliferating cell nuclear antigen (PCNA) and Bcl-2 in L-O2-X cells. Meanwhile, the BrdU incorporation assay was used to test cell proliferation mediated by upregulated cyclooxygenase-2 (COX-2). RESULTS: The microarray showed that the expression levels of 152 genes were remarkably altered; 82 of the genes were upregulated and 70 genes were downregulated in L-O2-X cells. The altered genes were associated with signal transduction pathways, cell cycle, metastasis, transcriptional regulation, immune response, metabolism, and other processes. PCNA and Bcl-2 were upregulated in L-O2-X cells. Furthermore, we found that COX-2 upregulation in L-O2-X cells enhanced proliferation using the BrdU incorporation assay, whereas indomethacin (an inhibitor of COX-2) abolished the promotion. CONCLUSION: Our findings provide new evidence that HBx is able to regulate many genes that may be involved in the carcinogenesis. These regulated genes mediated by HBx may serve as molecular targets for the prevention and treatment of hepatocellular carcinoma.


id: cord-002006-pwlybr2h
author: Liu, Yuan-yuan
date: 2016-03-14
txt: ./txt/cord-002006-pwlybr2h.txt
cache: ./cache/cord-002006-pwlybr2h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820803/
doi: 10.1038/aps.2015.165
summary:
  AIM: To investigate the antiviral effects of vectors expressing specific short hairpin RNAs (shRNAs) against Hantaan virus (HTNV) infection in vitro and in vivo. In mice infected with lethal doses of HTNV, intraperitoneal injection of pSilencer-S or pSilencer-M (30 μg) considerably increased the survival rates and mean time to death, and significantly reduced the mean virus yields and viral RNA level, and alleviated virus-induced pathological lesions in lungs, brains and kidneys. Based on these results and the viral antigen expression results detected by IFA (data not shown), we concluded that the shRNAs that targeted the S and M segments of the HTNV gene were able to inhibit RNA transcript and virus production in the HTNV-infected cells and that shRNA-S1 and shRNA-M2 exhibited a stronger inhibitory effect against HTNV. The RNAi pSilencer-S and pSilencer-M plasmids were constructed, and their antiviral effects were further evaluated by detecting the viral protein synthesis and RNA transcript and progeny virus titers in the HTNV-infected cells.

title:
  Specific interference shRNA-expressing plasmids inhibit Hantaan virus infection in vitro and in vivo

abstract:
  AIM: To investigate the antiviral effects of vectors expressing specific short hairpin RNAs (shRNAs) against Hantaan virus (HTNV) infection in vitro and in vivo. METHODS: Based on the effects of 4 shRNAs targeting different regions of HTNV genomic RNA on viral replication, the most effective RNA interference fragments of the S and M genes were constructed in pSilencer-3.0-H1 vectors, and designated pSilencer-S and pSilencer-M, respectively. The antiviral effect of pSilencer-S/M against HTNV was evaluated in both HTNV-infected Vero-E6 cells and mice. RESULTS: In HTNV-infected Vero-E6 cells, pSilencer-S and pSilencer-M targeted the viral nucleocapsid proteins and envelope glycoproteins, respectively, as revealed in the immunofluorescence assay. Transfection with pSilencer-S or pSilencer-M (1, 2, 4 μg) markedly inhibited the viral antigen expression in dose- and time-dependent manners. Transfection with either plasmid (2 μg) significantly decreased HTNV-RNA level at 3 day postinfectin (dpi) and the progeny virus titer at 5 dpi. In mice infected with lethal doses of HTNV, intraperitoneal injection of pSilencer-S or pSilencer-M (30 μg) considerably increased the survival rates and mean time to death, and significantly reduced the mean virus yields and viral RNA level, and alleviated virus-induced pathological lesions in lungs, brains and kidneys. CONCLUSION: Plasmid-based shRNAs potently inhibit HTNV replication in vitro and in vivo. Our results provide a basis for development of shRNA as therapeutics for HTNV infections in humans.


id: cord-012035-rhpfpku9
title: TRAIL-based gene delivery and therapeutic strategies
author: Zhong, Hui-hai
date: 2019-08-23
txt: ./txt/cord-012035-rhpfpku9.txt
cache: ./cache/cord-012035-rhpfpku9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889127/
doi: 10.1038/s41401-019-0287-8
summary:
  In order to sensitize the tumor cells to TRAIL-induced apoptosis, combination therapy of TRAIL DNA with other drugs by the codelivery methods for yielding a synergistic antitumor efficacy is summarized. Intriguingly, it was found that preparation via a high concentration The clinical trials can be found at https://www.clinicaltrials.gov TRAIL-based gene delivery and therapeutic strategies HH Zhong process (i.e., a small reaction volume) resulted in large PEI/DNA complexes that had a higher gene transfection efficiency than their small counterparts prepared at a low concentration (Fig. 3 ) [54] . reported a novel application of magnetic core-shell nanoparticles for the dual purpose of delivering and activating a heat-inducible gene vector that encodes TRAIL in adipose-derived mesenchymal stem cells (AD-MSCs) [86] . Mesenchymal stem cells as a novel carrier for targeted delivery of gene in cancer therapy based on nonviral transfection

abstract:
  TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), also known as APO2L, belongs to the tumor necrosis factor family. By binding to the death receptor 4 (DR4) or DR5, TRAIL induces apoptosis of tumor cells without causing side toxicity in normal tissues. In recent years TRAIL-based therapy has attracted great attention for its promise of serving as a cancer drug candidate. However, the treatment efficacy of TRAIL protein was under expectation in the clinical trials because of the short half-life and the resistance of cancer cells. TRAIL gene transfection can produce a “bystander effect” of tumor cell killing and provide a potential solution to TRAIL-based cancer therapy. In this review we focus on TRAIL gene therapy and various design strategies of TRAIL DNA delivery including non-viral vectors and cell-based TRAIL therapy. In order to sensitize the tumor cells to TRAIL-induced apoptosis, combination therapy of TRAIL DNA with other drugs by the codelivery methods for yielding a synergistic antitumor efficacy is summarized. The opportunities and challenges of TRAIL-based gene delivery and therapy are discussed.


id: cord-012682-7goljir4
title: N-myristoylation: from cell biology to translational medicine
author: Yuan, Meng
date: 2020-03-18
txt: ./txt/cord-012682-7goljir4.txt
cache: ./cache/cord-012682-7goljir4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468318/
doi: 10.1038/s41401-020-0388-4
summary:
  N-myristoylation refers to the attachment of 14-carbon fatty acid myristates to the N-terminal glycine of proteins by N-myristoyltransferases (NMT) and affects their physiology such as plasma targeting, subcellular tracking and localization, thereby influencing the function of proteins. For example, it was reported that both N-myristoylation and palmitoylation appear to have opposing roles and different membrane lipid microdomain preferences for the G protein-membrane interactions I (Gαi1) monomer, which are likely due to the conformational differences in the presence of different fatty acids [31] . Potential targets of cancer treatments Given that altered NMT expression is observed in many types of cancer tissues and because many N-myristoylated proteins are involved in signaling processes that regulate cell proliferation, growth and death, it has been proposed that N-myristoylation or NMTs can be considered as therapeutic targets for cancer.

abstract:
  Various lipids and lipid metabolites are bound to and modify the proteins in eukaryotic cells, which are known as ‘protein lipidation’. There are four major types of the protein lipidation, i.e. myristoylation, palmitoylation, prenylation, and glycosylphosphatidylinositol anchor. N-myristoylation refers to the attachment of 14-carbon fatty acid myristates to the N-terminal glycine of proteins by N-myristoyltransferases (NMT) and affects their physiology such as plasma targeting, subcellular tracking and localization, thereby influencing the function of proteins. With more novel pathogenic N-myristoylated proteins are identified, the N-myristoylation will attract great attentions in various human diseases including infectious diseases, parasitic diseases, and cancers. In this review, we summarize the current understanding of N-myristoylation in physiological processes and discuss the hitherto implication of crosstalk between N-myristoylation and other protein modification. Furthermore, we mention several well-studied NMT inhibitors mainly in infectious diseases and cancers and generalize the relation of NMT and cancer progression by browsing the clinic database. This review also aims to highlight the further investigation into the dynamic crosstalk of N-myristoylation in physiological processes as well as the potential application of protein N-myristoylation in translational medicine.


id: cord-012688-d0m23sgk
author: Zheng, Xu-yong
date: 2020-04-27
txt: ./txt/cord-012688-d0m23sgk.txt
cache: ./cache/cord-012688-d0m23sgk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468329/
doi: 10.1038/s41401-020-0410-x
summary:
  TLR4/MyD88 signaling pathway, as a key regulator of inflammation, plays an important role in the pathogenesis of obesity-induced cardiomyopathy. We previously demonstrated that LM9, a novel MyD88 inhibitor, attenuated inflammatory responses and fibrosis in obesity-induced cardiomyopathy by inhibiting the formation of TLR4/MyD88 complex. In HFD-fed mice, administration of LM9 (5, 10 mg/kg, ig, every other days for 8 weeks) dose-dependently alleviated inflammation and fibrosis in heart tissues and decreased serum lipid concentration. Thus, in the current study, we provide evidence that compound LM9, a novel MyD88 inhibitor from our previous study [21, 22] , efficiently attenuates inflammatory responses and fibrosis in obesity-induced cardiomyopathy by inhibiting the formation of the TLR4/MyD88 complex. We also examined the expression levels of profibrotic proteins in heart tissue, and our results revealed that LM9 attenuated HFD-induced cardiac fibrosis (Fig. 6d and Supplementary Fig. S1 ). Lipid accumulation activates harmful signaling pathways, resulting in the production of inflammatory factors and tissue remodeling in cardiomyocytes, leading to obesity-induced cardiomyopathy.

title:
  Compound LM9, a novel MyD88 inhibitor, efficiently mitigates inflammatory responses and fibrosis in obesity-induced cardiomyopathy

abstract:
  Mechanisms of cardiomyopathy caused by obesity/hyperlipidemia are complicated. Obesity is usually associated with chronic low-grade inflammation and may lead to the onset and progression of myocardial fibrosis and remodeling. TLR4/MyD88 signaling pathway, as a key regulator of inflammation, plays an important role in the pathogenesis of obesity-induced cardiomyopathy. We previously demonstrated that LM9, a novel MyD88 inhibitor, attenuated inflammatory responses and fibrosis in obesity-induced cardiomyopathy by inhibiting the formation of TLR4/MyD88 complex. In this study, we investigated the protective effects of LM9 on obesity-induced cardiomyopathy in vitro and in vivo. We showed that LM9 (5, 10 μM) significantly attenuates palmitic acid (PA)-induced inflammation in mouse peritoneal macrophages, evidenced by decreased expression of proinflammatory genes including TNF-α, IL-6, IL-1β, and ICAM-1. In cardiac-derived H9C2 cells, LM9 treatment suppressed PA-induced inflammation, lipid accumulation, and fibrotic responses. In addition, LM9 treatment also inhibited PA-activated TLR4/MyD88/NF-κB signaling pathway. We further revealed in HEK293 cells that LM9 treatment blocked the TLR4/MyD88 binding and MyD88 homodimer formation. In HFD-fed mice, administration of LM9 (5, 10 mg/kg, ig, every other days for 8 weeks) dose-dependently alleviated inflammation and fibrosis in heart tissues and decreased serum lipid concentration. In conclusion, this study demonstrates that MyD88 inhibitor LM9 exerts protective effects against obesity-induced cardiomyopathy, suggesting LM9 to be a promising therapeutic candidate drug for the obesity-related cardiac complications.


id: cord-012716-t19zmvm6
author: Guo, Chen-hong
date: 2020-02-28
txt: ./txt/cord-012716-t19zmvm6.txt
cache: ./cache/cord-012716-t19zmvm6.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468551/
doi: 10.1038/s41401-020-0379-5
summary:
  In this study, we employed DAT promoter-mediated Cre transgenic mice to establish tamoxifen-inducible Dicer conditional knockout (cKO) mice in an effort to mimic the progressive loss of DA neurons and the development of PD-like behavioral phenotypes. The results indicated that the chronic administration of either DHM or PRE-084 attenuated the Dicer cKO-induced loss of DA neurons and motor impairments, although the two drugs acted through different mechanisms. These results indicated that Dicer cKO in DA neurons in response to tamoxifen administration in adult mice induced the progressive development of PD-like phenotypes. Dicer cKO mice, which steadily developed PD-like behaviors in response to tamoxifen induction, were administered L-DOPA, and the results indicated that L-DOPA treatment significantly relieved motor impairments, as evidenced by performance on the pole test and rotarod test (Fig. 4) , indicating that the Dicer cKO mouse line can be used as an alternative animal model for evaluating the efficacy of PD drugs.

title:
  Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson’s disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin

abstract:
  Parkinson’s disease (PD) is a common neurodegenerative disease characterized by motor impairment and progressive loss of dopamine (DA) neurons. At present, the acute application of neurotoxic drugs such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are commonly used to simulate the pathology of PD; however, it is difficult to induce the progressive pathogenesis of PD with these models. In this study, we employed DAT promoter-mediated Cre transgenic mice to establish tamoxifen-inducible Dicer conditional knockout (cKO) mice in an effort to mimic the progressive loss of DA neurons and the development of PD-like behavioral phenotypes. The results showed that Dicer cKO mice exhibited progressive loss of DA neurons in the substantia nigra (SN) following tamoxifen administration. Significant DA loss was observed 6 weeks after tamoxifen administration; accordingly, progressive motor function impairment was also observed. We also found that a significant neuroinflammatory response, as evidenced by microglial proliferation, another hallmark of PD pathogenesis, accompanied the loss of DA neurons. The acute application of levo-DOPA (l-DOPA) relieved the PD-like motor impairments in Dicer cKO mice to exert its antiparkinsonian action, indicating that the model can be used to evaluate the antiparkinsonian efficacy of PD drugs. To further elucidate the potential application of this novel PD animal model for PD drug development, we employed the powerful neuroprotective agent dihydromyricetin (DHM) (10 mg/kg) and the selective sigma-1 receptor agonist PRE-084 (1 mg/kg), both of which were previously shown to produce antiparkinsonian effects. The results indicated that the chronic administration of either DHM or PRE-084 attenuated the Dicer cKO-induced loss of DA neurons and motor impairments, although the two drugs acted through different mechanisms. These data indicate that the Dicer cKO mouse model may be a useful model for investigating the pathological development of PD and intervention-mediated changes. In conclusion, this transgenic mouse model appears to simulate the progressive pathogenesis of PD and may be a potentially useful model for PD drug discovery.


id: cord-012720-eoovm5gh
author: Liu, Qi
date: 2020-01-14
txt: ./txt/cord-012720-eoovm5gh.txt
cache: ./cache/cord-012720-eoovm5gh.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468572/
doi: 10.1038/s41401-019-0335-4
summary:
  title: Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway In conclusion, these results demonstrate that oroxindin could be absorbed by the colon and attenuate inflammatory responses via inhibiting NLRP3 inflammasome formation and activation, which is related to the inhibitory effect on TXNIP-dependent NF-κB-signaling pathway. In the present study, we investigated the protective effects of oroxindin and the underlying mechanisms, and proved that oroxindin attenuates UC by inhibiting NLRP3 inflammasome activation via suppressing the TXNIP-dependent NF-κB-signaling pathway in colonic macrophages. According to the results, the expression of NLRP3 and caspase-1 was increased in macrophages in the DSS-treated mice, while oroxindin exerted specific protective effects in the inflamed tissue. Oroxindin could also suppress NLRP3 inflammasome activation by restoring TXNIP expression and inhibiting the TXNIP-dependent NF-κB-signaling pathway induced by LPS in macrophages.

title:
  Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway

abstract:
  Oroxindin is a flavonoid isolated from the traditional Chinese medicine Huang-Qin, which has shown various pharmacological activities including anti-inflammatory, antitumor, antioxidant, etc. Thus far, the effect of oroxindin on colonic inflammation and the underlying mechanism remain unknown. In this study, we investigated the tissue distribution of oroxindin and its therapeutic effects on ulcerative colitis (UC) as well as the underlying mechanisms. UC model was established in mice by administrating dextran sulfate sodium (DSS) in drinking water for 7 d. We first showed that oroxindin was largely absorbed by the colon as an active ingredient after normal mice received Huang-Qin-Tang, a traditional Chinese medicine decoction. UC mice were then treated with oroxindin (12.5, 25, 50 mg ·kg(−1) ·d(−1), i.g.) for 10 d. We found that oroxindin treatment greatly suppressed massive macrophages infiltration and attenuated pathological changes in colonic tissue. Furthermore, oroxindin treatment significantly inhibited the generation of IL-1β and IL-18 in the colon via inhibiting the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome formation and activation. In cultured macrophages, LPS induced NLRP3 inflammasome formation and caspase-1 activation, which were suppressed by oroxindin (12.5–50 μM). In LPS-treated macrophages, oroxindin dose-dependently restored the expression of TXNIP protein, leading to suppressing TXNIP-dependent NF-κB activation. In conclusion, these results demonstrate that oroxindin could be absorbed by the colon and attenuate inflammatory responses via inhibiting NLRP3 inflammasome formation and activation, which is related to the inhibitory effect on TXNIP-dependent NF-κB-signaling pathway. Hence, oroxindin has the potential of becoming an effective drug for treating UC.


id: cord-012722-ewc2awv1
author: Bian, Yu
date: 2019-10-23
txt: ./txt/cord-012722-ewc2awv1.txt
cache: ./cache/cord-012722-ewc2awv1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468574/
doi: 10.1038/s41401-019-0307-8
summary:
  Pyroptosis is a form of inflammatory cell death that could be driven by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation following myocardial infarction (MI). In contrast, the inhibition of the NLRP3 inflammasome signaling pathway reduces infarct size and preserves cardiac function via attenuating cardiomyocyte pyroptosis in post-MI mice [10] [11] [12] . Moreover, KLX significantly suppressed the expression of the NLRP3 inflammasome, the release of the pro-inflammatory cytokines IL-1β and IL-18 and pyroptotic cell death in both an in vivo model of MI and an in vitro model of ischemic injury by hypoxia or LPS (Fig. 6) . In conclusion, our study provides the first evidence that KLX exerts myocardial protection by inhibiting NLRP3 inflammasome activation and subsequent pyroptosis in MI hearts and in cardiomyocytes treated with hypoxia or LPS as a cellular model of MI injury.

title:
  Kanglexin, a novel anthraquinone compound, protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis

abstract:
  Pyroptosis is a form of inflammatory cell death that could be driven by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation following myocardial infarction (MI). Emerging evidence suggests the therapeutic potential for ameliorating MI-induced myocardial damages by targeting NLRP3 and pyroptosis. In this study, we investigated the myocardial protection effect of a novel anthraquinone compound (4,5-dihydroxy-7-methyl-9,10-anthraquinone-2-ethyl succinate) named Kanglexin (KLX) in vivo and in vitro. Male C57BL/6 mice were pre-treated either with KLX (20, 40 mg· kg(−1)per day, intragastric gavage) or vehicle for 7 consecutive days prior to ligation of coronary artery to induce permanent MI. KLX administration dose-dependently reduced myocardial infarct size and lactate dehydrogenase release and improved cardiac function as compared to vehicle-treated mice 24 h after MI. We found that MI triggered NLRP3 inflammasome activation leading to conversion of interleukin-1β (IL-1β) and IL-18 into their active mature forms in the heart, which could expand the infarct size and drive cardiac dysfunction. We also showed that MI induced pyroptosis, as evidenced by increased DNA fragmentation, mitochondrial swelling, and cell membrane rupture, as well as increased levels of pyroptosis-related proteins, including gasdermin D, N-terminal GSDMD, and cleaved caspase-1. All these detrimental alterations were prevented by KLX. In hypoxia- or lipopolysaccharide (LPS)-treated neonatal mouse ventricular cardiomyocytes, we showed that KLX (10 μM) decreased the elevated levels of terminal deoxynucleotidyl transferase dUTP nick end labeling- and propidium iodide-positive cells, and pyroptosis-related proteins. We conclude that KLX prevents MI-induced cardiac damages and cardiac dysfunction at least partly through attenuating NLRP3 and subsequent cardiomyocyte pyroptosis, and it is worthy of more rigorous investigations for its potential for alleviating ischemic heart disease.


id: cord-012723-2bbd30ud
title: Endothelin-1 enhances acid-sensing ion channel currents in rat primary sensory neurons
author: Wu, Lei
date: 2020-02-27
txt: ./txt/cord-012723-2bbd30ud.txt
cache: ./cache/cord-012723-2bbd30ud.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468575/
doi: 10.1038/s41401-019-0348-z
summary:
  In whole-cell voltage-clamp recording, ASIC currents were evoked by brief local application of pH 6.0 external solution in the presence of TRPV1 channel blocker AMG9810. These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ET(A)R and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats. Herein, we showed that ET-1 enhanced the electrophysiological activity of ASICs in DRG neurons through ET A R, which may contribute to ET-1-induced spontaneous flinching and mechanical hyperalgesia in rats. ET-1 increased ASIC-medicated currents and action potentials in rat primary sensory neurons, which may contribute to ET-1induced spontaneous flinching and mechanical hyperalgesia in rats. In summary, the major finding of this study was that ET-1 enhanced the electrophysiological activity of ASICs in DRG neurons via the intracellular PKC signaling pathway, which may contribute to ET-1-induced nociceptive behavior in rats.

abstract:
  Endothelin-1 (ET-1), an endogenous vasoactive peptide, has been found to play an important role in peripheral pain signaling. Acid-sensing ion channels (ASICs) are key sensors for extracellular protons and contribute to pain caused by tissue acidosis. It remains unclear whether an interaction exists between ET-1 and ASICs in primary sensory neurons. In this study, we reported that ET-1 enhanced the activity of ASICs in rat dorsal root ganglia (DRG) neurons. In whole-cell voltage-clamp recording, ASIC currents were evoked by brief local application of pH 6.0 external solution in the presence of TRPV1 channel blocker AMG9810. Pre-application with ET-1 (1−100 nM) dose-dependently increased the proton-evoked ASIC currents with an EC(50) value of 7.42 ± 0.21 nM. Pre-application with ET-1 (30 nM) shifted the concentration–response curve of proton upwards with a maximal current response increase of 61.11% ± 4.33%. We showed that ET-1 enhanced ASIC currents through endothelin-A receptor (ET(A)R), but not endothelin-B receptor (ET(B)R) in both DRG neurons and CHO cells co-expressing ASIC3 and ET(A)R. ET-1 enhancement was inhibited by blockade of G-protein or protein kinase C signaling. In current-clamp recording, pre-application with ET-1 (30 nM) significantly increased acid-evoked firing in rat DRG neurons. Finally, we showed that pharmacological blockade of ASICs by amiloride or APETx2 significantly alleviated ET-1-induced flinching and mechanical hyperalgesia in rats. These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ET(A)R and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats.


id: cord-012726-1i1mj3jw
title: Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis
author: Chen, Xue-han
date: 2019-06-13
txt: ./txt/cord-012726-1i1mj3jw.txt
cache: ./cache/cord-012726-1i1mj3jw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468578/
doi: 10.1038/s41401-019-0249-1
summary:
  In the second screen, the MM cell line LP1, which expresses a high level of c-Maf [5, 8] , was treated with all of the above drugs for 24 h, followed by IB assays to evaluate PARP cleavage, a hallmark of apoptosis, and c-Maf degradation. c-g LP1 and RPMI-8226 cells were treated with MBZ at the indicated concentrations for 24 h, followed by quantitative real-time PCR to measure the expression of genes, including USP5 (c), c-Maf (d), CCND2 (e), ITGB7 (f), and ARK5 (g). Therefore, mebendazole, especially at low concentrations, preferentially induces MM cell apoptosis in a manner dependent on the expression of c-Maf. Mebendazole exerts synergistic antimyeloma effects with a USP5 inhibitor Previous studies identified WP1130 as a small molecule compound that inhibits the deubiquitinase activity of USP5 [15] . Mebendazole delays the growth of human multiple myeloma xenografts in a nude mouse model The above studies provided strong evidence that mebendazole inhibits the USP5/c-Maf axis and induces MM cell apoptosis.

abstract:
  c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmintic drug, preferentially induced apoptosis in c-Maf-expressing myeloma cells. Moreover, oral administration of mebendazole delayed the growth of human myeloma xenografts in nude mice but did not show overt toxicity. Further studies showed that the selective antimyeloma activity of mebendazole was associated with the inhibition of the USP5/c-Maf axis. Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation. Mebendazole inhibited c-Maf transcriptional activity, as confirmed by both luciferase assays and expression measurements of c-Maf downstream genes. In summary, this study identified mebendazole as a USP5/c-Maf inhibitor that could be developed as a novel antimyeloma agent.


id: cord-012747-s4wf0pix
title: Angiogenin and tRNA fragments in Parkinson’s disease and neurodegeneration
author: Prehn, Jochen H M
date: 2020-03-06
txt: ./txt/cord-012747-s4wf0pix.txt
cache: ./cache/cord-012747-s4wf0pix.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470775/
doi: 10.1038/s41401-020-0375-9
summary:
  Loss-of-function mutations in the angiogenin gene (ANG) have been initially discovered in familial cases of amyotrophic lateral sclerosis (ALS), however, variants in ANG have subsequently been identified in PD and Alzheimer''s disease. Stress-induced tRNA fragments have been proposed to have multiple cellular functions, including inhibition of ribosome biogenesis, inhibition of protein translation and inhibition of apoptosis. Subsequent studies showed that angiogenin exerts neuroprotective activities in vitro in models of excitotoxic, hypoxic and trophic factor-withdrawal-induced injury to motor neurons and other neural cells, including dopaminergic SH-SY5Y neuroblastoma cells [31, 36, 37] . demonstrated significantly decreased levels of endogenous angiogenin in an alpha-synuclein transgenic mouse model of PD and showed that recombinant human angiogenin protected against dopaminergic neuronal cell death and inhibited caspase-3 activation in neurotoxin-induced in vitro models of PD [49] . Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis

abstract:
  In this review, we summarise the evidence for a role of the ribonuclease angiogenin in the pathophysiology of neurodegenerative disorders, with a specific focus on Parkinson’s disease (PD). Angiogenin is a stress-induced, secreted ribonuclease with both nuclear and cytosolic activities. Loss-of-function mutations in the angiogenin gene (ANG) have been initially discovered in familial cases of amyotrophic lateral sclerosis (ALS), however, variants in ANG have subsequently been identified in PD and Alzheimer’s disease. Delivery of angiogenin protein reduces neurodegeneration and delays disease progression in in vitro and in vivo models of ALS and in vitro models of PD. In the nucleus, angiogenin promotes ribosomal RNA transcription. Under stress conditions, angiogenin also translocates to the cytosol where it cleaves non-coding RNA into RNA fragments, in particular transfer RNAs (tRNAs). Stress-induced tRNA fragments have been proposed to have multiple cellular functions, including inhibition of ribosome biogenesis, inhibition of protein translation and inhibition of apoptosis. We will discuss recent evidence of tRNA fragment accumulation in PD, as well as their potential neuroprotective activities.


id: cord-012753-cu6qcen9
author: Qi, Fei-long
date: 2020-05-28
txt: ./txt/cord-012753-cu6qcen9.txt
cache: ./cache/cord-012753-cu6qcen9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470798/
doi: 10.1038/s41401-020-0423-5
summary:
  title: Reversal of the immunosuppressive tumor microenvironment by nanoparticle-based activation of immune-associated cells Based on the research of our group, we here introduce the new strategies being employed using nanoscale intelligent drug delivery systems to enhance the effects of cancer immunotherapy. In more recent years, cancer immunotherapy, which effectively kills cancer cells by enhancing immune system function in patients, has emerged as a new therapeutic approach [5, 6] . Many nanodrug delivery systems have achieved encouraging therapeutic efficacy in tumor inhibition through the codelivery of immune checkpoint inhibitors with other drugs or compounds expected to regulate the tumor microenvironment [33, 34] . It is generally accepted that tumor vaccines enable targeted delivery of tumor-associated antigens (TAAs) or adjuvants to DCs and induce long-lasting antitumor immune responses [75] [76] [77] [78] . Engineering nanoparticles for targeted remodeling of the tumor microenvironment to improve cancer immunotherapy

title:
  Reversal of the immunosuppressive tumor microenvironment by nanoparticle-based activation of immune-associated cells

abstract:
  Immunotherapy that activates the host immune system to reverse immunosuppression has emerged as a new generation of cancer treatment in both preclinical studies and clinical trials. Although immunotherapy has shown significant achievements in the treatment of various cancers, it faces challenges that limit its further evolution such as poor permeation and modest responsiveness. The development of nanoparticle drug delivery system has provided an opportunity to overcome these drawbacks and to achieve optimized immunotherapy. Based on the research of our group, we here introduce the new strategies being employed using nanoscale intelligent drug delivery systems to enhance the effects of cancer immunotherapy. We also provide a perspective on the further possible application of nanoparticles in more effective antitumor immunotherapy.


id: cord-012754-yp66g40r
author: Zhang, Na
date: 2020-01-13
txt: ./txt/cord-012754-yp66g40r.txt
cache: ./cache/cord-012754-yp66g40r.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470799/
doi: 10.1038/s41401-019-0325-6
summary:
  title: A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin αv expression We then showed that IMB-S7 treatment markedly suppressed the TGF-β/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-β1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-β-treated LX2 cells and liver samples of BDL rats. IMB-S7 significantly inhibits HSC activation in cell models and rat fibrotic livers To further verify the liver protective activity of IMB-S7, we first detected its effect on the TGF-β/Smad pathway, whose activation promotes the transcription of most fibrogenesis-associated genes. In normal or TGF-β1-activated LX2 cells, the mRNA and protein levels of integrin αv were both reduced after IMB-S7 treatment (Fig. 3a, b) .

title:
  A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin αv expression

abstract:
  Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg(−1)· d(−1), for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-β/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-β1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-β-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-β/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to the integrin αv (ITGAV) promoter (−173/−163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.


id: cord-012758-18c1rxg8
title: Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury
author: Wu, Xiao-li
date: 2020-02-27
txt: ./txt/cord-012758-18c1rxg8.txt
cache: ./cache/cord-012758-18c1rxg8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470806/
doi: 10.1038/s41401-020-0361-2
summary:
  We further revealed that ramelteon significantly inhibited autophagy in the peri-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway. To explore the neuroprotective effect of ramelteon against acute ischemic brain injury, mice were subjected to middle cerebral artery occlusion (MCAO) (Fig. 1a) . We next determined the Fig. 1 Ramelteon protected against middle cerebral artery occlusion (MCAO)-induced acute ischemic brain injury. Overall, these data supported the involvement of the AMPK/mTOR signaling pathway and autophagy in ramelteon-conferred neuroprotection in either acute or chronic ischemic brain injury. Ramelteon may activate the AMPK/mTOR signaling pathway and inhibit ischemia-induced autophagy in a melatonin receptor-related manner (Fig. 6) . Considering the safety of ramelteon in clinical application, our data indicated Fig. 4 Ramelteon activated the AMPK/mTOR signaling pathway and inhibited autophagy in acute ischemic brain injury. It took Fig. 5 Ramelteon activated the AMPK/mTOR signaling pathway and suppressed autophagy in chronic ischemic brain injury.

abstract:
  Melatonin receptors (MTs) are potential drug targets for stroke therapy. Ramelteon is a selective melatonin receptor agonist used to treat insomnia. In this study we investigated whether ramelteon could attenuate cerebral ischemia in mice. Acute focal cerebral ischemia was induced in mice via middle cerebral artery occlusion (MCAO). We found oral administration of ramelteon (3.0 mg/kg) significantly attenuated ischemic injury even when it was given 4 h after the onset of ischemia. We showed that administration of ramelteon (3.0 mg/kg) displayed comparable protective efficacy and length of effective time window as administration of edaravone (10 mg/kg, i.p.), which was used in clinic to treat ischemic stroke. Chronic ischemic brain injury was induced in mice using photothrombosis. Oral administration of ramelteon (3.0 mg · kg(−1) · d(−1)) for 7 days after ischemia significantly attenuated functional deficits for at least 15 days. The neuroprotection of ramelteon was blocked by 4-P-PDOT, a specific MT antagonist. We further revealed that ramelteon significantly inhibited autophagy in the peri-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway. Intracerebroventricular injection of rapamycin, an autophagy activator, compromised the neuroprotection of ramelteon, suggesting ramelteon might attenuate ischemic injury by counteracting autophagic cell death. These data demonstrate for the first time the potential benefits of ramelteon in the treatment of both acute and chronic ischemic brain injury and provide the rationale for the application of ramelteon in stroke therapy.


id: cord-012760-p6fdc191
author: Liu, Can-zhao
date: 2019-09-04
txt: ./txt/cord-012760-p6fdc191.txt
cache: ./cache/cord-012760-p6fdc191.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470808/
doi: 10.1038/s41401-019-0298-5
summary:
  In cultured basilar artery smooth muscle cells (BASMCs) isolated from 2k2c renohypertesive rats, treatment with angiotensin II (0.125−1 μM) dose-dependently increased endophilin A2 levels and decreased TMEM16A expression. Our recent study found that CaCC activity in the cardiovascular system, as well as TMEM16A expression level, was decreased in basilar artery smooth muscle cells (BASMCs) isolated from twokidney two-clip (2k2c) renohypertensive rats, possibly caused by a high concentration of angiotensin II during hypertension [10] . Endophilin A2 is upregulated during hypertension We previously identified TMEM16A as the molecular identity of the CaCC in smooth muscle cells and found that CaCC activity was associated with a high concentration of angiotensin II in the basilar artery of the 2k2c renohypertensive rat model. Considering the significant upregulation of endophilin A2 in the basilar arteries isolated from the hypertension model, we hypothesized that overexpression of endophilin A2 could reduce TMEM16A protein expression by modulating TMEM16A ubiquitination, which would further lead to downregulation of CaCC activation.

title:
  Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediated TMEM16A degradation

abstract:
  TMEM16A Ca(2+)-activated chloride channel (CaCC) plays an essential role in vascular homeostasis. In this study we investigated the molecular mechanisms underlying downregulation of TMEM16A CaCC activity during hypertension. In cultured basilar artery smooth muscle cells (BASMCs) isolated from 2k2c renohypertesive rats, treatment with angiotensin II (0.125−1 μM) dose-dependently increased endophilin A2 levels and decreased TMEM16A expression. Similar phenomenon was observed in basilar artery isolated from 2k2c rats. We then used whole-cell recording to examine whether endophilin A2 could regulate TMEM16A CaCC activity in BASMCs and found that knockdown of endophilin A2 significantly enhanced CaCC activity, whereas overexpression of endophilin A2 produced the opposite effect. Overexpression of endophilin A2 did not affect the TMEM16A mRNA level, but markedly decreased TMEM16A protein level in BASMCs by inducing ubiquitination and autophagy of TMEM16A. Ubiquitin-binding receptor p62 (SQSTM1) could bind to ubiquitinated TMEM16A and resulted in a process of TMEM16A proteolysis in autophagosome/lysosome. These data provide new insights into the regulation of TMEM16A CaCC activity by endophilin A2 in BASMCs, which partly explains the mechanism of angiotensin-II-induced TMEM16A inhibition during hypertension-induced vascular remodeling.


id: cord-012767-h5gv9g62
author: Wei, Xiao-min
date: 2020-03-09
txt: ./txt/cord-012767-h5gv9g62.txt
cache: ./cache/cord-012767-h5gv9g62.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470836/
doi: 10.1038/s41401-020-0374-x
summary:
  We showed that treatment with interleukin 1β (IL‐1β) induced EnMT of HUVECs via activation of NF-κB/Snail pathway, which was further exacerbated by knockdown of protein tyrosine phosphatase L1 (PTPL1). Similarly, PTPL1-knockdown HUVECs showed much higher NF-κB activity and Snail levels than control cells in response to treatment with IL-1β (Fig. 2i) . To validate NF-κB activation in vivo, The relative mRNA levels of the endothelial markers CD31 and CD144 and the mesenchymal markers α-SMA and SM-22-α in control and IL-1βtreated HUVECs were assessed by qRT-PCR (each bar represents the mean ± SEM. The results showed that PTPL1 levels were lower in the pulmonary arterial endothelial cells of PH patients than in control lung cancer patients (Fig. 5h) . In this study, we found that PTPL1 could inhibit IL-1β-induced EnMT in HUVECs, and knockdown of PTPL1 could activate NF-κB signaling and increase the level of Snail.

title:
  Protein tyrosine phosphatase L1 represses endothelial-mesenchymal transition by inhibiting IL-1β/NF-κB/Snail signaling

abstract:
  Endothelial–mesenchymal transition (EnMT) plays a pivotal role in various diseases, including pulmonary hypertension (PH), and transcription factors like Snail are key regulators of EnMT. In this study we investigated how these factors were regulated by PH risk factors (e.g. inflammation and hypoxia) in human umbilical vein endothelial cells (HUVECs). We showed that treatment with interleukin 1β (IL‐1β) induced EnMT of HUVECs via activation of NF-κB/Snail pathway, which was further exacerbated by knockdown of protein tyrosine phosphatase L1 (PTPL1). We demonstrated that PTPL1 inhibited NF-κB/Snail through dephosphorylating and stabilizing IκBα. IL‐1β or hypoxia could downregulate PTPL1 expression in HUVECs. The deregulation of PTPL1/NF-κB signaling was validated in a monocrotaline-induced rat PH (MCT-PH) model and clinical PH specimens. Our findings provide novel insights into the regulatory mechanisms of EnMT, and have implications for identifying new therapeutic targets for clinical PH.


id: cord-012768-9fvumvdc
author: Chen, Bao-yi
date: 2020-03-05
txt: ./txt/cord-012768-9fvumvdc.txt
cache: ./cache/cord-012768-9fvumvdc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470837/
doi: 10.1038/s41401-020-0357-y
summary:
  title: SGK1 mediates the hypotonic protective effect against H(2)O(2)-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway Our previous study shows that activation of volume-regulated Cl(−) channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (H(2)O(2))-induced apoptosis. The protective effect of hypotonic challenge against H(2)O(2)-induced apoptosis was mediated through inhibiting mitochondria-dependent apoptotic pathway, evidenced by increased Bcl-2/Bax ratio, stabilizing mitochondrial membrane potential (MMP), decreased cytochrome c release from the mitochondria to the cytoplasm, and inhibition of the activation of caspase-9 and caspase-3. Thus, we further explored whether the underlying mechanism of the protective effect of SGK1 on H 2 O 2induced apoptosis is related to the inhibition of the FOXO3a/Bim signaling pathway in BASMCs. Reagents and antibodies Cell culture medium (Dulbecco''s modified Eagle''s medium: nutrient mixture F-12 (DMEM/F-12)), fetal calf serum, bovine serum albumin (BSA), and protease inhibitor cocktail were obtained from GIBCO/Invitrogen (Carlsbad, CA, USA).

title:
  SGK1 mediates the hypotonic protective effect against H(2)O(2)-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway

abstract:
  Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl(−) channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (H(2)O(2))-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs. We showed that hypotonic challenge significantly reduced H(2)O(2)-induced apoptosis, and increased SGK1 phosphorylation, but did not affect SGK1 protein expression. The protective effect of hypotonic challenge against H(2)O(2)-induced apoptosis was mediated through inhibiting mitochondria-dependent apoptotic pathway, evidenced by increased Bcl-2/Bax ratio, stabilizing mitochondrial membrane potential (MMP), decreased cytochrome c release from the mitochondria to the cytoplasm, and inhibition of the activation of caspase-9 and caspase-3. These protective effects of hypotonic challenge against H(2)O(2)-induced apoptosis was diminished and enhanced, respectively, by SGK1 knockdown and overexpression. We further revealed that SGK1 activation significantly increased forkhead box O3a (FOXO3a) phosphorylation, and then inhibited the translocation of FOXO3a into nucleus and the subsequent expression of Bcl-2 interacting mediator of cell death (Bim). In conclusion, SGK1 mediates the protective effect of VRCCs against H(2)O(2)-induced apoptosis in BASMCs via inhibiting FOXO3a/Bim signaling pathway. Our results provide compelling evidences that SGK1 is a critical link between VRCCs and apoptosis, and shed a new light on the treatment of vascular apoptosis-associated diseases, such as vascular remodeling, angiogenesis, and atherosclerosis.


id: cord-012769-clbqckj2
author: Yan, You-you
date: 2020-02-11
txt: ./txt/cord-012769-clbqckj2.txt
cache: ./cache/cord-012769-clbqckj2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470838/
doi: 10.1038/s41401-019-0354-1
summary:
  title: A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells Valepotriate is the key bioactive component extracted from Valeriana and is reported to exert anti-proliferation cytotoxic effects by regulating the redox balance or suppressing the mitogen-activated protein kinase pathway in cancer cells [13, 14] . Amcp induced apoptosis in BxPC-3 and SW1990 cells A similarity search was employed to find derivatives of valepotriate that were potentially active against cancer cells and the results identified 16 hit compounds that were purchased for bioactivity tests. Combinatorial treatment with Amcp and gemcitabine synergistically induced apoptosis in BxPC-3 cells (Fig. 6b, d) and this effect could be partially overcome by the addition of the pancaspase inhibitor Z-VAD-FMK (Fig. 6c) . Amcp showed potent anticancer activity against pancreatic cancer cells through the inhibition of the Mcl-1 and PI3K/AKT pathways, thereby stimulating caspase-dependent apoptosis.

title:
  A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells

abstract:
  Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure–activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2’-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.


id: cord-012770-wvf8swyj
author: Sun, Shu-zhen
date: 2019-09-12
txt: ./txt/cord-012770-wvf8swyj.txt
cache: ./cache/cord-012770-wvf8swyj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470839/
doi: 10.1038/s41401-019-0292-y
summary:
  The above results suggest that AVP induces IL-6 induction in murine hearts via the V(1A) receptor-mediated β-arrestin2/ERK(1/2)/NF-κB pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V(1A)/β-arrestin 2/ERK(1/2)/NF-κB signaling pathway. β-Arrestin 2 is required for AVP-induced NF-κB activation Our previous study demonstrated that AVP induces IL-6 production via NF-κB signaling in neonatal rat cardiac fibroblasts [33] and cultured ARCFs (Fig. 4) . The following results were found in the present study: (1) AVP increased the mRNA and protein levels of IL-6 in murine hearts; (2) the silencing or deletion of β-arrestin 2 reduced AVP-induced IL-6 production, NF-κB activation and ERK 1/2 phosphorylation; (3) the pharmacological inhibition of ERK 1/2 signaling diminished AVP-induced NF-κB activation and IL-6 production; and (4) the blockade of the V 1A receptor by the selective antagonist SR49059 abolished AVP-evoked NF-κB phosphorylation and IL-6 induction in intact hearts and ARCFs. AVP is an antidiuretic hormone that is secreted by the hypothalamus-pituitary-adrenal axis.

title:
  β-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK(1/2)-NF-κB signal pathway in murine hearts

abstract:
  Evidence to date suggests that β-arrestins act beyond their role as adapter proteins. Arginine vasopressin (AVP) may be a factor in inflammation and fibrosis in the pathogenesis of heart failure. In the present study we investigated the effect of AVP on inflammatory cytokine IL-6 production in murine hearts and the impact of β-arrestin 2-dependent signaling on AVP-induced IL-6 production. We found that administration of AVP (0.5 U/kg, iv) markedly increased the levels of IL-6 mRNA in rat hearts with the maximum level occurred at 6 h. In β-arrestin 2 KO mouse hearts, deletion of β-arrestin 2 decreased AVP-induced IL-6 mRNA expression. We then performed in vitro experiments in adult rat cardiac fibroblasts (ARCFs). We found that AVP (10(−9)–10(−6) M) dose-dependently increased the expression of IL-6 mRNA and protein, activation of NF-κB signaling and ERK(1/2) phosphorylation, whereas knockdown of β-arrestin 2 blocked AVP-induced IL-6 increase, NF-κB activation and ERK(1/2) phosphorylation. Pharmacological blockade of ERK(1/2) using PD98059 diminished AVP-induced NF-κB activation and IL-6 production. The selective V(1A) receptor antagonist SR49059 effectively blocked AVP-induced NF-κB phosphorylation and activation as well as IL-6 expression in ARCFs. In AVP-treated mice, pre-injection of SR49059 (2 mg/kg, iv) abolished AVP-induced NF-κB activation and IL-6 production in hearts. The above results suggest that AVP induces IL-6 induction in murine hearts via the V(1A) receptor-mediated β-arrestin2/ERK(1/2)/NF-κB pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V(1A)/β-arrestin 2/ERK(1/2)/NF-κB signaling pathway.


id: cord-012771-3ukffdmq
title: The hypoglycemic mechanism of catalpol involves increased AMPK-mediated mitochondrial biogenesis
author: Xu, Deng-qiu
date: 2020-01-14
txt: ./txt/cord-012771-3ukffdmq.txt
cache: ./cache/cord-012771-3ukffdmq.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470840/
doi: 10.1038/s41401-019-0345-2
summary:
  Catalpol increased mitochondrial biogenesis, evidenced by significant elevations in the number of mitochondria, mitochondrial DNA levels, and the expression of three genes associated with mitochondrial biogenesis: peroxisome proliferator-activated receptor gammaco-activator 1 (PGC-1α), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF1). The expression levels of three genes associated with mitochondrial biogenesis (PGC-1α, NRF1, and TFAM) were markedly decreased in the skeletal muscle of db/db mice, but these decreases were reversed by catalpol (Fig. 1i) , as revealed by Western blotting (Fig. 1j, k) . Using db/db mice and C2C12 cells, we showed that catalpol increases mitochondrial biogenesis by activating the AMPK/PGC-1α/TFAM signaling pathway, which improves both mitochondrial function and glucose homeostasis in skeletal muscle (Fig. 6) . Catalpol increased AMPK/PGC-1α/TFAM-mediated mitochondrial biogenesis in skeletal muscle cells. The catalpol-induced activation of AMPK/PGC-1α/TFAM signaling increased mitochondrial biogenesis in skeletal muscle, thereby increasing glucose uptake and ATP production.

abstract:
  Mitochondria serve as sensors of energy regulation and glucose levels, which are impaired by diabetes progression. Catalpol is an iridoid glycoside that exerts a hypoglycemic effect by improving mitochondrial function, but the underlying mechanism has not been fully elucidated. In the current study we explored the effects of catalpol on mitochondrial function in db/db mice and C2C12 myotubes in vitro. After oral administration of catalpol (200 mg·kg(−1)·d(−1)) for 8 weeks, db/db mice exhibited a decreased fasting blood glucose level and restored mitochondrial function in skeletal muscle. Catalpol increased mitochondrial biogenesis, evidenced by significant elevations in the number of mitochondria, mitochondrial DNA levels, and the expression of three genes associated with mitochondrial biogenesis: peroxisome proliferator-activated receptor gammaco-activator 1 (PGC-1α), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF1). In C2C12 myotubes, catalpol significantly increased glucose uptake and ATP production. These effects depended on activation of AMP-activated protein kinase (AMPK)-mediated mitochondrial biogenesis. Thus, catalpol improves skeletal muscle mitochondrial function by activating AMPK-mediated mitochondrial biogenesis. These findings may guide the development of a new therapeutic approach for type 2 diabetes.


id: cord-012773-wtgk2d68
title: Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein
author: Xu, Ming-ming
date: 2019-10-04
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470848/
doi: 10.1038/s41401-019-0304-y
abstract:
  Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson’s disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.


id: cord-012778-yr8zuvw9
author: Zhang, Lei
date: 2019-08-06
txt: ./txt/cord-012778-yr8zuvw9.txt
cache: ./cache/cord-012778-yr8zuvw9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470854/
doi: 10.1038/s41401-019-0285-x
summary:
  We quantified the time course of PSP improvement in patients after treatment with these three antipsychotics: olanzapine, risperidone, and aripiprazole reached an E(max) value of 80.3%, 68.2%, and 23.9% at weeks 56.7, 29.2, and 36.8, respectively. In addition, quantitative information on the long-term social functioning of schizophrenic patients treated with SGAs is scarce in current clinical practice [12, 13] , and the available information does not reflect the differences in therapeutic efficacies between various drugs. Using data from the Study of Long-term Outcomes for Schizophrenia by Atypical Antipsychotic Treatment in China (SALT-C) study, which is a multicenter, real-world clinical study, we examined the differences in efficacy between three antipsychotics (olanzapine, risperidone, and aripiprazole) to provide a guide for clinicians when choosing an antipsychotic for the individualized treatment of schizophrenia. The SALT-C study was registered at https://www.clinicaltrials.gov (identifier: NCT02640911) and produced a large data set of real-world schizophrenia patients in China recruited in an open-label 3-year follow-up clinical trial of widely used atypical antipsychotics.

title:
  Quantitative efficacy of three antipsychotic drugs for schizophrenia based on a real-world study in China

abstract:
  Atypical antipsychotics exert remarkable long-term efficacy on the personal and social functions of schizophrenic patients. However, quantitative information on the social function of schizophrenic patients treated with atypical antipsychotics is scarce in the current clinical guidelines. In this study, we established pharmacodynamic models to quantify the time–efficacy relationship of three antipsychotic drugs based on the data from a real-world study conducted in China. A total of 373 schizophrenic patients who received antipsychotic monotherapy with olanzapine (n = 144), risperidone (n = 160), or aripiprazole (n = 69) were selected from a three-year prospective, multicenter study. The follow-up times were 13, 26, 52, 78, 104, 130, and 156 weeks after baseline. A time–efficacy model was developed with nonlinear mixed effect method based on changes in Personal and Social Performance (PSP) score compared with the baseline level. Crucial pharmacodynamic parameters, including maximum efficacy and drug onset time, were used to distinguish the efficacy of the three drugs. We quantified the time course of PSP improvement in patients after treatment with these three antipsychotics: olanzapine, risperidone, and aripiprazole reached an E(max) value of 80.3%, 68.2%, and 23.9% at weeks 56.7, 29.2, and 36.8, respectively. General psychotic symptoms, onset frequency, and illness course were identified as significant factors affecting the efficacy of these drugs. The newly constructed models provide an evidence of the benefit of long-term maintenance therapy with atypical antipsychotics in individualized schizophrenia treatment in China.


id: cord-012781-e4js9qrs
title: Cancer nanomedicine meets immunotherapy: opportunities and challenges
author: Sun, Qingxue
date: 2020-06-17
txt: ./txt/cord-012781-e4js9qrs.txt
cache: ./cache/cord-012781-e4js9qrs.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470866/
doi: 10.1038/s41401-020-0448-9
summary:
  Combining nanomedicines with immunotherapy aims to reinforce the cancer-immunity cycle, via potentiating key steps in the immune reaction cascade, namely antigen release, antigen processing, antigen presentation, and immune cell-mediated killing. The clinical potential of nano-immunotherapy has recently been demonstrated in a phase III trial in which nano-albumin paclitaxel (Abraxane®) was combined with atezolizumab (Tecentriq®) for the treatment of patients suffering from advanced triple-negative breast cancer. In this context, a low degree of tumor accumulation for a specific nanoparticle or cancer type is not necessarily a disadvantage anymore, since nanomedicines targeting other cells and tissues may help to boost the therapeutic efficacy of combination immunotherapy, including that with checkpoint antibodies [22] . As will be outlined in this paper, the ability of nanomedicines to activate cancer immunity and improve immunotherapeutic responses holds great potential, and there are already several pieces of evidence demonstrating that nano-immunotherapy has a bright clinical future.

abstract:
  Cancer nanomedicines have shown promise in combination immunotherapy, thus far mostly preclinically but also already in clinical trials. Combining nanomedicines with immunotherapy aims to reinforce the cancer-immunity cycle, via potentiating key steps in the immune reaction cascade, namely antigen release, antigen processing, antigen presentation, and immune cell-mediated killing. Combination nano-immunotherapy can be realized via three targeting strategies, i.e., by targeting cancer cells, targeting the tumor immune microenvironment, and targeting the peripheral immune system. The clinical potential of nano-immunotherapy has recently been demonstrated in a phase III trial in which nano-albumin paclitaxel (Abraxane®) was combined with atezolizumab (Tecentriq®) for the treatment of patients suffering from advanced triple-negative breast cancer. In the present paper, besides strategies and initial (pre)clinical success stories, we also discuss several key challenges in nano-immunotherapy. Taken together, nanomedicines combined with immunotherapy are gaining significant attention, and it is anticipated that they will play an increasingly important role in clinical cancer therapy.


id: cord-012784-c74jr4ga
title: Identification of nagilactone E as a protein synthesis inhibitor with anticancer activity
author: Zhang, Le-le
date: 2020-02-11
txt: ./txt/cord-012784-c74jr4ga.txt
cache: ./cache/cord-012784-c74jr4ga.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470872/
doi: 10.1038/s41401-019-0332-7
summary:
  We previously reported that nagilactone E (NLE), a dinorditerpenoid isolated from Podocarpus nagi, possessed anticancer effects against lung cancer cells in vitro. To better understand the potential biological processes associated with the effects of NLE in lung cancer A549 cells, GO analysis was performed using the online DAVID 6.8 bioinformatics resource. To clarify the mechanisms underlying the anticancer effect of NLE in A549 lung cancer cells, we further analyzed the DEGs using the CMap dataset. As shown in Fig. 4a , the mRNA levels of NRF2, p21, STAT3, and ATF4 were upregulated after NLE treatment, which was consistent with the results obtained by RNA-seq analysis. Thereafter, the inhibitory effect of NLE on de novo protein synthesis in A549 cells was further confirmed using the Click-iT assay. CMap dataset analysis supported NLE as a protein synthesis inhibitor, which was further confirmed by the Click-iT assay.

abstract:
  Norditerpenoids and dinorditerpenoids represent diterpenoids widely distributed in the genus Podocarpus with notable chemical structures and biological activities. We previously reported that nagilactone E (NLE), a dinorditerpenoid isolated from Podocarpus nagi, possessed anticancer effects against lung cancer cells in vitro. In this study we investigated the in vivo effect of NLE against lung cancer as well as the underlying mechanisms. We administered NLE (10 mg·kg(−1)·d(−1), ip) to CB-17/SCID mice bearing human lung cancer cell line A549 xenograft for 3 weeks. We found that NLE administration significantly suppressed the tumor growth without obvious adverse effects. Thereafter, RNA sequencing (RNA-seq) analysis was performed to study the mechanisms of NLE. The effects of NLE on A549 cells have been illustrated by GO and pathway enrichment analyses. CMap dataset analysis supported NLE to be a potential protein synthesis inhibitor. The inhibitory effect of NLE on synthesis of total de novo protein was confirmed in Click-iT assay. Using the pcDNA3-RLUC-POLIRES-FLUC luciferase assay we further demonstrated that NLE inhibited both cap-dependent and cap-independent translation. Finally, molecular docking revealed the low-energy binding conformations of NLE and its potential target RIOK2. In conclusion, NLE is a protein synthesis inhibitor with anticancer activity.


id: cord-012785-d53k16ow
author: Zhang, Shi-rong
date: 2020-02-17
txt: ./txt/cord-012785-d53k16ow.txt
cache: ./cache/cord-012785-d53k16ow.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470873/
doi: 10.1038/s41401-019-0351-4
summary:
  title: Chalcomoracin inhibits cell proliferation and increases sensitivity to radiotherapy in human non-small cell lung cancer cells via inducing endoplasmic reticulum stress-mediated paraptosis Furthermore, exposure to low and median doses of CMR induced paraptosis but not apoptosis, which was presented as the formation of extensive cytoplasmic vacuolation with increased expression of endoplasmic reticulum stress markers, Bip and Chop, as well as activation of MAPK pathway in the lung cancer cells. In lung cancer H460 cell xenograft nude mice, combined treatment of CMR and radiation caused greatly enhanced tumor growth inhibition with upregulation of endoplasmic reticulum stress proteins and activation of pErk in xenograft tumor tissue. Our results showed that CMR increased clonogenic cell death by inducing paraptosis in NSCLC cells in response to radiotherapy, with characterized cytoplasmic vacuolation and dilated ER triggering ER stress.

title:
  Chalcomoracin inhibits cell proliferation and increases sensitivity to radiotherapy in human non-small cell lung cancer cells via inducing endoplasmic reticulum stress-mediated paraptosis

abstract:
  Chalcomoracin (CMR) is a kind of Diels–Alder adduct extracted from the mulberry leaves. Recent studies showed that CMR has a broad spectrum of anticancer activities and induces paraptosis in breast cancer and prostate cancer cells. In this study, we investigated the effects of CMR against human non-small cell lung cancer cells and the underlying mechanisms. We found that CMR dose-dependently inhibited the proliferation of human lung cancer H460, A549 and PC-9 cells. Furthermore, exposure to low and median doses of CMR induced paraptosis but not apoptosis, which was presented as the formation of extensive cytoplasmic vacuolation with increased expression of endoplasmic reticulum stress markers, Bip and Chop, as well as activation of MAPK pathway in the lung cancer cells. Knockdown of Bip with siRNA not only reduced the cell-killing effect of CMR, but also decreased the percentage of cytoplasmic vacuoles in H460 cells. Moreover, CMR also increased the sensitivity of lung cancer cells to radiotherapy through enhanced endoplasmic reticulum stress. In lung cancer H460 cell xenograft nude mice, combined treatment of CMR and radiation caused greatly enhanced tumor growth inhibition with upregulation of endoplasmic reticulum stress proteins and activation of pErk in xenograft tumor tissue. These data demonstrate that the anticancer activity and radiosensitization effect of CMR result from inducing paraptosis, suggesting that CMR could be considered as a potential anticancer agent and radiation sensitizer in the future cancer therapeutics.


id: cord-012791-dyk5mr1q
author: Zheng, Yong
date: 2019-09-25
txt: ./txt/cord-012791-dyk5mr1q.txt
cache: ./cache/cord-012791-dyk5mr1q.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470889/
doi: 10.1038/s41401-019-0300-2
summary:
  title: Icariside II inhibits lipopolysaccharide-induced inflammation and amyloid production in rat astrocytes by regulating IKK/IκB/NF-κB/BACE1 signaling pathway Moreover, ICS II not only exerted the inhibitory effect on LPS-induced IκB-α degradation and NF-κB activation, but also decreased the levels of Aβ(1–40), Aβ(1–42), amyloid precursor protein (APP) and beta secretase 1 (BACE1) in the astrocytes. The present study revealed that (1) ICS II protects against LPSinduced inflammation in primary-cultured astrocytes; (2) the inhibitory effect of ICS II is due to regulation of the IKK/IκB/NF-κB signaling pathway; and (3) ICS II decreases Aβ 1-40 and Aβ 1-42 levels by downregulating APP and BACE1 expression (Fig. 7) . In conclusion, the current study revealed that ICS II exerts inhibitory effects on LPS-induced inflammation in astrocytes through the IKK/IκB/NF-κB/BACE1 signaling pathway, and thus ICS II may be a promising therapeutic agent for neuroinflammatory diseases, including AD.

title:
  Icariside II inhibits lipopolysaccharide-induced inflammation and amyloid production in rat astrocytes by regulating IKK/IκB/NF-κB/BACE1 signaling pathway

abstract:
  β-amyloid (Aβ) is one of the inducing factors of astrocytes activation and neuroinflammation, and it is also a crucial factor for the development of Alzheimer’s disease (AD). Icariside II (ICS II) is an active component isolated from a traditional Chinese herb Epimedium, which has shown to attnuate lipopolysaccharide (LPS)-induced neuroinflammation through regulation of NF-κB signaling pathway. In this study we investigated the effects of ICS II on LPS-induced astrocytes activation and Aβ accumulation. Primary rat astrocytes were pretreated with ICS II (5, 10, and 20 μM) or dexamethasone (DXMS, 1 μM) for 1 h, thereafter, treated with LPS for another 24 h. We found that ICS II pretreatment dose dependently mitigated the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) in the astrocytes. Moreover, ICS II not only exerted the inhibitory effect on LPS-induced IκB-α degradation and NF-κB activation, but also decreased the levels of Aβ(1–40), Aβ(1–42), amyloid precursor protein (APP) and beta secretase 1 (BACE1) in the astrocytes. Interestingly, molecular docking revealed that ICS II might directly bind to BACE1. It is concluded that ICS II has potential value as a new therapeutic agent to treat neuroinflammation-related diseases, such as AD.


id: cord-012795-6m88m81v
title: Nanomedicine and cancer immunotherapy
author: Yu, Hai-jun
date: 2020-05-28
txt: ./txt/cord-012795-6m88m81v.txt
cache: ./cache/cord-012795-6m88m81v.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471393/
doi: 10.1038/s41401-020-0426-2
abstract: nan
summary:
  The prime aim for the special issue is to deliver both high-impact review and research articles to the wide international readership regarding the most recent progress in nano-immunotherapy as well as the approaches for enhancing the efficacy of cancer immunotherapy. To increase cancer immunotherapies'' impact, we organized this special issue to deepen our understanding about the mechanisms underlying the tumor and immune cells to evade immunity, how nanomedicines can be used to reprogram the tumor microenvironment and how nanomedicines interact with the immune system, and the potential challenges and the critical limitations of immunotherapy approaches, which impede their clinical applications. However, ICD-based immunotherapy is restricted by the ITM limiting its efficacy in eliciting a long-term anti-tumor immune response as well as severe systemic toxicity. To address these challenges, nanomedicine-based drug delivery strategies have been exploited to improve cancer immunotherapy by boosting ICD of tumor cells.


id: cord-012796-wfdt07vs
author: Zhang, Sai-long
date: 2020-01-16
txt: ./txt/cord-012796-wfdt07vs.txt
cache: ./cache/cord-012796-wfdt07vs.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471395/
doi: 10.1038/s41401-019-0343-4
summary:
  However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl(−/−) mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl(−/−) mice compared with WT mice. The conditional knockout of Metrnl in intestinal epithelial cells can downregulate autophagy levels in DSS-induced colitis through inhibition of the AMPK-mTOR-p70S6K pathway, thereby aggravating intestinal inflammation (Fig. 8) . It has been reported that the activation of the AMPK-mTOR-p70S6K signaling pathway can significantly induce or increase autophagy levels in a variety of cells and diseases [33, 34] .

title:
  Aggravated ulcerative colitis caused by intestinal Metrnl deficiency is associated with reduced autophagy in epithelial cells

abstract:
  Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl(−/−) (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl(−/−) mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl(−/−) mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl(−/−) mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.


id: cord-012802-xm2ftrw2
author: Zhao, Wu-li
date: 2020-01-13
txt: ./txt/cord-012802-xm2ftrw2.txt
cache: ./cache/cord-012802-xm2ftrw2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471404/
doi: 10.1038/s41401-019-0333-6
summary:
  Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. All the above-mentioned results demonstrated that IMB-HDC depressed STAT5a nuclear translocation, transcriptional activity, and triggers DNA breakage and apoptosis via blocking 694 and 780 phosphorylation IMB-HDC-induced proliferation inhibition depends on the decreased phosphorylation of 694 and 780 in vivo Next, in a tumor xenograft nude mouse model, we examined IMB-HDC anticancer efficacy. Our previous chip assay analysis showed that the level of several STAT5a target genes decreased; thus, we speculated that STAT5a might be implicated in IMB-HDC-induced apoptosis and DNA breakage in tumor cells.

title:
  The novel quinolizidine derivate IMB-HDC inhibits STAT5a phosphorylation at 694 and 780 and promotes DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation

abstract:
  Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out, and the potent anticancer compound IMB-HDC was acquired. Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage, the underlying mechanisms of inhibition of DNA damage repair (ATR inactivation) and the apoptosis independent of p53, have not been elucidated. Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. Meanwhile, IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis. More importantly, we give the first evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.


id: cord-012806-pjehkeh9
title: Antiangiogenesis effect of timosaponin AIII on HUVECs in vitro and zebrafish embryos in vivo
author: Zhou, Zhong-yan
date: 2019-09-12
txt: ./txt/cord-012806-pjehkeh9.txt
cache: ./cache/cord-012806-pjehkeh9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471416/
doi: 10.1038/s41401-019-0291-z
summary:
  In the present study, we investigated the antiangiogenesis effects of Timo AIII and the underlying mechanisms in human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish embryos in vivo. Timo AIII (0.5–4 µM) dose-dependently inhibited VEGF-induced proliferation, migration, invasion, and tube formation of HUVECs, but these inhibitory effects were not due to its cytotoxicity. The coexpression network analysis results showed that various biological processes and signaling pathways were enriched including angiogenesis, cell motility, cell adhesion, protein serine/threonine kinase activity, transmembrane signaling receptor activity, growth factor activity, etc., which was consistent with the antiangiogenesis effects of Timo AIII in HUVECs and zebrafish embryos. We found that Timo AIII suppressed VEGF-induced endothelial cell migration and invasion in HUVECs over the range of nontoxic concentrations of Timo AIII (Figs. Timo AIII inhibited endothelial cell proliferation, migration, invasion, and tube formation in HUVECs. The underlying mechanism of the antiangiogenesis effect of Timo AIII might be involved in the inhibition of the VEGF/PI3K/Akt/MAPK signaling pathway.

abstract:
  Timosaponin AIII (Timo AIII) is a natural steroidal saponin isolated from the traditional Chinese herb Anemarrhena asphodeloides Bge with proved effectiveness in the treatment of numerous cancers. However, whether Timo AIII suppresses tumor angiogenesis remains unclear. In the present study, we investigated the antiangiogenesis effects of Timo AIII and the underlying mechanisms in human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish embryos in vivo. We showed that treatment with Timo AIII (0.5–2 µM) partially disrupted the intersegmental vessels (ISVs) and subintestinal vessels (SIVs) growth in transgenic zebrafish Tg(fli-1a: EGFP)(y1). Timo AIII (0.5–4 µM) dose-dependently inhibited VEGF-induced proliferation, migration, invasion, and tube formation of HUVECs, but these inhibitory effects were not due to its cytotoxicity. We further demonstrated that Timo AIII treatment significantly suppressed the expression of VEGF receptor (VEGFR) and the phosphorylation of Akt, MEK1/2, and ERK1/2 in HUVECs. Timo AIII treatment also significantly inhibited VEGF-triggered phosphorylation of VEGFR2, Akt, and ERK1/2 in HUVECs. Moreover, we conducted RNA-Seq and analyzed the transcriptome changes in both HUVECs and zebrafish embryos following Timo AIII treatment. The coexpression network analysis results showed that various biological processes and signaling pathways were enriched including angiogenesis, cell motility, cell adhesion, protein serine/threonine kinase activity, transmembrane signaling receptor activity, growth factor activity, etc., which was consistent with the antiangiogenesis effects of Timo AIII in HUVECs and zebrafish embryos. We conclude that the antiangiogenesis effect of Timo AIII is mediated through VEGF/PI3K/Akt/MAPK signaling cascade; Timo AIII potentially exerts antiangiogenesis effect in cancer treatment.


id: cord-012818-zr4xw3ph
author: Zhang, Ying-ying
date: 2020-02-12
txt: ./txt/cord-012818-zr4xw3ph.txt
cache: ./cache/cord-012818-zr4xw3ph.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471444/
doi: 10.1038/s41401-019-0352-3
summary:
  These organized pharmacological disturbance was mainly focused on almost all stages of CHD intervention, such as anti-atherosclerosis, lipid metabolism, inflammation, vascular wall function, foam cells formation, platelets aggregation, thrombosis, arrhythmia, and ischemia-reperfusion injury. The calcium signaling pathway is a hub induction switch in CHD that is involved in the inflammatory process of atherogenesis [25] and affects coronary endothelial function [26] , foam cell formation [27] , vascular tension adjustment [28] , platelet aggregation [29] , and vascular smooth muscle cell (VSMC) and fibroblast proliferation [30, 31] . Compared with patients without coronary artery disease (CAD), CAD patients have significantly decreased bile acid excretion levels, which may be a risk factor in the process of atherosclerosis [43] ; in addition, bile acid may modulate endothelial function as vascular endothelial cells express the G protein-coupled bile acid receptor [44] .

title:
  A comparative pharmacogenomic analysis of three classic TCM prescriptions for coronary heart disease based on molecular network modeling

abstract:
  Traditional Chinese medicine (TCM) has evolved over several thousands of years, which has been shown to be efficacious in the treatment of ischemic heart disease. Three classical TCM prescriptions, namely Xuefu Zhuyu Decoction, Zhishi Xiebai Guizhi Decoction, and Gualou Xiebai Banxia Decoction, have been extensively used in the treatment of coronary heart disease (CHD). Based on molecular network modeling, we performed a comparative pharmacogenomic analysis to systematically determine the drug-targeting spectrum of the three prescriptions at molecular level. Wide-area target molecules of CHD were covered, which was a common feature of the three decoctions, demonstrating their therapeutic functions. Meanwhile, collective signaling involved metabolic/pro-metabolic pathways, driving and transferring pathways, neuropsychiatric pathways, and exocrine or endocrine pathways. These organized pharmacological disturbance was mainly focused on almost all stages of CHD intervention, such as anti-atherosclerosis, lipid metabolism, inflammation, vascular wall function, foam cells formation, platelets aggregation, thrombosis, arrhythmia, and ischemia-reperfusion injury. In addition, heterogeneity analysis of the global pharmacological molecular spectrum revealed that signaling crosstalk, cascade convergence, and key targets were tendentious among the three decoctions. After all, it is unadvisable to rank the findings on targeting advantages of the three decoctions. Comparative pharmacological evidence may provide an appropriate decoction scheme for individualized intervention of CHD.


id: cord-012822-8t6qg5fp
author: Papoutsis, Konstantinos
date: 2020-02-05
txt: ./txt/cord-012822-8t6qg5fp.txt
cache: ./cache/cord-012822-8t6qg5fp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471450/
doi: 10.1038/s41401-019-0350-5
summary:
  title: Tissue-specific relaxin-2 is differentially associated with the presence/size of an arterial aneurysm and the severity of atherosclerotic disease in humans The expression levels of metalloproteinases (MMPs) and endothelial nitric oxide synthetase (eNOS) were also detected for correlations with different phenotypes of atherosclerosis and AA. In the present study, we aimed to verify and expand the findings of our preliminary study for serum RL2 [9] by investigating the levels of tissue-specific RL2 in aneurysmal (AA) and atherosclerotic (ATH) arteries and establishing a correlation of tissue-specific RL2 levels with the presence/size of AA and the clinical severity of atherosclerosis. Moreover, we carried out tissue-specific measurements of MMP2, MMP9 and endothelial nitric oxide synthetase (eNOS) in the aforementioned groups of arterial specimens to investigate further correlations with different phenotypes of atherosclerosis and AA. AA aneurysm group, ATH atherosclerosis group, RL2 relaxin-2, MMP matrix metalloproteinase, eNOS endothelial nitric oxide synthetase Relaxin-2 in aneurysmatic and atherosclerotic disease K Papoutsis et al.

title:
  Tissue-specific relaxin-2 is differentially associated with the presence/size of an arterial aneurysm and the severity of atherosclerotic disease in humans

abstract:
  Circulating or tissue-related biomarkers are of clinical value for risk stratification in patients with abdominal aortic aneurysms. Relaxin-2 (RL2) has been linked to the presence and size of arterial aneurysms, and to the extent of atherosclerosis in human subjects. Here, we assessed the expression levels of RL2 in aneurysmal (AA, n = 16) and atherosclerotic (ATH, n = 22) arteries, and established the correlation between RL2 levels and the presence/size of AA and the clinical severity of atherosclerosis. The expression levels of metalloproteinases (MMPs) and endothelial nitric oxide synthetase (eNOS) were also detected for correlations with different phenotypes of atherosclerosis and AA. Temporal artery biopsy specimens (n = 6) and abdominal aortic tissues harvested from accident victims during autopsy (n = 10) were used as controls. Quantitative tissue biomarker analysis revealed that tissue-specific RL2 was increased in patients with larger or symptomatic AA compared to subjects with atherosclerotic disease and healthy controls. In situ RL2 levels were proportional to the size and the severity of aneurysmatic disease, and were substantially elevated in patients with symptomatic aneurysm of any diameter or asymptomatic aneurysm of a diameter >350% of that of the normal artery. In contrast, tissue RL2 was inversely associated with the clinical severity of atherosclerotic lesions. Correlation between RL2 and MMP2 was different between ATH1 and ATH2, depending on atherosclerosis grade. Overall, tissue RL2 is differentially associated with discrete phenotypes of arterial disease and might exert multipotent biological effects on vascular wall integrity and remodeling in human subjects.


id: cord-012823-i3yhaagz
author: Zhang, Zhi-hao
date: 2019-11-08
txt: ./txt/cord-012823-i3yhaagz.txt
cache: ./cache/cord-012823-i3yhaagz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471452/
doi: 10.1038/s41401-019-0319-4
summary:
  UUO group displayed significant degree of renal dysfunction, interstitial fibrosis, oxidative stress, and activation of the TGF-β/Smad and Wnt/β-catenin signaling pathway in the kidney, these pathological changes were greatly ameliorated by pretreatment with AA. Our results showed that AA upregulated the expression of nuclear-localized sterol regulatory element-binding proteins-1 (nSREBP-1), enhanced 15d-PGJ2, activated PPAR-γ, and consequentially attenuated renal damage in unilateral ureteral occlusion (UUO) models. The treatment of mice with 15d-PGJ2 produced a significant attenuation of the UUO-induced increase in Col I, FN, and α-SMA expression, indicating an improvement in interstitial fibrosis, while the administration of GW9662 abolished the protective effect mediated by 15d-PGJ2 (Fig. 5b) . Our major novel findings include the following: (1) AA attenuates renal injury, oxidative stress, and fibrosis induced by the activation of PPAR-γ through increasing its Fig. 3 a PCA scores plot from control and UUO groups.

title:
  Asiatic acid prevents renal fibrosis in UUO rats via promoting the production of 15d-PGJ2, an endogenous ligand of PPAR-γ

abstract:
  Renal fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Recently, asiatic acid (AA), a triterpenoid compound from Chinese medicine Centella asiatica, has been found to attenuate renal fibrosis. In the current study, we explored the mechanisms underlying antifibrotic effect of AA on UUO model. SD rats and ICR mice were subjected to unilateral ureteral occlusion (UUO) surgery. Prior the surgery, rats were administered AA (10 mg·kg(−1) per day, ig) for 7 days, whereas the mice received AA (15 mg·kg(−1) per day, ig) for 3 days. UUO group displayed significant degree of renal dysfunction, interstitial fibrosis, oxidative stress, and activation of the TGF-β/Smad and Wnt/β-catenin signaling pathway in the kidney, these pathological changes were greatly ameliorated by pretreatment with AA. In addition, we found that co-treatment with GW9662, a selective PPAR-γ antagonist (1 mg·kg(−1) per day, ip) for 7 days, abolished the protective effects of AA. We further revealed that AA pretreatment did not significantly change the expression levels of PPAR-γ in the kidney, but markedly increase the plasma levels of 15d-PGJ2, an endogenous ligand of PPAR-γ. In UUO mice, pretreatment with 15d-PGJ2 (24 μg·kg(−1) per day, ip, for 7 days) produced similar protective effect as AA. Moreover, AA pretreatment upregulated the expression levels of active, nuclear-localized SREBP-1 (nSREBP-1), whereas fatostatin, a specific inhibitor of SREBP-1, decreased the expression of nSREBP-1, as well as the level of 15d-PGJ2. These results provide new insight into the antifibrotic mechanism of AA and endogenous metabolites might become a new clue for investigation of drug mechanism.


id: cord-012826-72mz834w
author: Xu, Zhen-dong
date: 2019-10-23
txt: ./txt/cord-012826-72mz834w.txt
cache: ./cache/cord-012826-72mz834w.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471456/
doi: 10.1038/s41401-019-0303-z
summary:
  In addition, ATG5(−/−) MEF themselves released more Ca(2+) in cytosolic space and endoplasmic reticulum compared with WT cells, suggesting that autophagy deficiency made intracellular calcium signaling more vulnerable to external stimuli (propofol). After 24-h exposure to propofol, the MTT signal of ATG5 −/− cells was significantly enhanced at clinically relevant concentrations (10 µM); however, this effect was inverted at high pharmacological General anesthetics and autophagy ZD Xu et al. ATG5 plays a key role in propofol effects on cell growth We next determined whether the elevation of MTT by propofol at clinically relevant concentrations in ATG5 −/− cells (Fig. 1c) was caused by changes in mitochondrial reductase activity (early cell damage) or an increase in cell numbers (proliferation). While this enhances vulnerability to cell death triggered by calcium overload at high propofol doses, propofol at clinically relevant concentrations (10 μM) induces a moderate increase in Ca 2+ release from the ER into the cytosol, favoring cell survival and proliferation of autophagy-deficient cells (Fig. 6) .

title:
  Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy

abstract:
  Propofol is a commonly used intravenous anesthetic agent, which has been found to affect cell survival and proliferation especially in early life. Our previous studies show that propofol-induced neurodegeneration and neurogenesis are closely associated with cell autophagy. In the present study we explored the roles of autophagy-related gene 5 (ATG5) in propofol-induced autophagy in mouse embryonic fibroblasts (MEF) in vitro. We showed that ATG5 was functionally related to propofol-induced cell survival and damage: propofol significantly enhanced cell survival and proliferation at a clinically relevant dose (10 µM), but caused cell death at an extremely high concentration (200 µM) in ATG5(−/−) MEF, but not in WT cells. The dual effects found in ATG5(−/−) MEF could be blocked by intracellular Ca(2+) channel antagonists. We also found that propofol evoked a moderate (promote cell growth) and extremely high (cause apoptosis) cytosolic Ca(2+) elevation at the concentrations of 10 µM and 200 µM, respectively, only in ATG5(−/−) MEF. In addition, ATG5(−/−) MEF themselves released more Ca(2+) in cytosolic space and endoplasmic reticulum compared with WT cells, suggesting that autophagy deficiency made intracellular calcium signaling more vulnerable to external stimuli (propofol). Altogether, our results reveal that ATG5 plays a crucial role in propofol regulation of cell survival and proliferation by affecting intracellular Ca(2+) homeostasis.


id: cord-012828-wsjob1p8
author: Wang, Yan-hang
date: 2019-09-10
txt: ./txt/cord-012828-wsjob1p8.txt
cache: ./cache/cord-012828-wsjob1p8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471458/
doi: 10.1038/s41401-019-0296-7
summary:
  We further demonstrated that isosibiricin upregulated the expression of dopamine D1/2 receptors in LPS-treated BV-2 cells, resulting in inhibitory effect on nucleotide binding domain-like receptor protein 3 (NLRP3)/caspase-1 inflammasome pathway. Some previous research has suggested that spinal cord injury induces inflammatory cytokine production by activating the nucleotide-binding domain-like receptor protein 3 inflammasome pathway, which is significantly suppressed by DRD1 agonists [14] . Therefore, in this study, we explored the mechanism of the anti-neuroinflammatory effects of isosibiricin in a BV-2 microglial model and highlighted that isosibiricin can significantly inhibit the production of multiple inflammatory mediators induced by bacterial lipopolysaccharide stimulation via targeting the DRD1/D2-dependent inflammasome pathway, providing a potential therapeutic strategy for inflammation-related neurological disorders. Isosibiricin inhibits the NLRP3/caspase-1 inflammasome pathway in LPS-or nigericin-treated BV-2 cells and LPS-treated Balb/c mice It has been reported that the expression of the pro-inflammatory mediator IL-1β significantly increases in DRD2-null mice compared with wild-type mice [24] .

title:
  Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway

abstract:
  Microglia-mediated neuroinflammation is a crucial risk factor for neurological disorders. Recently, dopamine receptors have been found to be involved in multiple immunopathological processes and considered as valuable therapeutic targets for inflammation-associated neurologic diseases. In this study we investigated the anti-neuroinflammation effect of isosibiricin, a natural coumarin compound isolated from medicinal plant Murraya exotica. We showed that isosibiricin (10−50 μM) dose-dependently inhibited lipopolysaccharide (LPS)-induced BV-2 microglia activation, evidenced by the decreased expression of inflammatory mediators, including nitrite oxide (NO), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and interleukin-18 (IL-18). By using transcriptomics coupled with bioinformatics analysis, we revealed that isosibiricin treatment mainly affect dopamine receptor signalling pathway. We further demonstrated that isosibiricin upregulated the expression of dopamine D1/2 receptors in LPS-treated BV-2 cells, resulting in inhibitory effect on nucleotide binding domain-like receptor protein 3 (NLRP3)/caspase-1 inflammasome pathway. Treatment with dopamine D1/2 receptor antagonists SCH 23390 (1 μM) or sultopride (1 μM) could reverse the inhibitory effects of isosibiricin on NLRP3 expression as well as the cleavages of caspase-1 and IL-1β. Collectively, this study demonstrates a promising therapeutic strategy for neuroinflammation by targeting dopamine D1/2 receptors.


id: cord-012834-h9lrtecc
author: Yu, Hai-tao
date: 2019-11-25
txt: ./txt/cord-012834-h9lrtecc.txt
cache: ./cache/cord-012834-h9lrtecc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471469/
doi: 10.1038/s41401-019-0320-y
summary:
  title: Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms While in vivo environmental toxicity models allow the validation of requisite pathways using transgenic over-expression and knockout strategies, these studies can require treatment for weeks to months to identify phenotypes with both on-target and off-target effects of compounds and countermeasures of interest while in vitro ECT platforms can provide reproducible functional, biochemical, and molecular data within 7 days [4] . We noted a dose-dependent increase of cleaved caspase3, a surrogate for cell death, after ECT Cd treatment for 24 h, as well as a time-dependent effect of Cd toxicity measured by increasing induced cleaved caspase 3 expression (Fig. 1a) . It is important to note that Zn treatment partially suppressed Cd-induced increased cleaved caspase 3 and LDH release in MT-KO ECT (Fig. 4b, c ) consistent with an MT independent and as well as an MT requirement for Zn protective effects.

title:
  Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms

abstract:
  Cadmium (Cd) is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues (ECTs). In contrast, zinc (Zn) is a potent metallothionein (MT) inducer, which plays an important role in protection against Cd toxicity. In this study, we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms. ECTs were constructed from neonatal ventricular cells of wild-type (WT) mice and mice with global MT gene deletion (MT-KO). In WT-ECTs, Cd (5−20 μM) caused a dose-dependent toxicity that was detected within 8 h evidenced by suppressed beating, apoptosis, and LDH release; Zn (50−200 μM) dose-dependently induced MT expression in ECTs without causing ECT toxicity; co-treatment of ECT with Zn (50 µM) prevented Cd-induced toxicity. In MT-KO ECTs, Cd toxicity was enhanced; but unexpectedly, cotreatment with Zn provided partial protection against Cd toxicity. Furthermore, Cd, but not Zn, significantly activated Nrf2 and its downstream targets, including HO-1; inhibition of HO-1 by a specific HO-1 inhibitor, ZnPP (10 µM), significantly increased Cd-induced toxicity, but did not inhibit Zn protection against Cd injury, suggesting that Nrf2-mediated HO-1 activation was not required for Zn protective effect. Finally, the ability of Zn to reduce Cd uptake provided an additional MT-independent mechanism for reducing Cd toxicity. Thus, Zn exerts protective effects against Cd toxicity for murine ECTs that are partially MT-mediated. Further studies are required to translate these findings towards clinical trials.


id: cord-012837-fuwp08qt
author: Lu, Chen-chen
date: 2020-03-17
txt: ./txt/cord-012837-fuwp08qt.txt
cache: ./cache/cord-012837-fuwp08qt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471476/
doi: 10.1038/s41401-019-0326-5
summary:
  Therefore, we speculated that in the development of diabetes, the gut microbiota was likely to produce excessive SCFAs, especially acetate, which could bind to renal-related signal receptors, thus activating intrarenal RAS and mediating the early pathophysiological processes of DN. The immunofluorescence staining results also showed significantly decreased expression of glomerular podocyte-specific protein WT-1 and nephrin in the DM group compared with that in the control group, which was relatively recovered in the DM + AB group (Fig. 5e-g) , suggesting that unbalanced gut microbiota might be a key factor resulting in injuries to the glomerular filtration membrane in early DN. The Western blot results to evaluate the degree of intrarenal RAS activation showed that compared with the control group, the protein expression of ACE, Ang II, and AT1R in the kidney of the DM group was significantly increased, and antibiotic treatment showed a suppressing effect on these three RAS-activating indicators (Fig. 6d, e) .

title:
  Gut microbiota dysbiosis-induced activation of the intrarenal renin–angiotensin system is involved in kidney injuries in rat diabetic nephropathy

abstract:
  Some studies have shown that gut microbiota along with its metabolites is closely associated with diabetic mellitus (DM). In this study we explored the relationship between gut microbiota and kidney injuries of early diabetic nephropathy (DN) and its underlying mechanisms. Male SD rats were intraperitoneally injected with streptozotocin to induce DM. DM rats were orally administered compound broad-spectrum antibiotics for 8 weeks. After the rats were sacrificed, their blood, urine, feces, and renal tissues were harvested for analyses. We found that compared with the control rats, DM rats had abnormal intestinal microflora, increased plasma acetate levels, increased proteinuria, thickened glomerular basement membrane, and podocyte foot process effacement in the kidneys. Furthermore, the protein levels of angiotensin II, angiotensin-converting enzyme, and angiotensin II type 1 receptor in the kidneys of DM rats were significantly increased. Administration of broad-spectrum antibiotics in DM rats not only completely killed most intestinal microflora, but also significantly lowered the plasma acetate levels, inhibited intrarenal RAS activation, and attenuated kidney damage. Finally, we showed that plasma acetate levels were positively correlated with intrarenal angiotensin II protein expression (r = 0.969, P < 0.001). In conclusion, excessive acetate produced by disturbed gut microbiota might be involved in the kidney injuries of early DN through activating intrarenal RAS.


id: cord-012838-23odny3f
author: Lai, Qiong
date: 2020-03-02
txt: ./txt/cord-012838-23odny3f.txt
cache: ./cache/cord-012838-23odny3f.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471477/
doi: 10.1038/s41401-020-0377-7
summary:
  However, whether the cardioprotective effect of SA is associated with regulating endogenous metabolites remains unclear, thus we performed comprehensive metabolomics profiling in acute myocardial ischemia (AMI) mice following SA treatment. Furthermore, we selected the regulatory enzymes related to heart disease, including ecto-5''-nucleotidase (NT5E), guanidinoacetate N-methyltransferase (GAMT), platelet-derived endothelial cell growth factor (PD-ECGF) and methionine synthase (MTR), for validation. Acute myocardial ischemia (AMI) is a severe cardiovascular disease that is due to a sudden decrease in blood flow and oxygen supply to the heart, consequently leading to cardiac dysfunction, cardiac metabolic disorder, myocardial infarction, and even death [2] . Recent studies have identified 12 panels of specific biomarkers useful for the diagnosis of coronary artery disease based on metabolomics analysis of plasma samples from 2324 patients from 4 independent centers [13] . Furthermore, several potential new targets of SA, such as NT5E, PD-ECGF, and MTR, were identified and verified, and SA was shown to exert cardioprotective effects against AMI, at least in part through the PI3K/Akt-NOX2 signaling pathway.

title:
  Exploring the protective effects of schizandrol A in acute myocardial ischemia mice by comprehensive metabolomics profiling integrated with molecular mechanism studies

abstract:
  Schizandrol A (SA) is an bioactive component isolated from the Schisandra chinensis (Turcz.) Baill., which has been used as a remedy to prevent oxidative injury. However, whether the cardioprotective effect of SA is associated with regulating endogenous metabolites remains unclear, thus we performed comprehensive metabolomics profiling in acute myocardial ischemia (AMI) mice following SA treatment. AMI was induced in ICR mice by coronary artery ligation, then SA (6 mg·kg(−1)·d(−1), ip) was administered. SA treatment significantly decreased the infarct size, preserved the cardiac function, and improved the biochemical indicators and cardiac pathological alterations. Moreover, SA (10, 100 M) significantly decreased the apoptotic index in OGD-treated H8c2 cardiomycytes in vitro. By using HPLC-Q-TOF/MS, we conducted metabonomics analysis to screen the significantly changed endogenous metabolites and construct the network in both serum and urine. The results revealed that SA regulated the pathways of glycine, serine and threonine metabolism, lysine biosynthesis, pyrimidine metabolism, arginine and proline metabolism, cysteine and methionine metabolism, valine, leucine and isoleucine biosynthesis under the pathological conditions of AMI. Furthermore, we selected the regulatory enzymes related to heart disease, including ecto-5’-nucleotidase (NT5E), guanidinoacetate N-methyltransferase (GAMT), platelet-derived endothelial cell growth factor (PD-ECGF) and methionine synthase (MTR), for validation. In addition, SA was found to facilitate PI3K/Akt activation and inhibit the expression of NOX2 in AMI mice and OGD-treated H9c2 cells. In conclusion, we have elucidated SA-regulated endogenous metabolic pathways and constructed a regulatory metabolic network map. Furthermore, we have validated the new potential therapeutic targets and underlying molecular mechanisms of SA against AMI, which might provide a reference for its future application in cardiovascular diseases.


id: cord-012840-tgcrg5db
author: Liu, Hao-chen
date: 2020-01-13
txt: ./txt/cord-012840-tgcrg5db.txt
cache: ./cache/cord-012840-tgcrg5db.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471499/
doi: 10.1038/s41401-019-0331-8
summary:
  Then this model was used to perform simulations, thus to propose an anti-hypertension indication, according to which the anti-hypertension treatment might yield relative low-level AUC and fluctuation of blood pressure. The simulation results suggest that the anti-hypertension agent may yield low-level AUC and fluctuation of blood pressure when relative ET-1 level ranges from −15% to 5% and relative NO level is more than 10% compared to control group. The aim of this study was to develop a mechanismbased pharmacokinetics-pharmacodynamic (PK/PD) model for proposing an optimized antihypertensive management method that can lower both blood pressure and its fluctuation in rats. Third, simulations based on the PK-PD model and progression analysis were performed according to the proposed hypothesis that the effect of antihypertensive treatment on blood pressure and its fluctuation are affected by variations in NO-ET homeostasis. Our study provides a mechanism-based model to optimize an antihypertensive treatment for hypertension induced by sunitinib that not only inhibits hypertension but also reduces blood pressure fluctuations in rats.

title:
  PK/PD modeling based on NO-ET homeostasis for improving management of sunitinib-induced hypertension in rats

abstract:
  Sunitinib is an oral small molecule multitargeted tyrosine kinase inhibitor, which is currently used to treat severe cancers. Clinical research has shown that patients treated with sunitinib develop hypertension. As soon as sunitinib-induced hypertension appears, it is usual to administer anti-hypertension agent. But this treatment may cause acute blood pressure fluctuation which may lead to additional cardiovascular risk. The aim of this study is to establish a mathematical model for managing sunitinib-induced hypertension and blood pressure fluctuation. A mechanism-based PK/PD model was developed based on animal experiments. Then this model was used to perform simulations, thus to propose an anti-hypertension indication, according to which the anti-hypertension treatment might yield relative low-level AUC and fluctuation of blood pressure. The simulation results suggest that the anti-hypertension agent may yield low-level AUC and fluctuation of blood pressure when relative ET-1 level ranges from −15% to 5% and relative NO level is more than 10% compared to control group. Finally, animal experiments were conducted to verify the simulation results. Macitentan (30 mg/kg) was administered based on the above anti-hypertension indication. Compared with the untreated group, the optimized treatment significantly reduced the AUC of blood pressure; meanwhile the fluctuation of blood pressure in optimized treatment group was 70% less than that in immediate treatment group. This work provides a novel model with potential translational value for managing sunitinib-induced hypertension.


id: cord-013544-x3eyimug
author: Hu, Yue-huai
date: 2020-04-01
txt: ./txt/cord-013544-x3eyimug.txt
cache: ./cache/cord-013544-x3eyimug.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608092/
doi: 10.1038/s41401-020-0364-z
summary:
  In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 μM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. The results described above indicated that the Wnt/PCP-JNK signaling pathway was involved in Dox-induced apoptosis of H9c2 cells. The results described above indicated that sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. In addition, anisomycin treatment induced the activation of Wnt/PCP-JNK signaling and the apoptosis of the H9c2 cells, and these effects were suppressed by sFRP1. The results described above led to the conclusion that sFRP1 protected the H9c2 cells from Dox-induced apoptosis by inhibiting Wnt/PCP-JNK signaling.

title:
  sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway

abstract:
  Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/β-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 μM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/β-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.


id: cord-013567-qnp65w53
author: Cheng, Qiao-qiao
date: 2020-03-12
txt: ./txt/cord-013567-qnp65w53.txt
cache: ./cache/cord-013567-qnp65w53.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608121/
doi: 10.1038/s41401-020-0382-x
summary:
  Our results suggest that GAS may protect H9c2 cardiomycytes against oxidative injury via increasing the nuclear translocation of Nrf2, regulating mitochondrial dynamics, and maintaining the structure and functions of mitochondria. Quantitative analysis of mitochondrial network characteristics showed similar results: in Nrf2-siRNA-treated cells, GAS pretreatment did not ameliorate the decrease in mitochondrial footprint, mean branch length, or median branch length induced by H 2 O 2 (Fig. 7c) . Knockdown of Nrf2 expression attenuated the effects of GAS on H 2 O 2 -induced mitochondrial dysfunction As shown in Fig. 9a , in negative control cells, H 2 O 2 treatment induced a considerable decrease in mitochondrial respiration potency, while GAS pretreatment partly ameliorates the H 2 O 2induced mitochondrial dysfunction. Importantly, in Nrf2-siRNA-treated cells, H 2 O 2 treatment also induced a considerable decrease in mitochondrial respiration potency, but GAS pretreatment did not ameliorate the H 2 O 2induced mitochondrial dysfunction (Fig. 9a) .

title:
  Gastrodin protects H9c2 cardiomyocytes against oxidative injury by ameliorating imbalanced mitochondrial dynamics and mitochondrial dysfunction

abstract:
  Gastrodin (GAS) is the main bioactive component of Tianma, a traditional Chinese medicine widely used to treat neurological disorders as well as cardio- and cerebrovascular diseases. In the present study, the protective effects of GAS on H9c2 cells against ischemia–reperfusion (IR)-like injury were found to be related to decreasing of oxidative stress. Furthermore, GAS could protect H9c2 cells against oxidative injury induced by H(2)O(2). Pretreatment of GAS at 20, 50, and 100 μM for 4 h significantly ameliorated the decrease in cell viability and increase in apoptosis of H9c2 cells treated with 400 μM H(2)O(2) for 3 h. Furthermore, we showed that H(2)O(2) treatment induced fragmentation of mitochondria and significant reduction in networks, footprint, and tubular length of mitochondria; H(2)O(2) treatment strongly inhibited mitochondrial respiration; H(2)O(2) treatment induced a decrease in the expression of mitochondrial fusion factors Mfn2 and Opa1, and increase in the expression of mitochondrial fission factor Fis1. All these alterations in H(2)O(2)-treated H9c2 cells could be ameliorated by GAS pretreatment. Moreover, we revealed that GAS pretreatment enhanced the nuclear translocation of Nrf2 under H(2)O(2) treatment. Knockdown of Nrf2 expression abolished the protective effects of GAS on H(2)O(2)-treated H9c2 cells. Our results suggest that GAS may protect H9c2 cardiomycytes against oxidative injury via increasing the nuclear translocation of Nrf2, regulating mitochondrial dynamics, and maintaining the structure and functions of mitochondria.


id: cord-013591-goaokk04
author: Ren, Si-yu
date: 2020-03-18
txt: ./txt/cord-013591-goaokk04.txt
cache: ./cache/cord-013591-goaokk04.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608191/
doi: 10.1038/s41401-020-0385-7
summary:
  The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Because the action of hydrolase on endocannabinoids increases endocannabinoid levels indirectly and thus causes fewer side effects than direct exogenous supplementation, two types of hydrolases, fatty acids amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have been examined as potential new drug targets for CNS disorders. Based on the hydrolytic mechanism of FAAH and MAGL, the study of endocannabinoids and their receptor system, as well as their potential therapeutic applications in several nervous system disorders, cancers, and neuroinflammatory diseases, a large number of irreversible/reversible inhibitors have been used to explore the different selectivities of these two enzymes.

title:
  Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases—focusing on FAAH/MAGL inhibitors

abstract:
  The endocannabinoid system (ECS) has received extensive attention for its neuroprotective effect on the brain. This system comprises endocannabinoids, endocannabinoid receptors, and the corresponding ligands and proteins. The molecular players involved in their regulation and metabolism are potential therapeutic targets for neuropsychiatric diseases including anxiety, depression and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Their antidepressant and anxiolytic mechanisms are considered to modulate the hypothalamic-pituitary-adrenal axis and regulate synaptic and neural plasticity. In terms of AD/PD, treatment with FAAH/MAGL inhibitors leads to reduction in amyloid β-protein deposition and inhibition of the death of dopamine neurons, which are commonly accepted to underlie the pathogenesis of AD and PD, respectively. Inflammation as the cause of depression/anxiety and PD/AD is also the target of FAAH/MAGL inhibitors. In this review, we summarize the application and involvement of FAAH/MAGL inhibitors in related neurological diseases. Focus on the latest research progress using FAAH/MAGL inhibitors is expected to facilitate the development of novel approaches with therapeutic potential.


id: cord-013601-y8pc4qfc
author: Zhou, Bo-ya
date: 2020-04-23
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608201/
doi: 10.1038/s41401-020-0381-y
title:
  Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization

abstract:
  Keloid is a benign skin tumor characterized by its cell hyperproliferative activity, invasion into normal skin, uncontrolled growth, overproduction and deposition of extracellular matrices and high recurrence rate after various therapies. Nintedanib is a receptor tyrosine kinase inhibitor targeting VEGF, PDGF, FGF, and TGF-β receptors with proved efficacy in anti-angiogenesis and in treating various types of cancers. In this study, we investigated the effects of nintedanib on keloid fibroblasts in both in vitro and ex vivo models. Keloid fibroblasts were prepared from 54 keloid scar samples in active stages collected from 49 patients. We found that nintedanib (1−4 μM) dose-dependently suppressed cell proliferation, induced G(0)/G(1) cell cycle arrest, and inhibited migration and invasion of keloid fibroblasts. The drug also significantly inhibited the gene and protein expression of collagen I (COL-1) and III (COL-3), fibronectin (FN), and connective growth factor (CTGF), as well as the gene expression of other pathological factors, such as alpha smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), FK506-binding protein 10 (FKBP10), and heat shock protein 47 (HSP47) in keloid fibroblasts. Furthermore, nintedanib treatment significantly suppressed the phosphorylation of p38, JNK, ERK, STAT3, and Smad, enhanced endocytosis of various growth factor receptors. Using an ex vivo tissue explant model, we showed that nintedanib significantly suppressed cell proliferation, migration, and collagen production. The drug also significantly disrupted microvessel structure ex vivo. In summary, our results demonstrate that nintedanib is likely to become a potential targeted drug for keloid systemic therapy.


id: cord-013717-e0cai9j3
author: Fusi, Fabio
date: 2020-03-04
txt: ./txt/cord-013717-e0cai9j3.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608335/
doi: 10.1038/s41401-020-0370-1
summary:
  In contrast, ketanserin-induced inhibition of current amplitude was b Average traces (recorded from five cells) of I Ca1.2 , elicited with 250 ms clamp pulses to 10 mV from a V h of −80 mV, measured in the absence (control) or presence of cumulative concentrations of ritanserin. The major findings supporting this conclusion are as follows: (1) in single vascular myocytes, ritanserin inhibited I Ca1.2 in a concentration-dependent manner; (2) this inhibition was antagonized by the Ca V 1.2 stimulator Bay K 8644 and was likely due to the interaction of ritanserin with the channel protein; (3) ritanserin stabilized the Ca V 1.2 channel in its inactivated state; and (4) since ritanserin relaxed vascular smooth muscle contraction resulting from the opening of Ca V 1.2 channels, the I Ca1.2 blockade is supposed to have functional relevance and supports previous data obtained in vascular and nonvascular tissues [15] [16] [17] , where such mechanism of action was hypothesized to account for the relaxant effects of the drug.

title:
  Ritanserin blocks Ca(V)1.2 channels in rat artery smooth muscles: electrophysiological, functional, and computational studies

abstract:
  Ca(V)1.2 channel blockers or 5-HT(2) receptor antagonists constitute effective therapy for Raynaud’s syndrome. A functional link between the inhibition of 5-HT(2) receptors and Ca(V)1.2 channel blockade in arterial smooth muscles has been hypothesized. Therefore, the effects of ritanserin, a nonselective 5-HT(2) receptor antagonist, on vascular Ca(V)1.2 channels were investigated through electrophysiological, functional, and computational studies. Ritanserin blocked Ca(V)1.2 channel currents (I(Ca1.2)) in a concentration-dependent manner (K(r) = 3.61 µM); I(Ca1.2) inhibition was antagonized by Bay K 8644 and partially reverted upon washout. Conversely, the ritanserin analog ketanserin (100 µM) inhibited I(Ca1.2) by ~50%. Ritanserin concentration-dependently shifted the voltage dependence of the steady-state inactivation curve to more negative potentials (K(i) = 1.58 µM) without affecting the slope of inactivation and the activation curve, and decreased I(Ca1.2) progressively during repetitive (1 Hz) step depolarizations (use-dependent block). The addition of ritanserin caused the contraction of single myocytes not yet dialyzed with the conventional method. Furthermore, in depolarized rings, ritanserin, and to a lesser extent, ketanserin, caused a concentration-dependent relaxation, which was antagonized by Bay K 8644. Ritanserin and ketanserin were docked at a region of the Ca(V)1.2 α(1C) subunit nearby that of Bay K 8644; however, only ritanserin and Bay K 8644 formed a hydrogen bond with key residue Tyr-1489. In conclusion, ritanserin caused in vitro vasodilation, accomplished through the blockade of Ca(V)1.2 channels, which was achieved preferentially in the inactivated and/or resting state of the channel. This novel activity encourages the development of ritanserin derivatives for their potential use in the treatment of Raynaud’s syndrome.


id: cord-278142-xnkqg4ef
title: Cobrotoxin could be an effective therapeutic for COVID-19
author: Lin, Fang
date: 2020-08-25
txt: ./txt/cord-278142-xnkqg4ef.txt
cache: ./cache/cord-278142-xnkqg4ef.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32843715/
doi: 10.1038/s41401-020-00501-7
abstract: nan
summary:
  Based on previous studies of cobra venom by the authors and other independent researchers, cobrotoxin, a short-chain αneurotoxin from Naja naja atra venom (NNAV), could be an alternative therapy for COVID-19. In addition, cobrotoxin was shown to attenuate LPSinduced pulmonary edema, decrease the number of hematological CD4 + T cells, inhibit immune cell accumulation in bronchoalveolar lavage fluid, and inhibit pro-inflammatory cytokine excretion in rat acute lung injury and acute respiratory distress syndrome [6] . At this time, it is believed that cobrotoxin has the potential to treat patients with COVID-19 or to inhibit SARS-COV-2 infection. 1. Anti-inflammatory activity: NNAV and α-neurotoxins have strong inhibitory effects on inflammation; thus, they could inhibit the cytokine storm caused by SARS-COV2 infection. NNAV also increases the concentration of serum IgG and IgM in mice with dexamethasone-induced immunosuppression, suggesting that NNAV or cobrotoxin could have the potential to restore the immune balance in patients with COVID-19.


id: cord-278523-djjtgbh6
author: Zhou, Bei-xian
date: 2020-06-05
txt: ./txt/cord-278523-djjtgbh6.txt
cache: ./cache/cord-278523-djjtgbh6.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41401-020-0403-9
doi: 10.1038/s41401-020-0403-9
summary:
  We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Together, these data demonstrate that β-sitosterol blocks the IAV-induced amplification of the proinflammatory response in IFN-β-activated A549 cells, which is due to inhibition of RIG-I levels by β-sitosterol, leading to the inactivation of STAT1, and thereby diminishes the transcriptional activity of interferon-stimulated gene factor 3 (ISGF3).

title:
  β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling

abstract:
  β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Moreover, β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of β-sitosterol (50, 200 mg·kg(−1)·d(−1), i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of β-sitosterol protected mice from lethal IAV infection. Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.


id: cord-300445-qzu4gz2d
author: Zhang, Xiao-lei
date: 2020-09-23
txt: ./txt/cord-300445-qzu4gz2d.txt
cache: ./cache/cord-300445-qzu4gz2d.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41401-020-00519-x
doi: 10.1038/s41401-020-00519-x
summary:
  Chloroquine phosphate and its derivative hydroxychloroquine, which have been used in the treatment and prevention of malaria and autoimmune diseases for decades, were found to inhibit SARS-CoV-2 infection with high potency in vitro and have shown clinical and virologic benefits in COVID-19 patients. However, chloroquine phosphate and its derivative hydroxychloroquine, which have been used for decades in the treatment and prevention of malaria and chronic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus, were discovered to have a high inhibitory potency against SARS-CoV-2 infection in vitro [2] [3] [4] [5] and favorable clinical and virologic benefits in COVID-19 patients [6] [7] [8] [9] [10] , and they have emerged as important therapies for COVID-19 in several countries, including China, France, USA, and India, although the mechanisms of their anti-COVID-19 effects remain unclear.

title:
  Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with chloroquine derivatives

abstract:
  The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and an ongoing severe pandemic. Curative drugs specific for COVID-19 are currently lacking. Chloroquine phosphate and its derivative hydroxychloroquine, which have been used in the treatment and prevention of malaria and autoimmune diseases for decades, were found to inhibit SARS-CoV-2 infection with high potency in vitro and have shown clinical and virologic benefits in COVID-19 patients. Therefore, chloroquine phosphate was first used in the treatment of COVID-19 in China. Later, under a limited emergency-use authorization from the FDA, hydroxychloroquine in combination with azithromycin was used to treat COVID-19 patients in the USA, although the mechanisms of the anti-COVID-19 effects remain unclear. Preliminary outcomes from clinical trials in several countries have generated controversial results. The desperation to control the pandemic overrode the concerns regarding the serious adverse effects of chloroquine derivatives and combination drugs, including lethal arrhythmias and cardiomyopathy. The risks of these treatments have become more complex as a result of findings that COVID-19 is actually a multisystem disease. While respiratory symptoms are the major clinical manifestations, cardiovascular abnormalities, including arrhythmias, myocarditis, heart failure, and ischemic stroke, have been reported in a significant number of COVID-19 patients. Patients with preexisting cardiovascular conditions (hypertension, arrhythmias, etc.) are at increased risk of severe COVID-19 and death. From pharmacological and cardiovascular perspectives, therefore, the treatment of COVID-19 with chloroquine and its derivatives should be systematically evaluated, and patients should be routinely monitored for cardiovascular conditions to prevent lethal adverse events.


id: cord-314714-ehxxvenb
title: Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication
author: Pang, Xiaocong
date: 2020-06-24
txt: ./txt/cord-314714-ehxxvenb.txt
cache: ./cache/cord-314714-ehxxvenb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32581256/
doi: 10.1038/s41401-020-0430-6
abstract: nan
summary:
  title: Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication However, the addition of exogenous ACE2 could be a potential treatment for SARS-CoV-2 infection, which might not only restrain the spread of SARS-CoV-2 by blocking its interaction with ACE2 on the host cell, but also modulate RAS to treat SARS-CoV-2-related underlying comorbidities and protect the lung from developing ARDS. Although Ang II receptor and ACE blockage were also effective in lung failure in animal models, this treatment could cause potential adverse effects, causing systemic hypotension in humans [22] . Currently, phase I (NCT00886353) and phase II (NCT01597635) clinical studies with a recombinant version of the catalytic ectodomain of human ACE2 (GSK2586881) have been successfully completed, providing safety and efficacy for ARDS treatment [25, 26] . Recombinant human ACE2 and the angiotensin 1-7 axis as potential new therapies for heart failure A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome


id: cord-329011-spiuqngp
author: Huang, Yuan
date: 2020-08-03
txt: ./txt/cord-329011-spiuqngp.txt
cache: ./cache/cord-329011-spiuqngp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41401-020-0485-4
doi: 10.1038/s41401-020-0485-4
summary:
  The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. A large number of glycosylated S proteins cover the surface of SARS-CoV-2 and bind to the host cell receptor angiotensinconverting enzyme 2 (ACE2), mediating viral cell entry [8] . The SARS-CoV-2 S protein is highly conserved among all human coronaviruses (HCoVs) and is involved in receptor recognition, viral attachment, and entry into host cells. Structure of the S1 subunit The binding of virus particles to cell receptors on the surface of the host cell is the initiation of virus infection; therefore, receptor recognition is an important determinant of viral entry and a drug design target. Therefore, the development of antibodies targeting this functional motif may cross-bind and neutralize these two viruses and related CoVs. Antiviral peptides prevent SARS-CoV-2 membrane fusion and can potentially be used for the prevention and treatment of infection.

title:
  Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

abstract:
  Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.


id: cord-338901-1kzy7rts
title: Overview of therapeutic drug research for COVID-19 in China
author: Li, Heng
date: 2020-06-17
txt: ./txt/cord-338901-1kzy7rts.txt
cache: ./cache/cord-338901-1kzy7rts.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41401-020-0438-y
doi: 10.1038/s41401-020-0438-y
summary:
  According to the information that we have collected so far, this article provides an overview of potential therapeutic drugs and compounds with much attention, including favipiravir and hydroxychloroquine, as well as traditional Chinese medicine, which have been reported with good clinical treatment effects. In these 155 pooled clinical trials, a number of approved chemical and biomacromolecule drugs have been used in COVID-19 treatment clinical trials for drug repurposing, most of which are nucleotide analogs and protease inhibitors against other viral pathogens, including influenza virus, HIV and HCV. In vitro studies have shown that lopinavir/ritonavir can inhibit the replication of MERS-CoV and SARS-CoV and exert antiviral effects [22] [23] [24] [25] . In the latest "Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia", it is recommended to use ribavirin at a dose of 500 mg each time for adults and in combination with interferon or lopinavir/ritonavir, with 2-3 intravenous infusions daily. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment acute respiratory syndrome Coronavirus 2 (SARS-CoV-2)

abstract:
  Since the outbreak of novel coronavirus pneumonia (COVID-19) in December 2019, more than 2,500,000 people worldwide have been diagnosed with SARS-CoV-2 as of April 22. In response to this epidemic, China has issued seven trial versions of diagnosis and treatment protocol for COVID-19. According to the information that we have collected so far, this article provides an overview of potential therapeutic drugs and compounds with much attention, including favipiravir and hydroxychloroquine, as well as traditional Chinese medicine, which have been reported with good clinical treatment effects. Moreover, with further understanding of SARS-CoV-2 virus, new drugs targeting specific SARS-CoV-2 viral components arise and investigations on these novel anti-SARS-CoV-2 agents are also reviewed.


