Summary of your 'study carrel' ============================== This is a summary of your Distant Reader 'study carrel'. The Distant Reader harvested & cached your content into a collection/corpus. It then applied sets of natural language processing and text mining against the collection. The results of this process was reduced to a database file -- a 'study carrel'. The study carrel can then be queried, thus bringing light specific characteristics for your collection. These characteristics can help you summarize the collection as well as enumerate things you might want to investigate more closely. This report is a terse narrative report, and when processing is complete you will be linked to a more complete narrative report. Eric Lease Morgan Number of items in the collection; 'How big is my corpus?' ---------------------------------------------------------- 50 Average length of all items measured in words; "More or less, how big is each item?" ------------------------------------------------------------------------------------ 5235 Average readability score of all items (0 = difficult; 100 = easy) ------------------------------------------------------------------ 46 Top 50 statistically significant keywords; "What is my collection about?" ------------------------------------------------------------------------- 13 Fig 9 cell 4 SARS 3 cancer 3 RNA 3 COVID-19 3 AMPK 2 patient 2 USA 2 TGF 2 NLRP3 2 LPS 2 IMB 2 ACE2 1 tumor 1 tmem16a 1 therapy 1 syn 1 study 1 ritanserin 1 rig 1 protein 1 o2-x 1 nmt 1 myristoylation 1 mitochondrial 1 lm9 1 keloid 1 immunotherapy 1 gene 1 gas 1 dna 1 decoction 1 compound 1 chloroquine 1 chinese 1 c2c12 1 antipsychotic 1 a549 1 XFZY 1 Wnt 1 VEGF 1 USP5 1 Timo 1 TXNIP 1 TRAIL 1 TLR4 1 SGK1 1 SBP 1 S780 Top 50 lemmatized nouns; "What is discussed?" --------------------------------------------- 2884 cell 1066 protein 1005 effect 800 treatment 783 study 742 expression 728 mouse 688 % 672 group 584 pathway 583 disease 580 receptor 580 level 510 analysis 501 cancer 487 h 477 gene 465 activity 461 result 458 p 457 drug 453 activation 433 tumor 427 inhibitor 416 apoptosis 412 model 404 patient 390 role 371 mechanism 352 concentration 344 tissue 333 rat 331 control 317 datum 311 c 306 α 303 response 302 function 300 factor 291 injury 288 β 287 inhibition 279 membrane 273 assay 262 virus 256 addition 250 time 247 system 246 compound 245 syn Top 50 proper nouns; "What are the names of persons or places?" -------------------------------------------------------------- 885 Fig 342 SARS 278 USA 227 IMB 226 CoV-2 218 PD 206 RNA 204 China 197 TRAIL 187 c 182 . 172 IFN 164 ± 153 al 153 II 149 κB 149 α 149 S 144 IAV 138 ET-1 135 mg 135 AIII 130 Maf 128 β 122 K 122 IL-6 119 Timo 115 et 113 CMR 110 Zn 110 COVID-19 109 LPS 109 HDC 108 SGK1 107 H9c2 105 NLE 103 sitosterol 101 STAT5a 101 Cd 99 S7 99 PCR 97 AMPK 94 ET 93 L 93 AVP 91 kg 91 d 91 Dox 91 Ca 89 Parkinson Top 50 personal pronouns nouns; "To whom are things referred?" ------------------------------------------------------------- 759 we 393 it 180 i 74 they 23 them 11 us 7 he 5 you 4 themselves 4 itself 4 imagej 3 mg 2 herg 1 rhace2 1 phlips 1 nlrp3-inflammasome 1 mrnas 1 itgb7-that 1 il-1β 1 endothelin-1 1 cord-012768 1 bace1 1 5,5',6,6'tetrachloro-1,1',3,3 Top 50 lemmatized verbs; "What do things do?" --------------------------------------------- 7918 be 1095 have 1012 induce 861 use 749 show 542 inhibit 536 increase 408 signal 392 treat 372 mediate 327 indicate 291 include 285 find 279 bind 276 reduce 268 suggest 259 target 256 perform 243 decrease 241 regulate 232 base 229 activate 228 follow 222 relate 212 associate 201 cause 197 compare 193 determine 188 report 187 involve 182 demonstrate 167 measure 166 promote 166 observe 161 express 161 block 157 suppress 156 enhance 154 play 153 contain 148 describe 147 lead 145 do 143 provide 141 incubate 140 identify 139 detect 137 attenuate 137 analyze 136 protect Top 50 lemmatized adjectives and adverbs; "How are things described?" --------------------------------------------------------------------- 506 also 456 - 440 not 336 significantly 322 human 300 mitochondrial 281 further 278 high 277 anti 272 clinical 268 inflammatory 255 such 245 other 241 then 233 dependent 231 however 211 therapeutic 210 cardiac 196 well 195 viral 194 low 193 significant 193 potential 185 specific 185 different 182 novel 179 therefore 178 myocardial 168 endothelial 154 western 153 immune 147 thus 146 important 145 previous 143 more 142 new 140 acute 138 cardiovascular 136 vascular 135 molecular 133 various 133 like 127 multiple 125 previously 123 only 117 first 115 protective 114 similar 110 moreover 109 mean Top 50 lemmatized superlative adjectives; "How are things described to the extreme?" ------------------------------------------------------------------------- 36 most 32 least 14 high 10 late 9 Most 7 low 5 good 4 great 2 vRNA 2 simple 2 large 1 weighs~1.5 1 strong 1 severe 1 postt 1 farth Top 50 lemmatized superlative adverbs; "How do things do to the extreme?" ------------------------------------------------------------------------ 72 most 29 least 4 well 2 vrna 1 highest Top 50 Internet domains; "What Webbed places are alluded to in this corpus?" ---------------------------------------------------------------------------- 20 doi.org 2 www.clinicaltrials.gov 2 www 1 www.who.int 1 www.ncmi.cn 1 www.ncbi.nlm.nih.gov 1 www.ncbi.nlm 1 www.metascape.org 1 www.metaboanalyst.ca 1 www.fao.org 1 www.chemcpd.csdb 1 www.cbioportal 1 string905.embl.de 1 string-db 1 stitch.embl.de 1 rnaidesigner 1 metlin.scripps 1 imagej.nih.gov 1 david-d.ncifcrf.gov 1 ctdbase.org 1 creativecommons 1 clue.io 1 clinicaltrials.gov Top 50 URLs; "What is hyperlinked from this corpus?" ---------------------------------------------------- 2 http://www.clinicaltrials.gov 2 http://www 1 http://www.who.int/ 1 http://www.ncmi.cn/ 1 http://www.ncbi.nlm.nih.gov/omim/ 1 http://www.ncbi.nlm 1 http://www.metascape.org/ 1 http://www.metaboanalyst.ca/ 1 http://www.fao.org/ag/againfo/programmes/en/empres/h7n9/ 1 http://www.chemcpd.csdb 1 http://www.cbioportal 1 http://string905.embl.de/ 1 http://string-db 1 http://stitch.embl.de/ 1 http://rnaidesigner 1 http://metlin.scripps 1 http://imagej.nih.gov/ij/download.html 1 http://doi.org/10.1038/s41401-020-0410-x 1 http://doi.org/10.1038/s41401-020-0403-9 1 http://doi.org/10.1038/s41401-020-0382-x 1 http://doi.org/10.1038/s41401-020-0381-y 1 http://doi.org/10.1038/s41401-020-0377-7 1 http://doi.org/10.1038/s41401-020-0375-9 1 http://doi.org/10.1038/s41401-020-0361-2 1 http://doi.org/10.1038/s41401-020-0357-y 1 http://doi.org/10.1038/s41401-019-0352-3 1 http://doi.org/10.1038/s41401-019-0351-4 1 http://doi.org/10.1038/s41401-019-0350-5 1 http://doi.org/10.1038/s41401-019-0335-4 1 http://doi.org/10.1038/s41401-019-0332-7 1 http://doi.org/10.1038/s41401-019-0319-4 1 http://doi.org/10.1038/s41401-019-0307-8 1 http://doi.org/10.1038/s41401-019-0298-5 1 http://doi.org/10.1038/s41401-019-0296-7 1 http://doi.org/10.1038/s41401-019-0292-y 1 http://doi.org/10.1038/s41401-019-0291-z 1 http://doi.org/10.1038/s41401-019-0285-x 1 http://david-d.ncifcrf.gov/ 1 http://ctdbase.org/ 1 http://creativecommons 1 http://clue.io/cmap 1 http://clinicaltrials.gov/ Top 50 email addresses; "Who are you gonna call?" ------------------------------------------------- Top 50 positive assertions; "What sentences are in the shape of noun-verb-noun?" ------------------------------------------------------------------------------- 14 cells were then 8 mice were randomly 7 levels were significantly 5 group was significantly 4 genes were mainly 4 studies have also 3 cells was further 3 cells were transiently 3 expression was markedly 3 genes were specifically 3 group had significantly 3 level was significantly 3 results are consistent 3 results were consistent 2 analysis using anti 2 cells are also 2 cells was significantly 2 cells were also 2 cells were continuously 2 cells were cultured 2 effect was dose 2 effect was significantly 2 effects were not 2 effects were significantly 2 expression is essential 2 expression was also 2 expression was significantly 2 expressions was relative 2 expressions were relative 2 genes were remarkably 2 group has recently 2 groups targeting hub 2 levels were also 2 levels were lower 2 mice were then 2 pathway is also 2 pathway was partially 2 receptor signalling pathway 2 receptors are also 2 results are representative 2 treatment induced fragmentation 2 tumors were palpable 1 % had substantial 1 % have coronary 1 % reported irreversible 1 % using lipofectamine 1 * indicates statistical 1 activation following myocardial 1 activation inhibits beta 1 activation is critical Top 50 negative assertions; "What sentences are in the shape of noun-verb-no|not-noun?" --------------------------------------------------------------------------------------- 2 effects were not due 1 drugs are not available 1 group showed no significant 1 groups showed no significant 1 h had no effect 1 level was not obviously 1 levels were not significantly 1 result was not significant 1 results showed no changes 1 results showed no differences 1 results showed no significant 1 studies have not fully 1 treatment has no significant 1 treatment has not yet A rudimentary bibliography -------------------------- id = cord-012722-ewc2awv1 author = Bian, Yu title = Kanglexin, a novel anthraquinone compound, protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis date = 2019-10-23 keywords = GSDMD; KLX; NLRP3 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. doi = 10.1038/s41401-019-0307-8 id = cord-012768-9fvumvdc author = Chen, Bao-yi 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 date = 2020-03-05 keywords = SGK1; cell 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). doi = 10.1038/s41401-020-0357-y id = cord-012726-1i1mj3jw author = Chen, Xue-han title = Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis date = 2019-06-13 keywords = Maf; USP5 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. doi = 10.1038/s41401-019-0249-1 id = cord-013567-qnp65w53 author = Cheng, Qiao-qiao title = Gastrodin protects H9c2 cardiomyocytes against oxidative injury by ameliorating imbalanced mitochondrial dynamics and mitochondrial dysfunction date = 2020-03-12 keywords = Fig; Nrf2; gas 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) . doi = 10.1038/s41401-020-0382-x id = cord-013717-e0cai9j3 author = Fusi, Fabio title = Ritanserin blocks Ca(V)1.2 channels in rat artery smooth muscles: electrophysiological, functional, and computational studies date = 2020-03-04 keywords = Bay; Ca1.2; ritanserin 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. doi = 10.1038/s41401-020-0370-1 id = cord-012716-t19zmvm6 author = Guo, Chen-hong 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 date = 2020-02-28 keywords = Dicer 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. doi = 10.1038/s41401-020-0379-5 id = cord-013544-x3eyimug author = Hu, Yue-huai title = sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway date = 2020-04-01 keywords = Dox; JNK; Wnt 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. doi = 10.1038/s41401-020-0364-z id = cord-329011-spiuqngp author = Huang, Yuan title = Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19 date = 2020-08-03 keywords = ACE2; CoV-2; RBD; SARS 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. doi = 10.1038/s41401-020-0485-4 id = cord-012838-23odny3f author = Lai, Qiong title = Exploring the protective effects of schizandrol A in acute myocardial ischemia mice by comprehensive metabolomics profiling integrated with molecular mechanism studies date = 2020-03-02 keywords = AMI; Akt; China; Fig; NT5E 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. doi = 10.1038/s41401-020-0377-7 id = cord-338901-1kzy7rts author = Li, Heng title = Overview of therapeutic drug research for COVID-19 in China date = 2020-06-17 keywords = COVID-19; RNA; SARS; chinese 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) doi = 10.1038/s41401-020-0438-y id = cord-278142-xnkqg4ef author = Lin, Fang title = Cobrotoxin could be an effective therapeutic for COVID-19 date = 2020-08-25 keywords = COVID-19; NNAV 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. doi = 10.1038/s41401-020-00501-7 id = cord-012760-p6fdc191 author = Liu, Can-zhao title = Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediated TMEM16A degradation date = 2019-09-04 keywords = Endophilin; Fig; tmem16a 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. doi = 10.1038/s41401-019-0298-5 id = cord-012840-tgcrg5db author = Liu, Hao-chen title = PK/PD modeling based on NO-ET homeostasis for improving management of sunitinib-induced hypertension in rats date = 2020-01-13 keywords = SBP 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. doi = 10.1038/s41401-019-0331-8 id = cord-012720-eoovm5gh author = Liu, Qi title = Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway date = 2020-01-14 keywords = Fig; NLRP3; TXNIP 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. doi = 10.1038/s41401-019-0335-4 id = cord-002006-pwlybr2h author = Liu, Yuan-yuan title = Specific interference shRNA-expressing plasmids inhibit Hantaan virus infection in vitro and in vivo date = 2016-03-14 keywords = HTNV; RNA 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. doi = 10.1038/aps.2015.165 id = cord-012837-fuwp08qt author = Lu, Chen-chen title = Gut microbiota dysbiosis-induced activation of the intrarenal renin–angiotensin system is involved in kidney injuries in rat diabetic nephropathy date = 2020-03-17 keywords = RAS 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) . doi = 10.1038/s41401-019-0326-5 id = cord-314714-ehxxvenb author = Pang, Xiaocong title = Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication date = 2020-06-24 keywords = ACE2; SARS 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 doi = 10.1038/s41401-020-0430-6 id = cord-012822-8t6qg5fp author = Papoutsis, Konstantinos title = Tissue-specific relaxin-2 is differentially associated with the presence/size of an arterial aneurysm and the severity of atherosclerotic disease in humans date = 2020-02-05 keywords = ATH; MMP2; MMP9; RL2 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. doi = 10.1038/s41401-019-0350-5 id = cord-012747-s4wf0pix author = Prehn, Jochen H M title = Angiogenin and tRNA fragments in Parkinson’s disease and neurodegeneration date = 2020-03-06 keywords = ANG; Angiogenin 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 doi = 10.1038/s41401-020-0375-9 id = cord-012753-cu6qcen9 author = Qi, Fei-long title = Reversal of the immunosuppressive tumor microenvironment by nanoparticle-based activation of immune-associated cells date = 2020-05-28 keywords = cancer; cell; tumor 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 doi = 10.1038/s41401-020-0423-5 id = cord-013591-goaokk04 author = Ren, Si-yu title = Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases—focusing on FAAH/MAGL inhibitors date = 2020-03-18 keywords = AEA; CB2; FAAH; MAGL 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. doi = 10.1038/s41401-020-0385-7 id = cord-012781-e4js9qrs author = Sun, Qingxue title = Cancer nanomedicine meets immunotherapy: opportunities and challenges date = 2020-06-17 keywords = cancer; cell 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. doi = 10.1038/s41401-020-0448-9 id = cord-012770-wvf8swyj author = Sun, Shu-zhen title = β-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK(1/2)-NF-κB signal pathway in murine hearts date = 2019-09-12 keywords = AVP; IL-6 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. doi = 10.1038/s41401-019-0292-y id = cord-012828-wsjob1p8 author = Wang, Yan-hang title = Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway date = 2019-09-10 keywords = BV-2; DRD1; IL-18; LPS 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] . doi = 10.1038/s41401-019-0296-7 id = cord-012767-h5gv9g62 author = Wei, Xiao-min title = Protein tyrosine phosphatase L1 represses endothelial-mesenchymal transition by inhibiting IL-1β/NF-κB/Snail signaling date = 2020-03-09 keywords = PTPL1 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. doi = 10.1038/s41401-020-0374-x id = cord-012723-2bbd30ud author = Wu, Lei title = Endothelin-1 enhances acid-sensing ion channel currents in rat primary sensory neurons date = 2020-02-27 keywords = ASIC; DRG; ET-1 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. doi = 10.1038/s41401-019-0348-z id = cord-012758-18c1rxg8 author = Wu, Xiao-li title = Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury date = 2020-02-27 keywords = AMPK; Fig; MCAO 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. doi = 10.1038/s41401-020-0361-2 id = cord-012771-3ukffdmq author = Xu, Deng-qiu title = The hypoglycemic mechanism of catalpol involves increased AMPK-mediated mitochondrial biogenesis date = 2020-01-14 keywords = AMPK; Fig; c2c12; mitochondrial 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. doi = 10.1038/s41401-019-0345-2 id = cord-012773-wtgk2d68 author = Xu, Ming-ming title = Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein date = 2019-10-04 keywords = Lewy; Parkinson; compound; syn summary = doi = 10.1038/s41401-019-0304-y id = cord-012826-72mz834w author = Xu, Zhen-dong title = Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy date = 2019-10-23 keywords = ATG5; USA; cell 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) . doi = 10.1038/s41401-019-0303-z id = cord-012769-clbqckj2 author = Yan, You-you title = A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells date = 2020-02-11 keywords = Amcp; Fig; cell 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. doi = 10.1038/s41401-019-0354-1 id = cord-012795-6m88m81v author = Yu, Hai-jun title = Nanomedicine and cancer immunotherapy date = 2020-05-28 keywords = cancer; immunotherapy 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. doi = 10.1038/s41401-020-0426-2 id = cord-012834-h9lrtecc author = Yu, Hai-tao title = Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms date = 2019-11-25 keywords = ECT 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. doi = 10.1038/s41401-019-0320-y id = cord-012682-7goljir4 author = Yuan, Meng title = N-myristoylation: from cell biology to translational medicine date = 2020-03-18 keywords = NMT1; NMT2; myristoylation; nmt; protein 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. doi = 10.1038/s41401-020-0388-4 id = cord-012784-c74jr4ga author = Zhang, Le-le title = Identification of nagilactone E as a protein synthesis inhibitor with anticancer activity date = 2020-02-11 keywords = Fig; NLE; RNA; a549 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. doi = 10.1038/s41401-019-0332-7 id = cord-012778-yr8zuvw9 author = Zhang, Lei title = Quantitative efficacy of three antipsychotic drugs for schizophrenia based on a real-world study in China date = 2019-08-06 keywords = antipsychotic; patient; study 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. doi = 10.1038/s41401-019-0285-x id = cord-012754-yp66g40r author = Zhang, Na title = A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin αv expression date = 2020-01-13 keywords = BDL; IMB; TGF 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) . doi = 10.1038/s41401-019-0325-6 id = cord-012796-wfdt07vs author = Zhang, Sai-long title = Aggravated ulcerative colitis caused by intestinal Metrnl deficiency is associated with reduced autophagy in epithelial cells date = 2020-01-16 keywords = AMPK; DSS; Metrnl 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] . doi = 10.1038/s41401-019-0343-4 id = cord-012785-d53k16ow author = Zhang, Shi-rong 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 date = 2020-02-17 keywords = CMR; cell 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. doi = 10.1038/s41401-019-0351-4 id = cord-001268-sc0ersky author = Zhang, Wei-ying title = Gene expression profiles of human liver cells mediated by hepatitis B virus X protein date = 2009-04-03 keywords = cell; o2-x 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. doi = 10.1038/aps.2009.22 id = cord-300445-qzu4gz2d author = Zhang, Xiao-lei title = Pharmacological and cardiovascular perspectives on the treatment of COVID-19 with chloroquine derivatives date = 2020-09-23 keywords = COVID-19; SARS; chloroquine; patient 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. doi = 10.1038/s41401-020-00519-x id = cord-012818-zr4xw3ph author = Zhang, Ying-ying title = A comparative pharmacogenomic analysis of three classic TCM prescriptions for coronary heart disease based on molecular network modeling date = 2020-02-12 keywords = CHD; Fig; GLXBBX; XFZY; decoction 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] . doi = 10.1038/s41401-019-0352-3 id = cord-012802-xm2ftrw2 author = Zhao, Wu-li 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 date = 2020-01-13 keywords = Fig; HDC; IMB; S780; dna 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. doi = 10.1038/s41401-019-0333-6 id = cord-012688-d0m23sgk author = Zheng, Xu-yong title = Compound LM9, a novel MyD88 inhibitor, efficiently mitigates inflammatory responses and fibrosis in obesity-induced cardiomyopathy date = 2020-04-27 keywords = TLR4; lm9 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. doi = 10.1038/s41401-020-0410-x id = cord-012791-dyk5mr1q author = Zheng, Yong title = Icariside II inhibits lipopolysaccharide-induced inflammation and amyloid production in rat astrocytes by regulating IKK/IκB/NF-κB/BACE1 signaling pathway date = 2019-09-25 keywords = ICS; LPS 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. doi = 10.1038/s41401-019-0300-2 id = cord-012035-rhpfpku9 author = Zhong, Hui-hai title = TRAIL-based gene delivery and therapeutic strategies date = 2019-08-23 keywords = DR5; PEI; TRAIL; cell; gene; therapy 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 doi = 10.1038/s41401-019-0287-8 id = cord-278523-djjtgbh6 author = Zhou, Bei-xian 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 date = 2020-06-05 keywords = Fig; IAV; IFN; rig 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). doi = 10.1038/s41401-020-0403-9 id = cord-013601-y8pc4qfc author = Zhou, Bo-ya title = Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization date = 2020-04-23 keywords = Fig; TGF; USA; cell; keloid summary = doi = 10.1038/s41401-020-0381-y id = cord-012806-pjehkeh9 author = Zhou, Zhong-yan title = Antiangiogenesis effect of timosaponin AIII on HUVECs in vitro and zebrafish embryos in vivo date = 2019-09-12 keywords = AIII; Fig; Timo; VEGF 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. doi = 10.1038/s41401-019-0291-z