key: cord-0993285-ns9raq0l
authors: Qin, Xiaojiang; Xu, Xinrong; Hou, Xiaomin; Liang, Ruifeng; Chen, Liangjing; Hao, Yuxuan; Gao, Anqi; Du, Xufeng; Zhao, Liangyuan; Shi, Yiwei; Li, Qingshan
title: The pharmacological properties and corresponding mechanisms of farrerol: a comprehensive review
date: 2021-11-30
journal: Pharmaceutical biology
DOI: 10.1080/13880209.2021.2006723
sha: 67fb1ecce373c870fbcbd69adc9dd554bf72d4f1
doc_id: 993285
cord_uid: ns9raq0l

CONTEXT: Farrerol, a typical natural flavanone isolated from the traditional Chinese herb ‘Man-shan-hong’ [Rhododendron dauricum L. (Ericaceae)] with phlegm-reducing and cough-relieving properties, is widely used in China for treating bronchitis and asthma. OBJECTIVE: To present the anti-inflammatory, antioxidant, vasoactive, antitumor, and antimicrobial effects of farrerol and its underlying molecular mechanisms. METHODS: The literature was reviewed by searching PubMed, Medline, Web of Knowledge, Scopus, and Google Scholar databases between 2011 and May 2021. The following key words were used: ‘farrerol,’ ‘flavanone,’ ‘anti-inflammatory,’ ‘antioxidant,’ ‘vasoactive,’ ‘antitumor,’ ‘antimicrobial,’ and ‘molecular mechanisms’. RESULTS: Farrerol showed anti-inflammatory effects mainly mediated via the inhibition of interleukin (IL)-6/8, IL-1β, tumour necrosis factor(TNF)-α, NF-κB, NO, COX-2, JNK1/2, AKT, PI3K, ERK1/2, p38, Keap-1, and TGF-1β. Farrerol exhibited antioxidant effects by decreasing JNK, MDA, ROS, NOX4, Bax/Bcl-2, caspase-3, p-p38 MAPK, and GSK-3β levels and enhancing Nrf2, GSH, SOD, GSH-Px, HO-1, NQO1, and p-ERK levels. The vasoactive effects of farrerol were also shown by the reduced α-SMA, NAD(P)H, p-ERK, p-Akt, mTOR, Jak2, Stat3, Bcl-2, and p38 levels, but increased OPN, occludin, ZO-1, eNOS, CaM, IP3R, and PLC levels. The antitumor effects of farrerol were evident from the reduced Bcl-2, Slug, Zeb-1, and vimentin levels but increased p27, ERK1/2, p38, caspase-9, Bax, and E-cadherin levels. Farrerol reduced α-toxin levels and increased NO production and NF-κB activity to impart antibacterial activity. CONCLUSIONS: This review article provides a theoretical basis for further studies on farrerol, with a view to develop and utilise farrerol for treating of vascular-related diseases in the future.

Flavanone, a common class of polyphenol compounds naturally present in fruits, vegetables, nuts, seeds, flowers, and bark, exhibits a wide range of pharmacological properties, including antioxidant, anti-inflammatory, vasodilatory, antitumor, and antibacterial effects (Zhu et al. 2007; Zhao J et al. 2012; Abotaleb et al. 2018; Chen et al. 2019; Farhadi et al. 2019) . A common flavanone, farrerol, that is isolated from the traditional Chinese herb 'Man-shan-hong' [the dried leaves of Rhododendron dauricum L. (Ericaceae)] has phlegm-reducing and cough-relieving properties, and is thus widely used in China for treating bronchitis and asthma Liu et al. 2016) . However, to overcome its poor extraction yield on extraction from natural resources, farrerol and its derivatives have been successfully synthesised using multiple chemical methods to investigate their novel pharmacological properties (Shi et al. 2010 (Shi et al. , 2011 Zhang et al. 2019) . Consequently, research on farrerol in the field of medicine has progressed rapidly in recent years. Moreover, farrerol enhances in-frame integration of exogenous donor DNA and has the ability to efficiently generate knock-in mice with germline transmission capacity (Zhang, Murugesan, et al. 2020) . Consequently, research on farrerol in the field of medicine has progressed rapidly in recent years with many novel molecular mechanisms having been characterized.

Many studies on farrerol have investigated its biological activities; however, the different pharmacological activities of farrerol and its associated molecular mechanisms remain unclear. Therefore, we have systematically reviewed the pharmacological properties and underlying mechanisms of farrerol and have identified challenges, hoping to provide directions and ideas for future research. antioxidant, vasoactive, antitumor, and antibacterial effects of farrerol, published from 2011 until the end of May 2021. The following key words were used: 'farrerol,' 'flavanone, ' 'antiinflammatory,' 'antioxidant,' 'vasoactive,' 'antitumor,' 'antimicrobial,' and 'molecular mechanisms'.

Inflammation plays a vital role in the body's defense response, limiting inflammatory cytokines and facilitating the repair of damaged parts of the body (Ray and Rai 2017; Luscher 2019) . In contrast, excessive inflammatory response can cause degeneration and necrosis of the cells and tissues (Afonina et al. 2017; Kearney & Martin 2017; Abplanalp et al. 2020) . For a long time, steroids and cyclooxygenase inhibitors have been used to treat diseases associated with inflammatory response, but their relative limitations have made developing new replacement drugs a priority (Ci et al. 2012; Zarrin et al. 2021) .

Flavonoids are a large group of polyphenolic natural products that are widely distributed in higher plants and are well known to have a variety of therapeutic activities (Deng et al. 2021; Zhan et al. 2021) . Some flavonoids isolated from Rhododendron roots have potential anti-inflammatory agents, based on the results of dose-dependent inhibition of the expressions of inflammatory mediators (Mulvihill et al. 2016; Rengasamy et al. 2019; Zhang et al. 2021) . Farrerol, a flavonoid extracted initially from Rhododendron, is a traditional Chinese herbal medicine (Zhao et al. 2010; Fu et al. 2012) . Although the anti-inflammatory mechanism of farrerol has not been clearly elucidated so far, it has therapeutic advantages in inflammatory diseases.

In vivo experiments, the anti-inflammatory activity of farrerol was reported by Xin Ran (2018) and Xiong (2013) . Ci et al. (2012) found that farrerol markedly alleviated the allergic airway inflammation in an allergic asthma model, and its mechanism of action was related to the activation of phosphorylation of Akt and nuclear factor (NF-jB) subunit p65. Ci et al. (2012) proved that farrerol could exert anti-inflammatory effects in the treatment of asthma by inhibiting the PI3K and NF-jB signalling pathways. Ci et al. (2012) found that farrerol significantly inhibited T cell-mediated delayed-type hypersensitivity in female BALB/c mice. The mechanism of action may be related to the downregulation of NF-jB activation and nuclear factor of activated T cell 2 signal transduction pathways (Taylor et al. 2013) . Additionally, in 2018, Ran et al. (2018) reported that farrerol administration significantly improved the weight changes, clinical scores, colonic length and intestinal epithelial barrier damage and markedly decreased inflammatory cytokine production in TNBS-induced mice. This anti-inflammatory effect was mediated by decreasing the production of interlekin (IL)-1b, IL-6, and tumour necrotic factor (TNF)-a and increasing the expression of claudin-1, zonula occludens 1 (ZO-1), and occludin (Ran et al. 2018) . Li et al. (2018) reported that farrerol could ameliorate pathological damage in the mammary glands; attenuate myeloperoxidase (MPO) activity; and inhibit the production of proinflammatory mediators and phosphorylation of AKT, NF-jB p65, p38, and ERK1/2 in lipopolysaccharide (LPS)-induced mouse mastitis.

In vitro experiments, Ran et al. (2018) also revealed that farrerol remarkably decreased the production of inflammatory mediators, including IL-1b, IL-6, and TNF-a, and the expression of COX-2 and iNOS in LPS-induced RAW264.7 cells by suppressing AKT, ERK1/2, JNK1/2, and NF-jB p65 phosphorylation. Similarly, Li et al. (2018) confirmed that farrerol could inhibited LPS-induced inflammatory response and the related signalling pathways in mouse mammary epithelial cells (mMECs). Zhang et al. (2015) found that farrerol exhibited antiinflammatory effects by preventing IL-6b-induced P13K/Akt phosphorylation and significantly inhibiting IL-6b-induced NO and PGE2 production and expression of iNOS and COX-2 in chondrocytes. Wang et al. (2016) demonstrated that farrerol suppressed LPS-induced IL-6 and IL-8 expression, both at the mRNA and protein levels. Farrerol significantly inhibited the phosphorylation of PI3K and AKT, thus attenuating IL-6 and IL-8 production and inhibiting NF-jB P65 phosphorylation and IjBa degradation in LPS-stimulated human gingival fibroblasts. Moreover, found that farrerol attenuated Ab-induced inflammation in BV-2 cells by enhancing the activation of the Nrf2/Keap1 pathway. In 2019, Cui et al. reported that farrerol could inhibit the TLR4 signalling pathway to alleviate MPP þ -induced inflammatory response in BV-2 cells and suppress proinflammatory mediators' production (mediators, such as iNOS, COX-2, IL-1b, IL-6, TNF-a, NO, and PGE2) in LPStreated BV-2 cells. Farrerol inhibits NF-jB p65 and AKT phosphorylation, but it has no significant effect on MAPKs phosphorylation (ERK1/2, p38, and JNK1/2) Li Y et al. 2019) . The results are shown in Table 1 and Figure 1 .

Oxidative stress is considered to be involved in the pathogenesis of various diseases and is defined as an imbalance between the production of free radicals and reactive metabolites (Takahashi et al. 2018; Hayes et al. 2020; Mendiola et al. 2020) . Normal amounts of reactive oxygen species (ROS) can produce beneficial physiological effects, including liver detoxification and cell division regulation. However, surplus free radicals have adverse effects on the body, such as inducing DNA damage and affecting the DNA damage response (DDR) (Ardolino et al. 2011; Panikkanvalappil et al. 2013; Srinivas et al. 2019) . Under oxidative stress, high levels of ROS contribute to several chronic human diseases, such as cardiovascular diseases and rheumatism (Blanco et al. 2018; Gong et al. 2018; Chen et al. 2019; . Ci et al. published four articles between 2015 and 2020 on the antioxidant effects of farrerol, emphasising on the following: First, farrerol induced Hnti-oxidant O-1 protein expression in a time-and dose-dependent manner in RAW 264.7 macrophage cells, suggesting that its antioxidative property accounts for the induction of Heme Oxygenase-1 (HO-1) expression. In addition, farrerol attenuated the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38) and the activation of phosphorylated nuclear factor-jB (p-NF-jB) and nucleotidebinding domain (NOD)-like receptor protein 3 (NLRP3) (Ci et al. 2015) . Second, farrerol could protect against acetaminophen-induced hepatotoxicity, which may be related to the activation of Nrf2 . Third, farrerol improved cisplatin-induced nephrotoxicity by ameliorating oxidative and activating nuclear factor erythroid 2-related factor 2 (Nrf2). Farrerol effectively activated Nrf2 and subsequently increased the expression of Nrf2-targeted antioxidant enzymes, including HO-1 and NAD(P)H quinone oxidoreductase-1 (NQO1), but inhibited Kelch-like ECH-associated protein 1 (Keap1) and NADPH oxidase type 4 (NOX4) (Ma et al. 2019) . Finally, farrerol protected the retinal pigment epithelium cells from H 2 O 2 -associated oxidation by inhibiting ROS generation. Farrerol could ameliorate H 2 O 2 -induced cell death by activating Akt and MAPK and consequently increasing Nrf2/HO-1 generation in an adult retinal pigment epithelial cell line . Farrerol shows promise in treating or preventing age-related macular degeneration, acute liver injury, acute kidney injury, and oxidative stress-related diseases.

Nrf2 regulates the basal and inducible expression of antioxidant genes and other cytoprotective phase II detoxifying enzymes as key transcription factors (Eberhardt et al. 2012; Silva-Palacios et al. 2018; Chen Y et al. 2020 ). In addition, Cui, Zhang, et al. (2019) also revealed that the effect of farrerol on oxidative damage was mediated by the Nrf2/Keap1 signalling pathway. Chen et al. (2020) suggested that treatment with farrerol dose-dependently suppressed HG-induced mesangial cell damage through the Nox4/ROS/ERK/TGF-b signalling pathway. Besides, there is a new direction for the TGF-b1/Smad2 pathway to act as one of the downstream ERK1/2 pathways involved in farrerolmediated anti-oxidative effects on HG-induced mesangial cell injury . Consistent with previous studies, our research team observed that farrerol exhibited protective effects on H 2 O 2 -induced EA.hy926 cells by enhancing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and inhibiting the elevation of intracellular MDA and ROS. In an ongoing study, farrerol could induce HO-1 and NQO1 expression, which are considered to be typical antioxidant enzymes against oxidative stress. The underlying mechanism is to specifically target GSK-3b and further activate the Nrf2-ARE signalling pathway (Yan et al. 2020) . The sections are summarised in Table 1 and Figure 2 .

Taken together, since HO-1, Nrf2, and NF-jB play a critical role in the antioxidant effect of farrerol, their specific and indepth mechanisms require further investigation. Furthermore, farrerol may serve as a potential candidate for the treatment of cardiovascular diseases.

Vascular diseases are the most common cause of death worldwide (Huynh 2017; Mencke et al. 2017) . Commonly associated pathological mechanisms include endothelial dysfunction, vascular smooth muscle cell proliferation, and metal matrix protein deposition (Tousoulis et al. 2014; Uhrin et al. 2018; Carmo et al. 2019; Yang et al. 2019) . Our team has conducted extensive work on the vasoactive mechanisms of farrerol and published eight papers. The main findings are as follows in Table 2 .

In 2013, Li et al. (2013) evaluated the vasoactive effect of farrerol on the human endothelial EA.hy926 cells to prevent or treat for cardiovascular diseases, such as atherosclerosis, hypertension, and heart failure. The underlying mechanism may be related to the regulation of intracellular MDA and ROS levels; the expression of Bax, Bcl-2, cleaved caspase-3; and the phosphorylation of p38. Vascular endothelial permeability plays an important physiological role. Endothelial dysfunction is considered to be relevant to the pathogenesis of many cardiovascular diseases (Haybar et al. 2019) . When there is a loss of membraneassociated adhesion molecules, vascular permeability increases excessively, adversely affecting blood vessels and organisms (Fang et al. 2018) . Thus, in 2014, we investigated the effect of farrerol on the maintenance of vascular integrity. As part of our ongoing research, our results indicate that the regulation of occludin expression by farrerol in H 2 O 2 -induced EA.hy926 cells in a dose-dependent manner may be associated with the inhibition of ERK1/2 activation ). Qin, et al. (2014) demonstrated the vasodilatory effect of farrerol in rat aortic vascular smooth muscle cells (VSMCs) for the first time; a possible mechanism is blocking Ca 2þ release from the sarcoplasmic reticulum by the ryanodine receptors than by endothelium-derived vasodilator factors. Subsequently, in 2015, our research team reported that farrerol could attenuate the aortic lesions in spontaneously hypertensive rats (SHRs) by upregulating eNOS and decrease in NAD(P)H oxidase activity, which was also mediated by increased expression of eNOS and reduced p22 phox expression. Moreover, the results showed that farrerol partially reversed the morphological remodelling of the SHR aorta in media thickness, wall area, media-lumen ratio, and nuclei size . In 2017, our research team reported the discovery of ADRA1, a novel potential target gene for farrerol-treated SHRs through the gene expression profiling (Qin et al. 2018) . In 2019, our team further verified the function of this gene in the contraction and relaxation of VSMCs. The experimental evidence suggested that farrerol could attenuate the rat aortic lesions, which involved inhibiting of the increased mRNA and protein expression of MLCK and SM22a and reducting of Ang II-induced increase in phosphorylation levels of MYPT1 and MLC by activating the a 1D -adrenoceptor gene (Qin et al. 2019) . In 2020, our research team indicated that farrerol could maintain the contractile phenotype of VSMCs partly by inactivating the ERK1/2 and p38 MAPK signalling pathways. Hence, we established that farrerol could prevent and treat vascular diseases as a natural product. At present, concerted efforts are being made to investigate the vasoactive effects of farrerol on vascular-related diseases.

In addition, we found that two other units studied the vasoactivity of farrerol. Li et al. (2011) showed that farrerol could inhibit FBS-induced VSMC proliferation as a functional phytoestrogen, which may be useful in preventing or treating cardiovascular diseases arising from abnormal VSMC proliferation. suggested that farrerol could inhibit angiogenesis through the downregulation of the AKT/mTOR, ERK, and Jak2/ Stat3 signalling pathways. In summary, we will provide new ideas by summarizing the reported studies on the vasoactivity of farrerol for further research. 

Over the past few centuries, cancer incidence has continuously increased and become the primary cause of morbidity and mortality worldwide (Mi Ah et al. 2019; Wang et al. 2020) . At present, the treatment modalities for cancer are divided into surgery, radiation therapy, and systemic treatment, including chemotherapy, targeted therapy, hormonal therapy, and immunotherapy (Miller et al. 2019; Ward et al. 2020 ). However, different therapies have their limitations and have severe adverse effect, such as chemotherapy-induced vascular toxicity (Ben-Aharon et al. 2012 Gupta et al. 2016) . Farrerol has the potential to treat tumours. Liu et al. (2016) observed selective cytotoxicity of farrerol against SGC7901 cells, but not HUVECs. Furthermore, their results showed that farrerol could inhibit cancer cell proliferation though G 0 /G 1 -phase cell cycle arrest mediated by sustained ERK activation. Furthermore, farrerol modulated the expression of EMT proteins to suppress the metastatic potential of lung squamous cell carcinoma , as shown in Table 2 .

The death toll due to antimicrobial resistance (AMR) may increase to 10 million globally by 2050, making the situation quite serious (Ghosh et al. 2019; Sanchez-Buso et al. 2021) . Antibiotics have long been widely used and have good effects. However, the rapid changes in antimicrobial resistance have made it necessary for us to look for better options (Revie et al. 2018) . Therefore, there is a pressing need to develop novel and potent antimicrobial agents to treat life-threatening infections.

Flavonoids, especially flavanones, have been considered as potential candidates for developing antibacterial and antifungal agents. Farrerol decreased the production of a-toxin by methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus. These experiments suggested that farrerol may inhibit the production of other exotoxin genes, including enterotoxins and toxic shock syndrome toxin 1, and enhance the expression of surface-related virulence factors (Qiu et al. 2011) .

Previous studies demonstrated that farrerol (4-16 lg/mL) reduced the internalization of S. aureus into bMEC ). Farrerol downregulated the mRNA expression of tracheal antimicrobial peptide (TAP) and bovine neutrophilb-defensin5 (BNBD5) in bovine mammary epithelial cells (bMECs) infected with S. aureus. In addition, farrerol treatment decreased nitric oxide (NO) production by bMECs after S. aureus stimulation. Farrerol suppressed S. aureus-induced NF-jB activation in bMECs but had no effect on bMEC viability. These results suggest that farrerol modulates the expression of TAP and BNBD5 gene in mammary glands, enhances bMECs defense against S. aureus infection and may be useful for protection against bovine mastitis.

In addition to its antibacterial effect, the antifungal effect of farrerol has also been investigated (Meragelman et al. 2005) .

Pharmacologists have previously demonstrated that farrerol can restrict the growth of certain important plant pathogenic fungi in vitro . However, in a panel of 14 strains of Candida, farrerol was inactive against all test strains at the highest concentration tested (32 mg/mL) (Meragelman et al. 2005) . Moreover, farrerol also showed moderate antibacterial activity against B. cereus , as shown in Table 2 .

This review discusses the anti-inflammatory, antioxidant, vasoactive, antitumor, and antimicrobial activities of farrerol and its underlying molecular mechanisms, as shown by in vitro and in vivo studies.

Flavonoids, a major group, have been continuously explored and applied in therapeutics. In the last few decades, as we stated above, the pharmacological properties of farrerol have been constantly discovered, including anti-inflammatory, antioxidant, vasoactive, antitumor, antibacterial effects, etc. (Androutsopoulos et al. 2010; Maleki et al. 2019; Nagula and Wairkar 2019; Zeng et al. 2019) . Their corresponding mechanisms are mainly focussed on the NF-jB, AKT, p38, ERK, and Nrf2-ARE signalling pathways. In 2020, a novel application of farrerol was first reported as a potentiator of CRISPR/Cas9-mediated genome editing through the high-throughput small-molecule screen identification . In this study, farrerol was shown to effectively facilitate precise targeted integration in human cells, mouse cells, and mouse embryos at multiple genomic loci. In addition, treatment of cells with farrerol did not have any obvious negative effects on genomic stability. Moreover, farrerol significantly improved the knock-in efficiency in blastocysts, and the subsequently generated knock-in mice retained the capacity for germline transmission. Therefore, in view of its various characteristics, farrerol has great potential to address a wide range of current and future medical problems. Our review of the pharmacological activities and mechanisms associated with farrerol may provide new ideas for its use, especially in the context of the global COVID-19 epidemic, and help explore whether farrerol can enhance the immunity of the population against this disease (Riva et al. 2020; Meganck and Baric 2021) . This review brings together the most recent studies in the field of farrerol and provides clues and basis for further research.

No conflict of interest was reported by the author(s). 

Flavonoids in cancer and apoptosis

Association of clonal hematopoiesis of indeterminate potential with inflammatory gene expression in patients with severe degenerative aortic valve stenosis or chronic postischemic heart failure

Limiting inflammation-the negative regulation of NF-jB and the NLRP3 inflammasome

Dietary flavonoids in cancer therapy and prevention: substrates and inhibitors of cytochrome P450 CYP1 enzymes

DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction

Long-term follow-up of chemotherapy-induced ovarian failure in young breast cancer patients: the role of vascular toxicity

Chemotherapy-induced ovarian failure as a prototype for acute vascular toxicity

Mitochondrial DNA variation and the pathogenesis of osteoarthritis phenotypes

Expansive vascular remodeling and increased vascular calcification response to cholecalciferol in a murine model of obesity and insulin resistance

Antioxidant and anti-inflammatory properties of flavonoids from lotus plumule

Farrerol alleviates high glucose-induced renal mesangial cell injury through the ROS/Nox4/ERK1/2 pathway

2020. c-Jun NH2-terminal protein kinase phosphorylates the Nrf2-ECH homology 6 domain of nuclear factor erythroid 2-related factor 2 and downregulates cytoprotective genes in acetaminophen-induced liver injury in mice

Different effects of farrerol on an OVA-induced allergic asthma and LPS-induced acute lung injury

The antioxidative potential of farrerol occurs via the activation of Nrf2 mediated HO-1 signaling in RAW 264.7 cells

Farrerol attenuates MPPþ-induced inflammatory response by TLR4 signaling in a microglia cell line

Farrerol attenuates b-amyloidinduced oxidative stress and inflammation through Nrf2/Keap1 pathway in a microglia cell line

Farrerol inhibited angiogenesis through Akt/mTOR, Erk and Jak2/Stat3 signal pathway

The role and mechanism of Citrus flavonoids in cardiovascular diseases prevention and treatment

The talar axis-first metatarsal base angle in CVT treatment: a comparison of idiopathic and non-idiopathic cases treated with the Dobbs method

Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins

Antibacterial activity of flavonoids and their structure-activity relationship: an update review

Far infrared-assisted extraction followed by MEKC for the simultaneous determination of flavones and phenolic acids in the leaves of Rhododendron mucronulatum Turcz

Alternatives to conventional antibiotics in the era of antimicrobial resistance

MicroRNAs regulating reactive oxygen species in cardiovascular diseases

Risk of vascular toxicity with platinum based chemotherapy in elderly patients with bladder cancer

Endothelial cells: from dysfunction mechanism to pharmacological effect in cardiovascular disease

Oxidative stress in cancer

Vascular diseases: shear-thinning biomaterial for endovascular embolization

An inflammatory perspective on necroptosis

Farrerol overcomes the invasiveness of lung squamous cell carcinoma cells by regulating the expression of inducers of epithelial mesenchymal transition

Involvement of estrogen receptor-b in farrerol inhibition of rat thoracic aorta vascular smooth muscle cell proliferation

Protective effects of farrerol against hydrogen-peroxide-induced apoptosis in human endothelium-derived EA.hy926 cells

Farrerol regulates occludin expression in hydrogen peroxide-induced EA.hy926 cells by modulating ERK1/2 activity

Farrerol relieve lipopolysaccharide (LPS)-induced mastitis by inhibiting AKT/NF-B p65, ERK1/2 and P38 signaling pathway

Farrerol protects dopaminergic neurons in a rat model of lipopolysaccharide-induced Parkinson's disease by suppressing the activation of the AKT and NF-kappa B signaling pathways

Activity of flavanones isolated from Rhododendron hainanense against plant pathogenic fungi

Sustained ERK activation-mediated proliferation inhibition of farrerol on human gastric carcinoma cell line by G0/G1-phase cell-cycle arrest

Farrerol maintains the contractile phenotype of VSMCs via inactivating the extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinase signaling

Cardio-oncology: low-grade inflammation as a common pathway of cancer and cardiovascular disease

Farrerol attenuates cisplatin-induced nephrotoxicity by inhibiting the reactive oxygen species-mediated oxidation, inflammation, and apoptotic signaling pathways

Farrerol enhances Nrf2-mediated defense mechanisms against hydrogen peroxide-induced oxidative damage in human retinal pigment epithelial cells by activating Akt and MAPK

Anti-inflammatory effects of flavonoids

Developing therapeutic approaches for twentyfirst-century emerging infectious viral diseases

The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology

Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation

Antifungal flavonoids from Hildegardia barteri

Reduction of red and processed meat intake and cancer mortality and incidence: a systematic review and meta-analysis of cohort studies

Cancer treatment and survivorship statistics

Citrus flavonoids as regulators of lipoprotein metabolism and atherosclerosis

Recent advances in topical delivery of flavonoids: a review

Surface-enhanced Raman spectroscopy for real-time monitoring of reactive oxygen species-induced DNA damage and its prevention by platinum nanoparticles

Farrerol can attenuate the aortic lesion in spontaneously hypertensive rats via the upregulation of eNOS and reduction of NAD(P)H oxidase activity

Farrerol modulates aorta gene expression profile in spontaneously hypertensive rats

a1D-adrenoceptor involves the relaxation effect of farrerol in rat aortic vascular smooth muscle cells

Relaxation of rat aorta by farrerol correlates with potency to reduce intracellular calcium of VSMCs

Subinhibitory concentrations of farrerol reduce a-toxin expression in Staphylococcus aureus

Farrerol ameliorates TNBS-induced colonic inflammation by inhibiting ERK1/2, JNK1/2, and NF-kappa B signaling pathway

Lysophosphatidic acid converts monocytes into macrophages in both mice and humans

The role of flavonoids in autoimmune diseases: Therapeutic updates

Antifungal drug resistance: evolution, mechanisms and impact

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

A community-driven resource for genomic epidemiology and antimicrobial resistance prediction of Neisseria gonorrhoeae at Pathogenwatch

Synthesis and biological activity of flavanone derivatives

Synthesis of new flavanone derivatives of farrerol and preliminary SAR studies on anti-VSMCs vegetation activity

Nrf2: molecular and epigenetic regulation during aging

ROS and the DNA damage response in cancer

Cancer cells coopt the neuronal redox-sensing channel TRPA1 to promote oxidativestress tolerance

Brief report: do the nature of communication impairments in autism spectrum disorders relate to the broader autism phenotype in parents?

Endothelial dysfunction in conduit arteries and in microcirculation. Novel therapeutic approaches

Vascular smooth muscle cell proliferation as a therapeutic target. Part 2: Natural products inhibiting proliferation

Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies

Farrerol ameliorates APAPinduced hepatotoxicity via activation of Nrf2 and autophagy

Farrerol inhibits IL-6 and IL-8 production in LPS-stimulated human gingival fibroblasts by suppressing PI3K/AKT/NF-jB signaling pathway

The role and contribution of treatment and imaging modalities in global cervical cancer management: survival estimates from a simulation-based analysis

Investigation of effects of farrerol on suppression of murine T lymphocyte activation in vitro and in vivo

Farrerol directly targets GSK-3b to activate Nrf2-ARE pathway and protect EA.hy926 Cells against oxidative stress-induced injuries

Effects of spraying salicylic acid and potassium dihydrogen phosphate on physiological cha-racteristics and grain yield of single-season rice

Ying Yong Sheng Tai Xue Bao

Farrerol regulates antimicrobial peptide expression and reduces Staphylococcus aureus internalization into bovine mammary epithelial cells

Kinase inhibition in autoimmunity and inflammation

Protective roles of flavonoids and flavonoidrich plant extracts against urolithiasis: a review

Natural stereoisomeric flavonoids exhibit different disruptive effects and the mechanism of action on Ab42 protofibril

Anti-inflammatory effects of farrerol on IL-1b-stimulated human osteoarthritis chondrocytes

A high-throughput small molecule screen identifies farrerol as a potentiator of CRISPR/Cas9-mediated genome editing

Efficient biosynthesis, analysis, solubility and anti-bacterial activities of succinylglycosylated naringenin

NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets

Polyphenol-based nanomedicine evokes immune activation for combination cancer treatment

Isolation, modification and cytotoxic evaluation of flavonoids from Rhododendron hainanense

Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloidinduced cell death