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Heshouwu ( Polygonum multiflorum Thunb.) has been a common Chinese medicine and a folk Taoist medicine for over a thousand years. There are two drug forms, Shengshouwu ( Polygoni Multiflori Radix ) and Zhiheshouwu ( Polygoni Multiflori Radix Prapaerata ) in the Chinese Pharmacopoeia. In this review, we retrieved articles with such keywords as Heshouwu , liver protection and liver toxicity in the databases of PubMed and the China National Knowledge Infrastructure (CNKI). Hepatoprotection and hepatotoxicity of Shengshouwu and Zhiheshouwu in vitro and in vivo , and their clinical settings and adverse drug reactions (ADR) were summarized, analyzed and critically reviewed. In bench research, both drug forms had effects against nonalcoholic fatty liver disease, oxidation, fibrosis, cirrhosis, and liver cancer. Clinically, Heshouwu was used for treating fatty liver disease (FLD), hyperlipidemia, cirrhosis and hepatitis B. In contrast, both drug forms could lead to drug-induced liver injury and even death in vitro , in vivo and in clinical settings. In addition, the active components of both drug forms had hepatic benefits and toxicity in interaction with emodin, physcion, and probably 2,3,5,4′-tetrahydroxy-stilbene-2-O-beta- d -glucoside (TSG). In conclusion, Heshouwu exhibited both hepatoprotection and hepatotoxicity. It is essential to evaluate the advantages and disadvantages when Heshouwu is in clinical use. [ABSTRACT FROM AUTHOR]

Background and Purpose: Thrombosis is a major cause of morbidity and mortality worldwide. Platelet activation by exposed collagen through glycoprotein VI (GPVI) and formation of neutrophil extracellular traps (NETs) are critical pathogenic factors for arterial and venous thrombosis. Both events are regulated by spleen tyrosine kinase (Syk)‐mediated signalling events. Asebogenin is a dihydrochalcone whose pharmacological effects remain largely unknown. This study aims to investigate the antithrombotic effects of asebogenin and the underlying molecular mechanisms. Experimental Approach: Platelet aggregation was assessed using an aggregometer. Platelet P‐selectin exposure, integrin activation and calcium mobilization were determined by flow cytometry. NETs formation was assessed by SYTOX Green staining and immunohistochemistry. Quantitative phosphoproteomics, microscale thermophoresis, in vitro kinase assay and molecular docking combined with dynamics simulation were performed to characterize the targets of asebogenin. The in vivo effects of asebogenin on arterial thrombosis were investigated using FeCl3‐induced and laser‐induced injury models, whereas those of venous thrombosis were induced by stenosis of the inferior vena cava. Key Results: Asebogenin inhibited a series of GPVI‐induced platelet responses and suppressed NETs formation induced by proinflammatory stimuli. Mechanistically, asebogenin directly interfered with the phosphorylation of Syk at Tyr525/526, which is important for its activation. Further, asebogenin suppressed arterial thrombosis demonstrated by decreased platelet accumulation and fibrin generation and attenuated venous thrombosis determined by reduced neutrophil accumulation and NETs formation, without increasing bleeding risk. Conclusion and Implications: Asebogenin exhibits potent antithrombotic effects by targeting Syk and is a potential lead compound for the development of efficient and safe antithrombotic agents. [ABSTRACT FROM AUTHOR]

Background and Purpose: Considerable evidence indicates that the beta(2)-adrenoceptor agonist clenbuterol decreases apoptosis in a rodent model of ischaemic cardiomyopathy. In this study, we investigated the effects of clenbuterol on infarct size caused by myocardial ischaemia/reperfusion (I/R) in anaesthetized rats.Experimental Approach: Rats were randomly assigned to the following groups: (i) sham (ii) I/R (iii) clenbuterol + I/R (iv) ICI 118551 + clenbuterol + I/R (v) metoprolol + clenbuterol + I/R (vi) metoprolol + I/R (vii) pertussis toxin + clenbuterol + I/R. Under anaesthesia, left anterior descending coronary artery was occluded for 30 min followed by reperfusion for 2 h.Key Results: Compared with the control I/R group,the clenbuterol (0.5 mg.kg(-1), i.p.) group had reduced infarct size, improved diastolic function and sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity, increased superoxide dismutase activity, and decreased malondialdehyde (MDA) level and LDH, CK release. Clenbuterol increased the phosphorylation of ERK1/2, which resulted in inhibition of myocardial apoptosis as indicated by the reduction of terminal deoxynucleotidyltransferase end labelling-positive staining, Bax/Bcl-2 mRNA and caspase-3 protein expression. The G(i)-protein inhibitor pertussis toxin blocked the clenbuterol-induced improvement in cardiac function and infarct size. Pretreatment with ICI 118551(a selective beta(2)-adrenoceptor antagonist) inhibited the effects of clenbuterol mentioned above. The beta(1)-adrenoceptor agonist metoprolol had similar effects to clenbuterol but failed to reduce MDA and improve SERCA activity. When administered together, metoprolol and clenbuterol did not induce synergistic effects.Conclusions and Implications: Clenbuterol pretreatment provides significant cardioprotection against ischaemia/reperfusion injury and this is mediated by the beta(2)-adrenoceptor-G(i)-protein signalling. A combination of the beta(2)-adrenoceptor agonist clenbuterol and the beta(1)-antagonist metoprolol did not lead to a synergistic anti-apoptotic effect. [ABSTRACT FROM AUTHOR]

Cervical cancer is the second most common cancer in women. Despite advances in cervical cancer therapy, tumor recurrence and metastasis remain the leading causes of mortality. High expression of BMI1 is significantly associated with poor tumor differentiation, high clinical grade, and poor prognosis of cervical cancer, and is an independent prognostic factor in cervical carcinoma. Alantolactone (AL), a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities. In this paper, we investigated the mechanism of AL in reducing the proliferation, migration, and invasion of HeLa and SiHa cervical cancer cells as well as its promotion of mitochondrial damage and autophagy. BMI1 silencing decreased epithelial-mesenchymal transformation-associated proteins and increased autophagy-associated proteins in HeLa cells. These effects were reversed by overexpression of BMI1 in HeLa cells. Thus, BMI1 expression is positively correlated with invasion and negatively correlated with autophagy in HeLa cells. Importantly, AL decreased the weight, volume, and BMI1 expression in HeLa xenograft tumors. Furthermore, the structure of BMI1 and target interaction of AL were virtually screened using the molecular docking program Autodock Vina; AL decreased the expression of N-cadherin, vimentin, and P62 and increased the expression of LC3B and Beclin-1 in xenograft tumors. Finally, expression of BMI1 increased the phosphorylation of STAT3, which is important for cell proliferation, survival, migration, and invasion. Therefore, we suggest that AL plays a pivotal role in inhibiting BMI1 in the tumorigenesis of cervical cancer and is a potential therapeutic agent for cervical cancer. [ABSTRACT FROM AUTHOR]

Aberrant signal transducer and activator of transcription 3 (STAT3) signaling promotes the initiation and progression of cancer in humans by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. The role of resveratrol（RES）in inhibiting the STAT3 signaling pathway in vivo, particularly in cervical cancer is still unknown. This study aims to investigate the role of STAT3 and its phosphorylation in RES‐mediated suppression of cervical cancer. The effects of RES on cervical cancer were determined by examining tumor tissues, their histological changes, and the volume and weight of tumor tissues grown from HeLa cells injected in female athymic BALB/C nude mice. The structure and target interaction of RES were virtually screened using the molecular docking program Autodock Vina. The status of phosphorylated STAT3, protein levels of epithelial‐mesenchymal transition molecular markers and extracellular matrix degradation enzymes were determined through Western blot. We demonstrated that RES could suppress the proliferation and metastatic potential of cervical cancer cells by inactivating phosphorylation of STAT3 at Tyr705 but not Ser727. This effect was intensified by inhibition of the STAT3 signal pathway. [ABSTRACT FROM AUTHOR]

Objectives: Chemoresistance induced by cisplatin has become the major impediment to lung cancer chemotherapy. This study explored the potential chemoresistant genes and underlying mechanisms of chemoresistance in NSCLC. Materials and methods: Gene expression profile was integrated with DNA methylation profile to screen the candidate chemoresistant genes. Bioinformatic analysis and immunohistochemistry were used to analyse the association of a candidate gene with the characteristics of NSCLC patients. Recombinant lentivirus vectors were utilized to overexpress or silence candidate gene. Microarrays and immunoblotting were applied to explore the downstream targets of candidate gene. Xenograft models were established to validate the findings in vitro. Results: An increased ZNF300 expression was detected in three chemoresistant cell lines of NSCLC, and the higher expression of ZNF300 was associated with poor OS of NSCLC patients. Cells with upregulated ZNF300 presented chemoresistance and enhanced aggressive growth compared to cells with downregulated ZNF300. ZNF300 inhibited MAPK/ERK pathways and activated CDK1 through inhibiting WEE1 and MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. ICA and ATRA improved the anti‐tumour effect of cisplatin on chemoresistant cells by inducing differentiation. Conclusions: ZNF300 promotes chemoresistance and aggressive behaviour of NSCLC through regulation of proliferation and differentiation by downregulating MAPK/ERK pathways and regulation of slow‐cycling phenotype via activating CDK1 by inhibiting WEE1/MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. Cisplatin, combined with ATRA and ICA, might be beneficial in chemoresistant cases of NSCLC. [ABSTRACT FROM AUTHOR]

The study determined the chemical constituents and anti-inflammatory effects of leaf oil from Cinnamomum subavenium (CS-LO) that has been used in folk medicine to treat various symptoms including inflammation. The anti-inflammatory effects of the oil were evaluated by LPS-stimulated RAW264.7 cells and the Carr-induced hind mouse paw edema model, respectively. In vitro, nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α, IL-6, and IL-1β were significantly decreased by CS-LO, and the expression of nuclear factor-κB (NF-κB) protein was blocked as well. In in vivo, the malondialdehyde (MDA) and paw edema levels were decreased by CS-LO, and the same result came up on the NO and tumor necrosis factor (TNF-a) of serum at the 5th h after Carr injection. In addition, iNOS and COX-2 immunoreactive cells of the paw tissue were decreased significantly by CS-LO (200 mg/kg) in histological examination. The present findings indicated that CS-LO have anti-inflammatory properties, and the effects might be caused through inhibiting iNOS, COX-2, TNF-α, IL-1β, and IL-6 expression via affecting NF-κB pathway, which will provide a power scientific basis for CS-LO to be used as the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the major incidence and one of the most life-threatening cancer. How to conquer HCC is a worldwide issue for patients. Zhiheshouwu ( Polygoni multiflori Radix Praeparata) is a Chinese medicinal herb exhibiting both lowering lipid and inhibiting cancer cells. However, it remains a matter if its inhibiting cancer cells is related to its lowering lipid. In this study, we investigate the effects of Zhiheshouwu ethanolic extract (HSWE) on apoptosis and the underlying mechanisms in Bel-7402 cells. The results showed that HSWE inhibited the proliferation with an increased level of ALT and AST in Bel-7402 cells. The decreased mitochondrial membrane potential (ΔΨm) was observed in HSWE-treated Bel-7402 cells. The flow cytometry results showed that HSWE triggered apoptosis. Since mitochondrial injury is characterized as intrinsic apoptotic cell death, these data indicated that HSWE may induce intrinsic apoptosis in Bel-7402 cells. In addition, HSWE decreased the production of unsaturated fatty acids, and inhibited the mRNA and protein of SCD1 and its up-stream factor, sterol-regulatory element binding proteins 1 (SREBP1), a master transcriptional regulator of lipogenic gene. Taken together, these data suggest that HSWE induces an intrinsic apoptosis, and reduced unsaturated fatty acids by blocking SREBP1 in hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]

Skeletal muscle serving as the major organ is responsible for energy expenditure and exercise endurance, which directly influence cardiometabolic risk factors. Transient receptor potential melastatin 8 (TRPM8), a Ca 2 + -permeable non-selective cation channel, plays vital roles in the regulation of various cellular functions. It has been reported that TRPM8 activation enhanced the energy metabolism of adipocytes. However, the involvement of TRPM8 in the energy metabolism of skeletal muscle remains unexplored. Our data revealed that TRPM8 was expressed in cultured C2C12 myocytes. Menthol treatment increased uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) expression in C2C12 myotubes through TRPM8 activation. Moreover, dietary menthol upregulated the expression of UCP1 and PGC1α in skeletal muscle of mice. In addition, dietary menthol enhanced exercise endurance and reduced blood lactic acid and triglycerides through TRPM8 activation. It is concluded that dietary menthol improves energy metabolism and exercise endurance by increasing UCP1 and PGC1α in skeletal muscles, suggesting dietary menthol might be a novel therapeutic approach for cardiometabolic diseases management and prevention. [ABSTRACT FROM AUTHOR]

ELONGATED HYPOCOTYL 5 (HY5), a member of the bZIP gene family, is a positive regulator of the light signaling pathway in Arabidopsis thaliana. Whereas the hy5 mutant exhibits an elongated hypocotyl when grown in the light, the hy5 homolog (hyh) mutant does not. Although the functions of HY5 and HYH in light-mediated seedling development have been revealed, the tissue-specific expression patterns of HY5 and HYH and their interconnected regulation are largely unknown. Here, we report that HY5 regulates HYH expression in roots and contributes to root growth under different light conditions. We generated HY5 and HYH transcriptional and translational fusion reporter lines to investigate their expression patterns. HY5 was constitutively expressed in all root tissues, while HYH was predominantly expressed in root xylem cells. Root growth after a dark-to-light transition was perturbed in the hy5 and hy5hyh mutant lines, but not in the hyh mutant line, indicating that HY5 plays a major role in light-regulated root growth. Light-induced HY5/HYH expression occurred autonomously in roots. HYH expression in roots was decreased in the hy5 mutant, suggesting that HY5 regulates HYH expression. Collectively, these results indicate that an organ-specific HY5-mediated pathway controls root photomorphogenic development independently of light signaling in the shoot. [ABSTRACT FROM AUTHOR]

Arabidopsis thaliana LONG HYPOCOTYL5 (HY5) is a positive regulator of the light signaling pathway. The hy5 mutant has an elongated hypocotyl in all light conditions, whereas the hy5 homolog ( hyh ) mutant has a very weak phenotype, but only in blue light. However, overexpression of HYH rescues the elongated hypocotyl phenotype in the hy5 null mutant. Here, we report the identification of four HYH splicing variants in Arabidopsis . Alternative splicing in the 5′ region of the HYH gene occurred such that the proteins encoded by all four HYH variants retained their bZIP domain. In hypocotyl tissue, transcript levels of HYH.2 , HYH.3 , and HYH.4 were higher than those of HYH.1 . Like HY5 , all HYH variants were induced by light. Functional analysis of the four HYH variants, based on their abilities to complement the hy5 mutant, indicated that they have similar roles in hypocotyl development, and may function redundantly with HY5 . Our results indicate that the bZIP domain in HYH is critical for the function of four variants in the compensation of hy5 mutant in hypocotyl development. Additionally, while HY5/HYH is found in plant species ranging from green algae to flowering plants, the potential alternative splicing events are distinct in different species, with certain HYH variants found with greater frequency in some species than others. [ABSTRACT FROM AUTHOR]

Currently, decision-making regarding biochemical recurrence (BCR) following prostatectomy relies solely on clinical parameters. We therefore attempted to develop an integrated prediction model based on a molecular signature and clinicopathological features, in order to forecast the risk for BCR and guide clinical decision-making for postoperative therapy. Using high-throughput screening and least absolute shrinkage and selection operator (LASSO) in the training set, a novel gene signature for biochemical recurrence-free survival (BCRFS) was established. Validation of the prognostic value was performed in five other independent datasets, including our patient cohort. Multivariate Cox regression analysis was performed to evaluate the importance of risk for BCR. Time-dependent receiver operating characteristic (tROC) was used to evaluate the predictive power. In combination with relevant clinicopathological features, a decision tree was built to improve the risk stratification. The gene signature exhibited a strong capacity for identifying high-risk BCR patients, and multivariate Cox regression analysis demonstrated that the gene signature consistently acted as a risk factor for BCR. The decision tree was successfully able to identify the high-risk subgroup. Overall, the gene signature established in the present study is a powerful predictor and risk factor for BCR after radical prostatectomy. [ABSTRACT FROM AUTHOR]