Anti-cancer effects of naturally derived compounds targeting histone deacetylase 6-related pathways.

Alterations of the epigenetic machinery, affecting multiple biological functions, represent a major hallmark enabling the development of tumors. Among epigenetic regulatory proteins, histone deacetylase (HDAC)6 has emerged as an interesting potential therapeutic target towards a variety of diseases including cancer. Accordingly, this isoenzyme regulates many vital cellular regulatory processes and pathways essential to physiological homeostasis, as well as tumor multistep transformation involving initiation, promotion, progression and metastasis. In this review, we will consequently discuss the critical implications of HDAC6 in distinct mechanisms relevant to physiological and cancerous conditions, as well as the anticancer properties of synthetic, natural and natural-derived compounds through the modulation of HDAC6-related pathways.

Comparative effectiveness of phlegm-heat clearing Chinese medicine injections for AECOPD: A systematic review and network meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingkailing (QKL), Reduning (RDN), Xiyanping (XYP), Tanreqing (TRQ) and Yuxingcao (YXC) injections are all phlegm-heat clearing Chinese medicine (CM) injections composed of the extract from traditional CM materials. Evidence from clinical studies and animal experiments indicates that the above CM injections are effective supplementary therapy for acute exacerbation chronic obstructive pulmonary disease (AECOPD), and clinicians are faced with a difficult choice on the optimal phlegm-heat clearing CM injection for AECOPD. AIM OF THE STUDY: This systematic review and Bayesian network meta-analysis aimed to evaluate the comparative effectiveness of five commonly used phlegm-heat clearing CM injections for COPD. MATERIALS AND METHODS: A pairwise and network meta-analyses were performed to assess the effectiveness of QKL, RDN, TRQ, XYP and YXC on AECOPD. Randomized controlled trials (RCTs) were identified by searching English and Chinese databases. The primary outcome was lung function (forced expiration volume [FEV1] and forced vital capacity [FVC]), blood gas analysis index was secondary outcome measure. Winbugs and Stata 15.0 software were used for data analysis. RESULTS: A total of 57 RCTs were included. The pairwise analyses showed that each of the injections combined with routine treatment were superior to routine treatment alone [FEV1: QKL, MD 0.20, 95% CI (0.06, 0.35); RDN, MD 0.24, 95% CI (0.08, 0.40); TRQ, MD 0.24, 95% CI (0.19, 0.29); XYP, MD 0.26, 95% CI (0.20, 0.32); YXC MD 0.73, 95% CI (0.06, 1.41)]. The network meta-analysis provided the following rank of lung function improvement: FEV1: YXC > TRQ > XYP > RDN > QKL; FVC: YXC > TRQ > QKL > RDN > XYP. RDN and YXC ranked highest in blood gas analysis index. RDN was the highest ranked injection for effectiveness, followed by QKL, TRQ, XYP, then YXC. Most of the injections appeared safe, with severe adverse events rarely reported. CONCLUSION: This study suggests that YXC and TRQ are the most effective therapies in treating AECOPD patients. RDN and YXC are more effective in the alleviation of clinical symptoms. Given that the safety of YXC is controversial, TRQ and RDN may be preferable as phlegm-heat clearing CM injections in the adjuvant treatment of AECOPD.

Prevention of cholesterol gallstone disease by schaftoside in lithogenic diet-induced C57BL/6 mouse model.

Schaftoside (SS) is a bioactive compound present in the Herba Desmodii Styracifolii (DS), a herb that has been used to treat cholelithiasis and urolithiasis in Chinese medicine. Whether SS inhibits cholesterol (Ch) gallstone formation has not been investigated. This study examined the effects of oral intake of SS on Ch gallstone formation in C57BL/6 mice fed a lithogenic diet. The rate of gallstone formation was recorded. Levels of Ch, triglycerides (TG) and bile salts (BS) were measured in the bile and serum. Liver histopathology was examined microscopically, and mRNA expression levels of key genes involved in cholesterol and bile metabolism were determined by qPCR. Mice fed SS were protected against gallstone formation, had increased biliary levels of BS, and reduced biliary Ch levels, resulting in a lower Ch saturation index (CSI). In addition, mice fed SS had lower serum TG and Ch levels, increased mRNA expression of liver X receptor α, ATP binding cassette transporter 5/8 (ABCG5/8), and ileal bile acid binding protein (IBABP) in the ileum, and of farnesoid X receptor and bile salt export protein (BSEP) in the liver and ileum. SS also protected against histologically determined liver damage. Overall, these data indicate that SS protects against Ch gallstone formation in mice, and that the effect is mediated by activation of ileal liver X receptor α and hepatic farnesoid X receptor.

Protection of tauroursodeoxycholic acid on high glucose-induced human retinal microvascular endothelial cells dysfunction and streptozotocin-induced diabetic retinopathy rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tauroursodeoxycholic acid (TUDCA), one of the main ingredients from bear gall which hold "Clearing heat and detoxification, Removing liver fire for improving eyesight" functions, is formed by the conjugation of ursodeoxycholic acid (UDCA) with taurine. However, the limited information of TUDCA on protecting diabetic retinopathy (DR) has been known. The present study was conducted to evaluate the protection of TUDCA on high glucose-induced human retinal microvascular endothelial cells (HRMECs) dysfunction and streptozotocin (STZ)-induced diabetic retinopathy (DR) rats and the possible mechanism underlying was also explored. MATERIALS AND METHODS: The proliferation of high glucose-induced HRMECs was determined by MTT assay. DR rats' model was established by an administration of high-glucose-fat diet and an intraperitoneal injection of STZ (30mg/kg). The cell supernatant and rats' serum were collected for the assays of NO content by ELISA kits. Retinas were stained with hematoxylin and eosin (HE) to observe pathological changes. Immunohistochemical assay was applied to examine the protein expression of ICAM-1, NOS, NF-κB p65 and VEGF in rat retinas. Furthermore, western blot analysis was carried out to examine the protein expression of ICAM-1, NOS, NF-κB p65 and VEGF in high glucose-induced HRMECs. RESULTS: After treating with TUDCA, high glucose-induced HRMECs proliferation could be significantly inhibited. TUDCA (5.0µM, 25.0µM and 125.0µM) could decrease NO content in high glucose-induced HRMECs. Furthermore, TUDCA (500mg/kg/d and 250mg/kg/d) also decrease NO content in serum of DR rats. Additionally, both immunocytochemistry analysis and western blot analysis showed that the over-expression of ICAM-1, NOS, NF-κB p65 and VEGF were significantly decreased by TUDCA. CONCLUSION: The data indicated that TUDCA could ameliorate DR by decreasing NO content and down-regulating the protein expression of ICAM-1, NOS, NF-κB p65 and VEGF. Thus, our experimental results suggested that TUDCA might be a potential drug for the prevention and treatment of DR.

Ursodeoxycholic acid inhibits overexpression of P-glycoprotein induced by doxorubicin in HepG2 cells.

The hepatoprotective action of ursodeoxycholic acid (UDCA) was previously suggested to be partially dependent on its antioxidative effect. Doxorubicin (DOX) and reactive oxygen species have also been implicated in the overexpression of P-glycoprotein (P-gp), which is encoded by the MDR1 gene and causes antitumor multidrug resistance. In the present study, we assessed the effects of UDCA on the expression of MDR1 mRNA, P-gp, and intracellular reactive oxygen species levels in DOX-treated HepG2 cells and compared them to those of other bile acids. DOX-induced increases in reactive oxygen species levels and the expression of MDR1 mRNA were inhibited by N-acetylcysteine, an antioxidant, and the DOX-induced increase in reactive oxygen species levels and DOX-induced overexpression of MDR1 mRNA and P-gp were inhibited by UDCA. Cells treated with UDCA showed improved rhodamine 123 uptake, which was decreased in cells treated with DOX alone. Moreover, cells exposed to DOX for 24h combined with UDCA accumulated more DOX than that of cells treated with DOX alone. Thus, UDCA may have inhibited the overexpression of P-gp by suppressing DOX-induced reactive oxygen species production. Chenodeoxycholic acid (CDCA) also exhibited these effects, whereas deoxycholic acid and litocholic acid were ineffective. In conclusion, UDCA and CDCA had an inhibitory effect on the induction of P-gp expression and reactive oxygen species by DOX in HepG2 cells. The administration of UDCA may be beneficial due to its ability to prevent the overexpression of reactive oxygen species and acquisition of multidrug resistance in hepatocellular carcinoma cells.