Physcion 8-O-ß-glucopyranoside ameliorates liver fibrosis through inflammation inhibition by regulating SIRT3-mediated NF-κB P65 nuclear expression.

Physcion 8-O-ß-glucopyranoside (PSG), an anthraquinone extracted from Rumex japonicus Houtt, has various pharmacological effects, however, the effect of PSG on liver fibrosis and its related mechanism remain to be determined. We here showed that PSG ameliorated liver injury and liver fibrosis, decreased collagen deposition and inhibited inflammation in carbon tetrachloride (CCl4)-induced rats. Consistent with the in vivo results, PSG suppressed the transforming growth factor-ß1 (TGF-ß1)-induced cell viability, liver fibrosis and secretion of inflammatory factors in hepatic stellate cells (HSCs). Interestingly, PSG increased the enzyme activity and promoter activity of sirtuin 3 (SIRT3) in fibrotic liver and activated HSCs. In addition, PSG notably increased the mRNA and protein expression of SIRT3 both in vivo and in vitro. Depletion of SIRT3 either by using 3-TYP (SIRT3 selective inhibitor) or SIRT3 siRNA attenuated the anti-inflammatory effect of PSG in activated HSCs. Further study found that TGF-ß1 increased the nuclear expression of NF-κB p65, but showed no obvious effect on the total NF-κB p65 expression. Compared to the control adenovirus (Ad.mk), overexpression of SIRT3 by infecting adenovirus encoding SIRT3 (Ad.SIRT3) notably decreased the nuclear expression of NF-κB p65 in activated HSCs. Our results demonstrated that PSG attenuated inflammation by regulating SIRT3-mediated NF-κB P65 nuclear expression in liver fibrosis, providing novel molecular insights into the anti-fibrotic effect of PSG.

Withaferin A Exerts Preventive Effect on Liver Fibrosis through Oxidative Stress Inhibition in a Sirtuin 3-Dependent Manner.

Sirtuin 3 (SIRT3) is a deacetylase involved in the development of many inflammation-related diseases including liver fibrosis. Withaferin A (WFA) is a bioactive constituent derived from the Withania somnifera plant, which has extensive pharmacological activities; however, little is known about the regulatory role of SIRT3 in the WFA-induced antifibrogenic effect. The current study is aimed at investigating the role of SIRT3 in WFA-induced antioxidant effects in liver fibrosis. Our study verified that WFA attenuated platelet-derived growth factor BB- (PDGF-BB-) induced liver fibrosis and promoted PDGF-BB-induced SIRT3 activity and expression in JS1 cells. SIRT3 silencing attenuated the antifibrogenic and antioxidant effects of WFA in activated JS1 cells. Moreover, WFA inhibited carbon tetrachloride- (CCl4-) induced liver injury, collagen deposition, and fibrosis; increased the SIRT3 expression; and suppressed the CCl4-induced oxidative stress in fibrotic livers of C57/BL6 mice. Furthermore, the antifibrogenic and antioxidant effects of WFA could be available in CCl4-induced WT (129S1/SvImJ) mice but were unavailable in CCl4-induced SIRT3 knockout (KO) mice. Our study suggested that WFA inhibited liver fibrosis through the inhibition of oxidative stress in a SIRT3-dependent manner. WFA could be a potential compound for the treatment of liver fibrosis.

PVAT: an important guardian of the cardiovascular system.

Perivascular adipose tissue (PVAT) had long been considered to serve only structural, vessel-supporting purposes, but today PVAT is recognized to be an endocrine organ with important physiological and pathological effects. The expansion of PVAT in vascular homeostasis and vascular disease has attracted much interest. PVAT has been shown to release a wide spectrum of molecules, such as PVAT-derived relaxing factors (PVATRFs) and PVAT-derived contracting factors (PVATCFs). PVAT dysfunction may lead to obesity, atherosclerosis, and other cardiovascular diseases. This review describes recent advances in our understanding of PVAT's important effects on the cardiovascular system.

Celastrol exerts anti-inflammatory effect in liver fibrosis via activation of AMPK-SIRT3 signalling.

Celastrol, a pentacyclic tritepene extracted from Tripterygium Wilfordi plant, showing potent liver protection effects on several liver-related diseases. However, the anti-inflammatory potential of celastrol in liver fibrosis and the detailed mechanisms remain uncovered. This study was to investigate the anti-inflammatory effect of celastrol in liver fibrosis and to further reveal mechanisms of celastrol-induced anti-inflammatory effects with a focus on AMPK-SIRT3 signalling. Celastrol showed potent ameliorative effects on liver fibrosis both in activated hepatic stellate cells (HSCs) and in fibrotic liver. Celastrol remarkably suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Interestingly, celastrol increased SIRT3 promoter activity and SIRT3 expression both in fibrotic liver and in activated HSCs. Furthermore, SIRT3 silencing evidently ameliorated the anti-inflammatory potential of celastrol. Besides, we found that celastrol could increase the AMPK phosphorylation. Further investigation showed that SIRT3 siRNA decreased SIRT3 expression but had no obvious effect on phosphorylation of AMPK. In addition, inhibition of AMPK by employing compound C (an AMPK inhibitor) or AMPK1α siRNA significantly suppressed SIRT3 expression, suggesting that AMPK was an up-stream protein of SIRT3 in liver fibrosis. We further found that depletion of AMPK significantly attenuated the inhibitory effect of celastrol on inflammation. Collectively, celastrol attenuated liver fibrosis mainly through inhibition of inflammation by activating AMPK-SIRT3 signalling, which makes celastrol be a potential candidate compound in treating or protecting against liver fibrosis.

Biomarkers in VSMC phenotypic modulation and vascular remodeling.

Vascular smooth muscle cells (VSMCs) are not terminally differentiated and can change their phenotype in response to environmental cues. Phenotype switching of VSMCs to less differentiated forms has led to an underestimation of their role in the development of vascular remodeling and many vascular diseases in both humans and animal models of this disease. In recent studies, many factors, such as microRNAs, matrix metalloproteinases, integrins, oxidative stress, autophagy, have been shown to play important roles in the mechanisms of VSMC phenotypic switch and vascular remodeling. This review highlights the current knowledge regarding the molecular mechanisms of VSMC phenotypic modulation in vascular remodeling. In this review, we want to provide effective molecular targets and opportunities for the future development of new therapeutics to regulate vascular remodeling diseases.

Cryptotanshinone inhibits the growth and invasion of colon cancer by suppressing inflammation and tumor angiogenesis through modulating MMP/TIMP system, PI3K/Akt/mTOR signaling and HIF-1α nuclear translocation.

The aim of this study was to evaluate the pharmacological effects of CPT on CT26 colon cancer cells in vivo and in vitro, and to reveal the potential mechanism. CPT suppressed the proliferation and growth of CT26 colon cancer in vitro and in vivo. CPT inhibited the invasion of CT26 cells in vitro, and decreased the protein expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 but increased those of tissue inhibitor of metallopeptidase-1 (TIMP-1) and TIMP-2 in vitro and in vivo. It also inhibited tumor cell-induced angiogenesis of endothelial cells in vitro and rat aortic ring angiogenesis ex vivo, and possibly by suppressing angiogenesis-associated factors. CPT suppressed the expressions of inflammatory factors in vivo and in vitro. Mechanism studies showed that CPT inhibited the PI3K/AKT/mTOR signaling pathway, as evidenced by decreased expressions of phospho-PI3K (p-PI3K), p-Akt and p-mTOR. Moreover, CPT significantly suppressed the nuclear expression but increased the cytosolic expression of hypoxia inducible factor-1α (HIF-1α). Collectively, CPT inhibited the growth, invasion, inflammation and angiogenesis in CT26 colon cancer, and at least partly, by regulating the PI3K/Akt/mTOR signaling and the nuclear translocation of HIF-1α.

Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis.

Autophagy has been regarded as an inflammation-associated defensive mechanism against chronic liver disease, which has been highlighted as a novel therapeutic target for the treatment of liver fibrosis. We herein aimed to study the effects of catalpol on liver fibrosis in vivo and in vitro, and to elucidate the role of autophagy in catalpol-induced anti-inflammation. Catalpol protected the liver against CCl4-induced injury, as evidenced by mitigated hepatic steatosis, necrosis, and fibrotic septa. Catalpol decreased the serum levels of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and bilirubin as well as the liver/body weight ratio. Masson and sirius red staining along with hydroxyproline detection showed that catalpol decreased collagen deposition significantly compared to that of the model group. Catalpol inhibited CCl4-induced liver fibrosis, manifested as decreased expressions of α-SMA, fibronectin and α1(I)-procollagen at both transcriptional and translational levels. Inflammatory factors, such as IL-1ß, TNF-α, IL-18, IL-6 and COX-2, were significantly elevated in rats receiving CCl4 and down-regulated by catalpol in a dose-dependent manner in vivo. Western blot and immunofluorescence assay revealed that catalpol activated the autophagy of rats with CCl4-caused liver fibrosis, as indicated by up-regulation of LC3-II and beclin1 and down-regulation of P62. The results of in vitro experiments were consistent. Interestingly, inhibition or depletion of autophagy by LY294002 or Atg5 siRNA significantly attenuated catalpol-induced anti-inflammatory effects on activated hepatic stellate cells in vitro. In conclusion, catalpol relieved liver fibrosis mainly by inhibiting inflammation, and autophagy inhibition attenuated the catalpol-induced anti-inflammatory effect on liver fibrosis.

Over expressing miR-19b-1 suppress breast cancer growth by inhibiting tumor microenvironment induced angiogenesis.

Metastastic breast cancer, especially triple-negative (TN), is one of the most common causes of cancer related deaths in women. Recent years, tumor-associate vessel formation is considered as a more generally and effective target to patient with malignant cancer. Our previous studies indicated that miR-19b-1 controls the intrinsic angiogenic activity of human umbilical vein endothelial cells (HUVECs) in vitro. In this study, in silico analysis indicated VEZF1 that implicates in angiogenesis and triple-negative breast cancer progression might be the target of miR-19b-1. Further investigation showed that overexpressing miR-19b-1 in human triple-negative breast cancer cell line(MDA-MB-231) led to impaired angiogenic activity of HUVECs in vitro and in vivo. Additionally, miR-19b-1 upregulation inhibited the vessel imitation mediated by MDA-MB-231. Furthermore, enforced expression of miR-19b-1 in MDA-MB-231 has impact on HUVECs apoptosis and altered the mitochondrial membrane potential, which suggested the possible mechanism involved in interaction between breast cancer and endothelial cells. What's more, we found that miR-19b-1 stable overexpression in MDA-MB-231 caused tumor growth arresting entirely. Besides, our results suggested that miR-19b-1 could inhibit angiogenesis by possibly targeting VEGF receptor endocytosis signaling pathway. Taking together, our findings suggest an important role of miR-19b-1 in crosstalk between metastatic breast cancer and endothelial cells and provide us new insights for exploring miR-19b-1 and its multiple targets as promising therapeutic candidates to interfere breast cancer progression.