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Glucose and lipid metabolism disorders and chronic inflammation in the kidney tissues are largely responsible for causative pathological mechanism of renal fibrosis in diabetic nephropathy (DN). As our previous findings confirmed that, sphingosine 1-phosphate (S1P)/sphingosine 1-phosphate receptor 2 (S1P2) signaling activation promoted renal fibrosis in diabetes. Numerous studies have demonstrated that the G protein-coupled bile acid receptor TGR5 exhibits effective regulation of glucose and lipid metabolism and anti-inflammatory effects. TGR5 is highly expressed in kidney tissues, whether it attenuates the inflammation and renal fibrosis by inhibiting the S1P/S1P2 signaling pathway would be a new insight into the molecular mechanism of DN. Here we investigated the effects of TGR5 on diabetic renal fibrosis, and the underlying mechanism would be also discussed. We found that TGR5 activation significantly decreased the expression of intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta 1 (TGF-β1), as well as fibronectin (FN) induced by high glucose in glomerular mesangial cells (GMCs), which were pathological features of DN. S1P2 overexpression induced by high glucose was diminished after activation of TGR5, and AP-1 activity, including the phosphorylation of c-Jun/c-Fos and AP-1 transcription activity, was attenuated. As a G protein-coupled receptor, S1P2 interacted with TGR5 in GMCs. Furthermore, INT-777 lowered S1P2 expression and promoted S1P2 internalization. Taken together, TGR5 activation reduced ICAM-1, TGF-β1 and FN expressions induced by high glucose in GMCs, the mechanism might be through suppressing S1P/S1P2 signaling, thus ameliorating diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is an aggressive and exceptionally fatal disease. Unlike non- small cell lung cancer (NSCLC), no targetable genetic driver events have been identified in SCLC to date. Here, we investigate the function of RAR-related orphan receptor gamma (RORγ) and identified the anti-cancer activity of its natural inhibitor against SCLC and illustrate the underlying mechanism. We show that RORγ depletion affected cell growth both in 2-D cell proliferation and 3-D organoids formation. Natural marine product N -hydroxyapiosporamide (N -hydap) directly bound to RORγ and inhibited its transcriptional activity, leading to the blocking of transmission process of RORγ signaling. Gene expression profiling analysis revealed that N -hydap reprograms neuroendocrine fate via inhibiting RORγ activity in SCLC. Chromatin immunoprecipitation analysis showed that N -hydap strongly reduced RORγ occupancy and transcriptional activation-linked histone marks H3K27ac on the promoter and/or enhancer sites of neurogenesis markers gene including aurora kinase a (AURKA), delta like canonical Notch ligand 3 (DLL3) and tubulin beta 3 class III (TUBB3). Therapeutically, N -hydap exhibited a strong inhibitory effect on tumor growth and did not show significant toxicity in SCLC mice xenograft models. Taken together, RORγ could be an attractive target for SCLC and thus N -hydap can be a promising therapeutic drug candidate for SCLC by inhibiting the RORγ activation. [Display omitted] • RORγ represents a potential therapeutic target in SCLC. • Natural product N -hydap was identified as a novel and potent RORγ inhibitor. • RORγ reprograms neuroendocrine fate of SCLC cells both in vitro and in vivo. • N -hydap can be a promising therapeutic drug candidate for SCLC. [ABSTRACT FROM AUTHOR]

Abstract: Growing evidences have shown that hypertension, cardiac hypertrophy and fibrosis were associated with an overactivity of NAD(P)H oxidase. It is unknown, however, which isoform of NAD(P)H oxidase yields O2 − formation in heart and aorta in two-kidney, two-clip (2K2C) hypertensive rats in vivo and thus is responsible for the development of cardiac remodeling. We examined the pathological change of NAD(P)H oxidase homologues and tested the effect of valsartan on the cardiac remodeling in 2K2C renovascular hypertensive rats. Four weeks after male Sprague–Dawley rats accepted 2K2C or sham operation, 2K2C hypertensive (>160mmHg) rats were divided into vehicle-treated (2K2C) and valsartan (30mgkg−1 per day, for 6 weeks)-treated (2K2C+Val) groups, which were compared with sham-operated controls (Sham). At week 10, 2K2C hypertensive rats showed increased serum level of angiotensin II (Ang II), MDA and blood pressure (BP), obvious cardiac hypertrophy and fibrosis, increased O2 − production and NAD(P)H oxidase activity and expression in aorta and heart. The heart in 2K2C hypertensive rats preferred to use NADH as substrate while the aorta used both NADH and NADPH. Valsartan treatment decreased BP, ameliorated cardiac hypertrophy and fibrosis, decreased O2 − production and NAD(P)H oxidase activity in aorta and heart. Nox2 and Nox4 protein expression increased in heart, while Nox1 and Nox4 increased in aorta in 2K2C hypertensive rats, which were all normalized after valsartan treatment. In conclusion, these data indicate that different Nox expression might account for substrate preference and the formation of O2 − by NAD(P)H oxidase resulting from elevated Ang II in the 2K2C model contributes to the development of renovascular hypertension and subsequent cardiac remodeling. [Copyright &y& Elsevier]

CKIP-1 participates in the activation of Nrf2 signaling pathway by Cx43 and the regulation of diabetic renal fibrosis Under normal conditions, CKIP-1 was combined with Cx43 via Cx43 CT domain on the membrane of GMCs, which induced the interaction between CKIP-1 and Nrf2 and the nuclear accumulation of Nrf2, leading the activation of Nrf2 anti-oxidative stress signaling pathway. When the cells were stimulated by high glucose, the expression of Cx43 was inhibited, following with the down-regulation of CKIP-1 protein level. Moreover, the interaction between CKIP-1 and Nrf2 was weaken whereas the binding of Nrf2 to its inhibitory protein Keap1 was enhanced, as a result of which the activity of Nrf2 signaling pathway was inhibited with the overproduction of intracellular superoxide. Increased oxidative stress further promoted the expression of FN eventually exacerbating diabetic renal fibrosis. • CKIP-1 participated in the activation of Nrf2 signaling pathway by Cx43 and the regulation of diabetic renal fibrosis. • Cx43 interacted with CKIP-1, and the interaction was weakened by high glucose treatment. • Cx43 regulated the expression of CKIP-1 and the interaction of CKIP-1 with Nrf2 via Cx43 carboxyl terminus domain. We previously reported that both Cx43 and CKIP-1 attenuated diabetic renal fibrosis via the activation of Nrf2 signaling pathway. However, whether CKIP-1, a scaffold protein, participates in regulating the activation of Nrf2 signaling pathway by Cx43 remains to be elucidated. In this study, the effect of adenovirus-mediated Cx43 overexpression on renal fibrosis in CKIP-1−/− diabetic mice was investigated. We found that overexpression of Cx43 could significantly alleviate renal fibrosis by activating the Nrf2 pathway in diabetic mice, but have no obvious effect in CKIP-1−/− diabetic mice. Cx43 overexpressed plasmid and CKIP-1 small interfering RNA were simultaneously transfected into glomerular mesangial cells and the result demonstrated that the effect of activation of Nrf2 signaling pathway by Cx43 was blocked by CKIP-1 depletion. The interaction between Cx43 and CKIP-1 was analyzed by immunofluorescence and immunoprecipitation assays. We found that Cx43 interacted with CKIP-1, and the interaction was weakened by high glucose treatment. Moreover, Cx43 regulated the expression of CKIP-1 and the interaction of CKIP-1 with Nrf2 via Cx43 carboxyl terminus (CT) domain, thereby activating Nrf2 signaling pathway. According to the results, we preliminary infer that CKIP-1 acts downstream to CX43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes, the mechanism of which might be related to the interaction of CKIP-1 with Nrf2 through Cx43 CT. Our study provides further experimental basis for targeting the Cx43-CKIP-1-Nrf2 axis to resist diabetic renal fibrosis. [ABSTRACT FROM AUTHOR]

Although histone lysine methylation has been extensively studied for their participation in pathological cardiac hypertrophy, the potential regulatory role of histone arginine methylation remains to be elucidated. The present study focused on H4R3 symmetric di-methylation (H4R3me2s) induced by protein arginine methyltransferase 5 (Prmt5), and explored its epigenetic regulation and underlying mechanisms in cardiomyocyte hypertrophy. 1. The expressions of Prmt5 and H4R3me2s were suppressed in cardiac hypertrophy models in vivo and in vitro ; 2. Prmt5 silencing or its inhibitor EPZ, or knockdown of cooperator of Prmt5 (Copr5) to disrupt H4R3me2s, facilitated cardiomyocyte hypertrophy, whereas overexpression of wild type Prmt5 rather than the inactive mutant protected cardiomyocytes against hypertrophy; 3. ChIP-sequence analysis identified Filip1L as a target gene of Prmt5-induced H4R3me2s; 4. Knockdown or inhibition of Prmt5 impaired Filip1L transcription and subsequently prevented β-catenin degradation, thus augmenting cardiomyocyte hypertrophy. The present study reveals that Prmt5-induced H4R3me2s ameliorates cardiomyocyte hypertrophy by transcriptional upregulation of Filip1L and subsequent enhancement of β-catenin degradation. Deficiency of Prmt5 and the resulting suppression of H4R3me2s might facilitate the development of pathological cardiac hypertrophy. Prmt5 might serve as a key epigenetic regulator in pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

• Gentiopicroside reversed the downregulation of TGR5 and the upregulation of ECM and inflammatory factors in HG-induced GMCs. • Gentiopicroside inhibited the activation of the NF-κB signalling pathway by preventing the phosphorylation of IκBα. • The depletion of TGR5 blocked the inhibition of the NF-κB signalling pathway by GPS. • Gentiopicroside enhanced the interaction between β-arrestin2 and IκBα via TGR5 activation. Our previous studies indicated that the G-protein-coupled bile acid receptor, Gpbar1 (TGR5), inhibits inflammation by inhibiting the NF-κB signalling pathway, eventually attenuating diabetic nephropathy (DN). Gentiopicroside (GPS), the main active secoiridoid glycoside of Gentiana manshurica Kitagawa , has been demonstrated to inhibit inflammation in various diseases via inhibiting the inflammatory signalling pathways. However, whether GPS inhibits the NF-κB signalling pathway by activating TGR5 and regulates the pathological progression of diabetic renal fibrosis requires further investigation. In this study, we found that GPS significantly reversed the downregulation of TGR5 and inhibited the overproduction of fibronectin (FN), transforming growth factor β1 (TGF-β1), intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMCs) exposed to high glucose (HG). Additionally, GPS prevented the phosphorylation and degradation of IκBα, and subsequently inhibited the activation of the NF-κB signalling pathway. Further investigation found that GPS enhanced the stabilization of IκBα by promoting the interaction of β-arrestin2 with IκBα via TGR5 activation, which contributed to the inhibition of NF-κB signalling pathway. Importantly, the depletion of TGR5 blocked the inhibition of the NF-κB signalling pathway and reversed the downregulation of FN, ICAM-1, VCAM-1 and TGF-β1 by GPS in HG-induced GMCs. Moreover, GPS increased the TGR5 protein levels and promoted the interaction between IκBα and β-arrestin2, thereby inhibiting the reduction of IκBα and blocked NF-κB p65 nuclear translocation in the kidneys of STZ-induced diabetic mice. Collectively, these data suggested that GPS regulates the TGR5-β-arrestin2-NF-κB signalling pathway to prevent inflammation in the kidneys of diabetic mice, and ultimately ameliorates the pathological progression of diabetic renal fibrosis. [ABSTRACT FROM AUTHOR]

A graphical abstract showing that Cryptotanshinone protected against pulmonary fibrosis through inhibition of both TGF-β/Smad and STAT3 signaling pathways. Cryptotanshinone (CTS), a lipophilic compound extracted from root of Salvia miltiorrhiza (Danshen), has demonstrated multiple pharmacological activities, including anti-inflammation, anti-proliferation and anti-infection. However, the effect of CTS on pulmonary fibrosis is unknown. This study aims to investigate the effects of CTS treatment on pulmonary fibrosis and its underlying mechanism. The pulmonary fibrosis model was established by intratracheal instillation of bleomycin (5 mg/kg) in Sprague-Dawley rats (in vivo) and stimulating human fetal lung fibroblasts (HLFs) with transforming growth factor-beta 1 (TGF-β1) (in vitro). CTS (7.5, 15, 30, 60 mg/kg/day) and pirfenidone (150 mg/kg/day, positive control) were administered by oral gavage for 28 days. In this study, we found CTS treatment improved pulmonary function, relieved pathological changes and attenuated the accumulation of extracellular matrix in pulmonary fibrosis rat model induced by bleomycin. Mechanistically, CTS suppressed phosphorylation of Smad2/3 and STAT3 induced by TGF-β1 in HLFs. Stattic, a 1-benzothiophene based small-molecule STAT3 inhibitor, resulted in a significant down-regulation of fibrosis biomarkers including fibronectin, collagen type I and alpha smooth muscle actin (α-SMA). Overexpression of STAT3 promoted expression of fibrosis biomarkers in HLFs cell model induced by TGF-β1 and partially blocked the inhibitory effect of CTS on TGF-β1-induced fibrosis response. Taken together, these results suggested that CTS protects against pulmonary fibrosis via inhibition of Smad and STAT3 signaling pathways. Thus, CTS may represent a promising drug candidate for treating pulmonary fibrosis. [ABSTRACT FROM AUTHOR]