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Background: The decreased renal function is known to be associated with biological aging, of which the main pathological features are chronic inflammation and renal interstitial fibrosis. In previous studies, we reported that total saponins from Panax japonicus (SPJs) can availably protect acute myocardial ischemia. We proposed that SPJs might have similar protective effects for aging-associated renal interstitial fibrosis. Thus, in the present study, we evaluated the overall effect of SPJs on renal fibrosis. Methods: Sprague-Dawley (SD) aging rats were given SPJs by gavage beginning from 18 months old, at 10 mg/kg/d and 60 mg/kg/d, up to 24 months old. After the experiment, changes in morphology, function and fibrosis of their kidneys were detected. The levels of serum uric acid (UA), β2-microglobulin (β2-MG) and cystatin C (Cys C) were assayed with ELISA kits. The levels of extracellular matrix (ECM), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), inflammatory factors and changes of oxidative stress parameters were examined. Results: After SPJs treatment, SD rats showed significantly histopathological changes in kidneys accompanied by decreased renal fibrosis and increased renal function; As compared with those in 3-month group, the levels of serum UA, Cys C and β2-MG in 24-month group were significantly increased (p

Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. In our study, ANXA10 upregulation was revealed by exome and transcription sequencing in 5 pairs of PHCCA and adjacent tissues. The clinical significance and prognostic value of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables and survival rates. As a result, ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and unfavorable prognosis. With in vitro and in vivo experiments, we demonstrated that ANXA10 promoted the epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of the PHCCA cell line QBC939. The key molecule in ANXA10-induced CCA progression was screened by mRNA sequencing. Consequently, PLA2G4A expression was regulated by ANXA10 and it was required in ANXA10-induced metastasis. High PLA2G4A expression also predicted poor prognosis in PHCCA and DCCA. With multiple in vivo experiments, we showed that ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. In conclusion, ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the proliferation, migration and invasion of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. Our results suggested that ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA. Funding Statement: Our study was supported by National Natural Science Foundation of China (Grant no. 81601668), Shandong Province Major Research and Design Program (Grant No. 2018GSF118169), Jinan City Science and Technology Development Program(Grant No. 201805017, 201805013), and Hengrui Hepatobiliary and Pancreatic Foundation (Grant No.Y-2017-144). Declaration of Interests: The authors declare no conflicts of interests. Ethics Approval Statement: All experiments were approved by the Ethics Committee of Qilu Hospital of Shandong University.

Visual Abstract, Highlights • Celecoxib use is associated with diagnosis of aortic stenosis in analysis of electronic medical records. • Celecoxib treatment increases dystrophic calcification of aortic valve interstitial cells in vitro. • Dimethyl celecoxib, which binds CDH11, prevents TGF-β1–mediated calcification of aortic valve interstitial cells in vitro., Summary Calcific aortic valve disease is a progressive fibrocalcific process that can only be treated with valve replacement. Cadherin-11 has recently been identified as a potential therapeutic target for calcific aortic valve disease. The already approved drug celecoxib, a cyclooxygenase-2 inhibitor, binds cadherin-11, and was investigated as a therapeutic against calcific aortic valve disease. Unexpectedly, celecoxib treatment led to hallmarks of myofibroblast activation and calcific nodule formation in vitro. Retrospective electronic medical record analysis of celecoxib, ibuprofen, and naproxen revealed a unique association of celecoxib use and aortic stenosis.

Background & Aims Fulminant hepatitis (FH) is a clinical syndrome characterized by sudden and severe liver dysfunction. Dot1L, a histone methyltransferase, is implicated in various physiologic and pathologic processes, including transcription regulation and leukemia. However, the role of Dot1L in regulating inflammatory responses during FH remains elusive. Methods Propionibacterium acnes (P. acnes)-primed, lipopolysaccharides (LPS)-induced FH was established in C57BL/6 mice and was treated with the Dot1L inhibitor EPZ-5676. Myeloid derived suppressor cells (MDSCs) were depleted by anti-Gr-1 antibody to evaluate their therapeutic roles in Dot1L treatment of FH. Moreover, peripheral blood of patients suffered with FH and healthy controls was collected to determine the expression profile of Dot1L-SOCS1-iNOS axis in their MDSCs. Results Here we identified that EPZ-5676, pharmacological inhibitor of Dot1L, attenuated the liver injury of mice subjected to FH. Dot1L inhibition led to decreased T helper 1 cell response and expansion of regulatory T cells (Tregs) during FH. Interestingly, Dot1L inhibition didn’t directly target T cells, but dramatically enhanced the immunosuppressive function of MDSCs. Mechanistically, Dot1L inhibition epigenetically suppressed SOCS1 expression, thus inducing inducible nitric oxide synthase (iNOS) expression in a STAT1-dependent manner. Moreover, in human samples, the levels of Dot1L and SOCS1 expression were upregulated in MDSCs, accompanied by decreased expression of iNOS in patients with FH, compared with healthy controls. Conclusions Altogether, our findings established Dot1L as a critical regulator of MDSC immunosuppressive function for the first time, and highlighted the therapeutic potential of Dot1L inhibitor for FH treatment., Graphical abstract

Graphical abstract, Highlights • miRNAs are key regulators of gene expression at both transcription and translation. • The role of miRNAs in xenobiotic toxicity and its potential as biomarkers are being explored. • In spite of numerous studies, the complex mechanism of miRNA biogenesis and its regulation remains unclear., The advent of new technologies has paved the rise of various chemicals that are being employed in industrial as well as consumer products. This leads to the accumulation of these xenobiotic compounds in the environment where they pose a serious threat to both target and non-target species. miRNAs are one of the key epigenetic mechanisms that have been associated with toxicity by modulating the gene expression post-transcriptionally. Here, we provide a comprehensive view on miRNA biogenesis, their mechanism of action and, their possible role in xenobiotic toxicity. Further, we review the recent in vitro and in vivo studies involved in xenobiotic exposure induced miRNA alterations and the mRNA-miRNA interactions. Finally, we address the challenges associated with the miRNAs in toxicological studies.

Background & Aims Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis. Methods Nrf2+/+ and Nrf2-/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, while still being fed the same HFFr or regular chow diets, with either TBE-31 or dimethyl sulfoxide vehicle control. Measures of whole-body glucose homeostasis, histologic assessment of liver, and biochemical and molecular measurements of steatosis, endoplasmic reticulum (ER) stress, inflammation, apoptosis, fibrosis, and oxidative stress were performed in livers from these animals. Results TBE-31 treatment reversed insulin resistance in HFFr-fed wild-type mice, but not in HFFr-fed Nrf2-null mice. TBE-31 treatment of HFFr-fed wild-type mice substantially decreased liver steatosis and expression of lipid synthesis genes, while increasing hepatic expression of fatty acid oxidation and lipoprotein assembly genes. Also, TBE-31 treatment decreased ER stress, expression of inflammation genes, and markers of apoptosis, fibrosis, and oxidative stress in the livers of HFFr-fed wild-type mice. By comparison, TBE-31 did not decrease steatosis, ER stress, lipogenesis, inflammation, fibrosis, or oxidative stress in livers of HFFr-fed Nrf2-null mice. Conclusions Pharmacologic activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory, and oxidative stress., Graphical abstract

Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance®), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF‐Leprfa/fa and 16 ZDF-Lepr+/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial)., Graphical abstract fx1, Highlights • Hyperglycemia induces vascular complications and cardiovascular disease. • Empagliflozin reduces hyperglycemia and cardiovascular mortality (EMPA-REG trial). • Here, empagliflozin normalized vascular function and oxidative stress in ZDF rats. • Here, empagliflozin reduced AGE/RAGE signaling, inflammation and oxidative stress. • Here, empagliflozin conferred glycemic control, epigenetic and pleiotropic effects.

Visual Abstract, Highlights • In a murine model of CA and CPR, intravenous application of hydrophilic pravastatin resulted in increased survival and neurofunctional outcome. • In contrast, intravenous application of lipophilic simvastatin did not improve survival or neurofunction following CA/CPR. • Pravastatin, but not simvastatin, treatment reduced post-resuscitation pulmonary edema and augmented pulmonary function. • In vitro, pravastatin augmented endothelial cell function, whereas simvastatin induced endothelial cell apoptosis. • This study supports previous requests for an intravenous formulation of hydrophilic statins for clinical use., Summary Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with high mortality and poor neurological outcome. We compared the effects of pravastatin and simvastatin on survival and neurofunction in a murine model of CA/CPR. Pravastatin, a hydrophilic statin, increased survival and neurofunction during a 28-day follow-up period. This therapy was associated with improved pulmonary function, reduced pulmonary edema, and increased endothelial cell function in vitro. In contrast, lipophilic simvastatin did not modulate survival but increased pulmonary edema and impaired endothelial cell function. Although pravastatin may display a therapeutic option for post-CA syndrome, the application of simvastatin may require re-evaluation.

The prostaglandin E2 receptor, EP2 (E-prostanoid 2), plays an important role in mice glomerular MCs (mesangial cells) damage induced by TGFβ1 (transforming growth factor-β1); however, the molecular mechanisms for this remain unknown. The present study examined the role of the EP2 signalling pathway in TGFβ1-induced MCs proliferation, ECM (extracellular matrix) accumulation and expression of PGES (prostaglandin E2 synthase). We generated primary mice MCs. Results showed MCs proliferation promoted by TGFβ1 were increased; however, the production of cAMP and PGE2 (prostaglandin E2) was decreased. EP2 deficiency in these MCs augmented FN (fibronectin), Col I (collagen type I), COX2 (cyclooxygenase-2), mPGES-1 (membrane-associated prostaglandin E1), CTGF (connective tissue growth factor) and CyclinD1 expression stimulated by TGFβ1. Silencing of EP2 also strengthened TGFβ1-induced p38MAPK (mitogen-activated protein kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2) and CREB1 (cAMP responsive element-binding protein 1) phosphorylation. In contrast, Adenovirus-mediated EP2 overexpression reversed the effects of EP2-siRNA (small interfering RNA). Collectively, the investigation indicates that EP2 may block p38MAPK, ERK1/2 and CREB1 phosphorylation via activation of cAMP production and stimulation of PGE2 through EP2 receptors which prevent TGFβ1-induced MCs damage. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the damage induced by TGFβ1.