The Role of miRNA and Long Noncoding RNA in Cholestatic Liver Diseases.

Cholestatic liver diseases encompass a range of organic damages, metabolic disorders, and dysfunctions within the hepatobiliary system, arising from various pathogenic causes. These factors contribute to disruptions in bile production, secretion, and excretion. Cholestatic liver diseases can be classified into intrahepatic and extrahepatic cholestasis, according to the location of occurrence. The etiology of cholestatic liver diseases is complex, and includes drugs, poisons, viruses, parasites, bacteria, autoimmune responses, tumors, and genetic metabolism. The pathogenesis of cholelstatic liver disease is not completely clarified, and effective therapy is lacking. Clarifying its mechanism to find more effective therapeutic targets and drugs is an unmet need. Increasing evidence demonstrates that miRNA and long noncoding RNA are involved in the progression of cholestatic liver diseases. This review provides a comprehensive summary of the research progress on the roles of miRNA and long noncoding RNA in cholestatic liver diseases. The aim of the review is to enhance the understanding of their potential diagnostic, therapeutic, and prognostic value for patients with cholestasis.

Predictors of amputation in patients with diabetic foot ulcers: a multi-centre retrospective cohort study.

PURPOSE: Investigating risk factors for amputation in patients with diabetic foot ulcer (DFU) and developing a nomogram prediction model. METHODS: We gathered case data of DFU patients from five medical institutions in Anhui Province, China. Following eligibility criteria, a retrospective case-control study was performed on data from 526 patients. RESULTS: Among the 526 patients (mean age: 63.32 ± 12.14), 179 were female, and 347 were male; 264 underwent amputation. Univariate analysis identified several predictors for amputation, including Blood type-B, Ambulation, history of amputation (Hx. Of amputation), Bacterial culture-positive, Wagner grade, peripheral arterial disease (PAD), and laboratory parameters (HbA1c, Hb, CRP, ALB, FIB, PLT, Protein). In the multivariate regression, six variables emerged as independent predictors: Blood type-B (OR = 2.332, 95%CI [1.488-3.657], p < 0.001), Hx. Of amputation (2.298 [1.348-3.917], p = 0.002), Bacterial culture-positive (2.490 [1.618-3.830], p <0.001), Wagner 3 (1.787 [1.049-3.046], p = 0.033), Wagner 4-5 (4.272 [2.444-7.468], p <0.001), PAD (1.554 [1.030-2.345], p = 0.036). We developed a nomogram prediction model utilizing the aforementioned independent risk factors. The model demonstrated a favorable predictive ability for amputation risk, as evidenced by its area under the receiver operating characteristics (ROC) curve of 0.756 and the well-fitted corrected nomogram calibration curve. CONCLUSION: Our findings underscore Blood type-B, Hx. Of amputation, Bacterial culture-positive, Wagner 3-5, and PAD as independent risk factors for amputation in DFU patients. The resultant nomogram exhibits substantial accuracy in predicting amputation occurrence. Timely identification of these risk factors can reduce DFU-related amputation rates.

miR-34a regulates macrophage-associated inflammation and angiogenesis in alcohol-induced liver injury.

BACKGROUND: Alcohol-associated liver disease (ALD) is a syndrome of progressive inflammatory liver injury and vascular remodeling associated with long-term heavy intake of ethanol. Elevated miR-34a expression, macrophage activation, and liver angiogenesis in ALD and their correlation with the degree of inflammation and fibrosis have been reported. The current study aims to characterize the functional role of miR-34a-regulated macrophage- associated angiogenesis during ALD. METHODS RESULTS: We identified that knockout of miR-34a in 5 weeks of ethanol-fed mice significantly decreased the total liver histopathology score and miR-34a expression, along with the inhibited liver inflammation and angiogenesis by reduced macrophage infiltration and CD31/VEGF-A expression. Treatment of murine macrophages (RAW 264.7) with lipopolysaccharide (20 ng/mL) for 24 h significantly increased miR-34a expression, along with the enhanced M1/M2 phenotype changes and reduced Sirt1 expression. Silencing of miR-34a significantly increased oxygen consumption rate (OCR) in ethanol treated macrophages, and decreased lipopolysaccharide-induced activation of M1 phenotypes in cultured macrophages by upregulation of Sirt1. Furthermore, the expressions of miR-34a and its target Sirt1, macrophage polarization, and angiogenic phenotypes were significantly altered in isolated macrophages from ethanol-fed mouse liver specimens compared to controls. TLR4/miR-34a knockout mice and miR-34a Morpho/AS treated mice displayed less sensitivity to alcohol-associated injury, along with the enhanced Sirt1 and M2 markers in isolated macrophages, as well as reduced angiogenesis and hepatic expressions of inflammation markers MPO, LY6G, CXCL1, and CXCL2. CONCLUSION: Our results show that miR-34a-mediated Sirt1 signaling in macrophages is essential for steatohepatitis and angiogenesis during alcohol-induced liver injury. These findings provide new insight into the function of microRNA-regulated liver inflammation and angiogenesis and the implications for reversing steatohepatitis with potential therapeutic benefits in human alcohol-associated liver diseases.

Up-regulation of the human-specific CHRFAM7A gene protects against renal fibrosis in mice with obstructive nephropathy.

Renal fibrosis is a major factor in the progression of chronic kidney diseases. Obstructive nephropathy is a common cause of renal fibrosis, which is also accompanied by inflammation. To explore the effect of human-specific CHRFAM7A expression, an inflammation-related gene, on renal fibrosis during obstructive nephropathy, we studied CHRFAM7A transgenic mice and wild type mice that underwent unilateral ureteral obstruction (UUO) injury. Transgenic overexpression of CHRFAM7A gene inhibited UUO-induced renal fibrosis, which was demonstrated by decreased fibrotic gene expression and collagen deposition. Furthermore, kidneys from transgenic mice had reduced TGF-ß1 and Smad2/3 expression following UUO compared with those from wild type mice with UUO. In addition, the overexpression of CHRFAM7A decreased release of inflammatory cytokines in the kidneys of UUO-injured mice. In vitro, the overexpression of CHRFAM7A inhibited TGF-ß1-induced increase in expression of fibrosis-related genes in human renal tubular epithelial cells (HK-2 cells). Additionally, up-regulated expression of CHRFAM7A in HK-2 cells decreased TGF-ß1-induced epithelial-mesenchymal transition (EMT) and inhibited activation f TGF-ß1/Smad2/3 signalling pathways. Collectively, our findings demonstrate that overexpression of the human-specific CHRFAM7A gene can reduce UUO-induced renal fibrosis by inhibiting TGF-ß1/Smad2/3 signalling pathway to reduce inflammatory reactions and EMT of renal tubular epithelial cells.

Liver-specific deletion of microRNA-34a alleviates ductular reaction and liver fibrosis during experimental cholestasis.

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammatory responses and fibrotic scar formation leading to cholestasis. Ductular reaction and liver fibrosis are typical liver changes seen in human PSC and cholestasis patients. The current study aimed to clarify the role of liver-specific microRNA-34a in the cholestasis-associated ductular reaction and liver fibrosis. We demonstrated that miR-34a expression was significantly increased in human PSC livers along with the enhanced ductular reaction, cellular senescence, and liver fibrosis. A liver-specific miR-34a knockout mouse was established by crossing floxed miR-34a mice with albumin-promoter-driven Cre mice. Bile duct ligation (BDL) induced liver injury characterized by necrosis, fibrosis, and immune cell infiltration. In contrast, liver-specific miR-34a knockout in BDL mice resulted in decreased biliary ductular pathology associated with the reduced cholangiocyte senescence and fibrotic responses. The miR-34a-mediated ductular reactions may be functioning through Sirt-1-mediated senescence and fibrosis. The hepatocyte-derived conditioned medium promoted LPS-induced fibrotic responses and senescence in cholangiocytes, and miR-34a inhibitor suppressed these effects, further supporting the involvement of paracrine regulation. In conclusion, we demonstrated that liver-specific miR-34a plays an important role in ductular reaction and fibrotic responses in a BDL mouse model of cholestatic liver disease.

Current Perspectives of Neuroendocrine Regulation in Liver Fibrosis.

Liver fibrosis is a complicated process that involves different cell types and pathological factors. The excessive accumulation of extracellular matrix (ECM) and the formation of fibrotic scar disrupt the tissue homeostasis of the liver, eventually leading to cirrhosis and even liver failure. Myofibroblasts derived from hepatic stellate cells (HSCs) contribute to the development of liver fibrosis by producing ECM in the area of injuries. It has been reported that the secretion of the neuroendocrine hormone in chronic liver injury is different from a healthy liver. Activated HSCs and cholangiocytes express specific receptors in response to these neuropeptides released from the neuroendocrine system and other neuroendocrine cells. Neuroendocrine hormones and their receptors form a complicated network that regulates hepatic inflammation, which controls the progression of liver fibrosis. This review summarizes neuroendocrine regulation in liver fibrosis from three aspects. The first part describes the mechanisms of liver fibrosis. The second part presents the neuroendocrine sources and neuroendocrine compartments in the liver. The third section discusses the effects of various neuroendocrine factors, such as substance P (SP), melatonin, as well as α-calcitonin gene-related peptide (α-CGRP), on liver fibrosis and the potential therapeutic interventions for liver fibrosis.

The emerging role of cellular senescence in renal diseases.

Cellular senescence represents the state of irreversible cell cycle arrest during cell division. Cellular senescence not only plays a role in diverse biological events such as embryogenesis, tissue regeneration and repair, ageing and tumour occurrence prevention, but it is also involved in many cardiovascular, renal and liver diseases through the senescence-associated secretory phenotype (SASP). This review summarizes the molecular mechanisms underlying cellular senescence and its possible effects on a variety of renal diseases. We will also discuss the therapeutic approaches based on the regulation of senescent and SASP blockade, which is considered as a promising strategy for the management of renal diseases.

Sodium/calcium overload and Sirt1/Nrf2/OH-1 pathway are critical events in mercuric chloride-induced nephrotoxicity.

Mercury (Hg), a significant toxic metal for nephrotoxicity, can be found in food (vegetable and seafood) and drinking water by contamination. Oxidative stress is involved in inorganic Hg-induced nephrotoxicity, but the Sirtuin1 (Sirt1)/Nrf2/OH-1 pathway and sodium (Na)/calcium (Ca) ions actions in mercuric chloride (HgCl2)-induced nephrotoxicity remains unclear to date. In this study, Kunming mice were treated HgCl2 (5 mg/kg) for 24 h to evaluate potential mechanism. Here, along with Sirt1 activation, pale kidney, hisologic conditions, typical apoptotic changes and TUNEL positive nuclei were observed under acute HgCl2 exposure. Specifically, although HgCl2 increased the expression of Nrf2, Keap1, OH-1 and NQO1, the mRNA levels of GSS, GCLC and GCLM showed no significant alterations in mice kidney. Moreover, mice exposed to HgCl2 decreased the concentrations of Mg, K, P, Mn, Fe, Zn, and elevated Na, Ca, Cu and Se in kidney. It was also observed that HgCl2 suppressed the ATPases (Na+-K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and Ca2+-Mg2+-ATPase) activities and decreased the mRNA levels of Atp1a1, Atp1a2 in the kidney. Further study showed that HgCl2 elevated Na+ concentrations by markedly increased the mRNA levels of Na+ transporter. The present study revealed that HgCl2 induced Sirt1/Nrf2/OH-1 pathway activation while did not inhibit apoptosis in kidney of mice. Additionally, HgCl2 regulates Na+ concentrations, which might create secondary disorders in absorption and excretion of other ions. Altogether we assume that Sirt1/Nrf2/Na+/Ca2+ pathway might be a potential therapeutic target for treating acute HgCl2 induced nephrotoxicity.