Whether sofosbuvir is suitable for hepatitis C virus (HCV) infected patients with severe renal impairment is inconclusive. This systematic review aims to evaluate the safety and effectiveness of SOF-based regimen in the setting of stage 4 and 5 chronic kidney disease (CKD). We conducted a systematic literature search in PubMed, Web of Science, EMBASE and Google Scholar with searching strategy: (sofosbuvir OR Sovaldi OR Harvoni OR Epclusa OR Vosevi) AND (severe kidney impairment OR severe renal impairment OR end-stage renal disease OR dialysis OR renal failure OR ESRD OR renal insufficiency OR hepatorenal syndrome OR HRS). Sustained virological response (SVR12/24) rate and serious adverse event (SAE) rate with 95% confidence intervals were aggregated. Subgroup analysis was implemented to evaluate the impact of treatment strategy and patient characteristics. Twenty-one studies met inclusion criteria, totaling 717 HCV infected patients with CKD stage 4 or 5 (58.4% on dialysis). Pooled SVR12/24 was 97.1% (95% CI 93.9–99.3%), and SAE rate was 4.8% (95% CI 2.1–10.3%). There was no significant difference at SVR12/24 (97.1% vs 96.2%, p = 0.72) or SAE rate (8.8% vs 2.9%, p = 0.13) between subgroups applying full or decreased dose of sofosbuvir. Cirrhotic and non-cirrhotic patients achieved comparable sustained virological response (RR 0.93, 95% CI 0.85–1.02). Four studies reported eGFR/serum creatinine pre- and post- treatment, with no significant modification. Our study suggests SOF-based regimen might be used safely and effectively in patients living with HCV infection/stage 4–5 CKD, with normal and reduced dose of sofosbuvir. Prospective and well-controlled trials are needed to confirm these findings. PROSPERO CRD42018107440 .

Pyrazinamide (PZA) is an anti-tuberculosis drug known to causes liver injury. phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling protects against liver injury by promoting cellular antioxidant defenses and reducing intracellular reactive oxygen species (ROS) and lipid peroxidation. The regulatory mechanisms and functions of PI3K/Akt signaling during the hepatotoxicity of PZA are however not fully understood. Rats were administered PZA or/and the PI3K activator (740Y-P) for 7 days. The levels of serum parameters were examined via standard enzymatic techniques and the pathological status of the liver was confirmed by H & E staining. The levels of lipid peroxidation and antioxidant production were determined using commercial kits. Liver apoptosis was assessed by TUNEL staining. The expression of apoptosis-related proteins and PI3K/Akt signaling were assessed by western blot analysis. PZA treatment significantly increased serum alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase and tall bilirubin leading to liver damage in rats. PZA also facilitated lipid peroxidation and suppressed antioxidant defenses. PZA led to apoptotic induction in rat liver cells through the downregulation of Bcl-2 and the upregulation of Bax and caspase-3. PZA also dramatically inhibited PI3K/Akt signaling in rat liver cells. We further verified that PI3K/Akt signaling in response to 740Y-P could attenuate hepatic injury, lipid peroxidation and apoptosis in rat liver cells in response to PZA. We reveal that PZA-induced liver injury in rats occurs through PI3k/Akt signaling, the recovery of which prevents liver injury in rat models.

This study aimed to determine the roles of microRNA (miR)-122 in the activation of hepatic stellate cells (HSCs) and liver cirrhosis. Rat primary HSCs were incubated with transforming growth factor-beta (TGF-β), during which miR-122 and EphB2 expression was measured. miR-122 mimic and/or pcDNA3.1 EphB2 was transfected into TGF-β-induced HSCs. A mouse model of liver cirrhosis was established via an intraperitoneal injection of carbon tetrachloride (CCl₄), followed by the injection of miR-122 agomir. Levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. Fibronectin (FN), alpha smooth muscle actin (α-SMA), Collagen I, miR-122, and EphB2 expression was evaluated in liver tissues and HSCs. Cell proliferation was measured using CCK-8 assay. Interactions between miR-122 and EphB2 were assessed using dual luciferase reporter assay. miR-122 (0.15-fold) was downregulated and EphB2 (mRNA: 5.06-fold; protein: 2.35-fold) was upregulated after TGF-β induction of HSCs. Overexpressed miR-122 decreased proliferation and EphB2 (mRNA: 0.46-fold; protein: 0.62-fold), FN (mRNA: 0.45-fold; protein: 0.64-fold), α-SMA (mRNA: 0.48-fold; protein: 0.51-fold), and Collagen I (mRNA: 0.44-fold; protein: 0.51-fold) expression in HSCs, which was abrogated by EphB2 upregulation. miR-122 expression was reduced by 0.21-fold and serum ALT and AST levels were enhanced in mice following 8-week CCl₄ induction along with increased expression of FN, α-SMA, and Collagen I in liver tissues, which was blocked by miR-122 overexpression. Moreover, EphB2 was a target gene of miR-122. miR-122 curtails HSC proliferation and activation by targeting EphB2 and suppresses liver cirrhosis in mice.

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is the virus that causes coronavirus disease 2019. Angiotensin‑converting enzyme 2 (ACE2) is the SARS‑CoV binding site and is ubiquitously expressed in endothelial cells of several organs, with the highest levels in the cardiovascular system, kidney and lungs. A disintegrin and metalloproteinase 17 (ADAM17) is involved in ectodomain shedding of ACE2. In the present study, reverse‑transcription‑quantitative PCR, transfection, TUNNEL assay, dual‑luciferase activity assay and western blotting were conducted to investigate the effects of microRNA (miR)‑28‑3p on ADAM17‑dependent shedding of the ACE2 ectodomain following treatment with the spike protein (S‑protein) of SARS‑CoV‑2. It was found that miR‑28‑3p was significantly downregulated in 293T cells treated with 100 ng/ml of S‑protein for 24 h at 37˚C, which led to upregulation of ADAM17. In addition, the expression of ADAM17 and miR‑28‑3p were negatively correlated based on Pearson's correlation test in 293T cells treated with S‑protein for 24 h. Overexpression of miR‑28‑3p and inhibition of ADAM17 regulated 293T cell viability, apoptosis and ACE2 ectodomain shedding. It was also demonstrated that ADAM17 was the target gene of miR‑28‑3p and that miR‑28‑3p negatively regulated ADAM17 expression. Notably, the inhibition of ADAM17 expression blocked the effects of miR‑28‑3p inhibitor on proliferation, apoptosis and ACE2 ectodomain shedding in 293T cells treated with S‑protein. The findings of the present study suggested that miR‑28‑3p inhibits ADAM17‑dependent ACE2 ectodomain shedding in 293T cells treated with the S‑protein of SARS‑CoV‑2, which suggested the potential therapeutic role of miR‑28‑3p mimic in the prevention and treatment of patients with SARS‑CoV‑2.