Many (+)RNA viruses employ translational recoding mechanisms, such as programmed ribosomal readthrough and ribosomal frameshifting, to direct a fraction of translating ribosomes in the infected cell to recode or bypass a stop codon in the zero reading frame and continue translation, thus producing protein isoforms with distinct functions. This creates a means to regulate both the quantity and time of synthesis of canonical and fusion proteins. The viral programmed ribosomal readthrough and ribosomal frameshifting signals are variable, with some being just short RNA sequences encompassing a stop codon, whereas others require elaborate RNA-RNA and RNA-protein interactions. Within virus evolutionary lineages, a given type of recoding signal is not universal, and its presence may be specific to a virus family, species, or even strain. It is possible that the establishment of virus recoding mechanisms and expression patterns occurs after the appearance of extant virus lineages, and these recoding signals might be acquired on multiple occasions during evolution. Recoding signals are the key regulators of gene expression in several clinically important viruses, such as human immunodeficiency viruses 1 and 2, human T-cell lymphotropic retroviruses, and severe acute respiratory syndrome coronavirus 2, as well as in a number of other animal and plant viruses of concern. The knowledge of viral recoding mechanisms is expected to provide new perspectives for the development of antiviral and synthetic biology strategies. Full article

Hepatic diseases have constituted a significant global problem for over two decades, numerous factors contribute to these diseases, and most eventually result in hepatocellular carcinoma. A particular pivotal factor responsible for hepatic diseases is the abnormal functioning of various metabolic processes. Pyruvate kinase is a crucial regulator of the glycolytic pathway, and overexpression of pyruvate kinase isoform M2 (PKM2) has been observed with various hepatic abnormalities due to genetic malfunctioning and other contributing factors. The present scenario for diagnosing and treating hepatic diseases includes surgery and immunosuppressant therapies. Kinase modulation may also be a potential therapeutic measure for rectifying hepatic diseases, and this can serve as a potential approach. This review summarizes the malfunctions and significance of PKM2 regulation and explores the potential of PKM2 as a target for treating hepatic abnormalities. Full article

Nanoparticle (NP) drug delivery systems have been developed recently to resolve the obstacle of drug resistance, contributing to the effective drug delivery to the target organ. A comparative study was carried out herein between doxorubicin (DOX), doxorubicin-loaded titanium NPs, DOX-loaded lactoferrin NPs, DOX-NPs, and PEGylated-doxorubicin (PEG-DOX) on the reno-carcinogenic impact of 3-methylcholanthrene (CA). In-vivo models were exposed to CA at a dose of 50 mg/kg body weight and left for 3 months till the incidence of chronic kidney disease, followed by one month of treatment with the aforementioned nanomedicines. CA downregulated DOX resistance biomarkers, including the gene expression of KRAS, FKBP5, P53, and JAK2, and the kidney tumor marker arginase II. In addition, CA increased the levels of the kidney biomarkers creatinine and urea as well as the minerals chloride and magnesium. Decreased gene expression of FKBP5, KRAS, P53, and JAK2 was reversed after the treatment with DOX-loaded titanium NPs, DOX-NPs, DOX-loaded lactoferrin NPs, and PEG-DOX. PEG-DOX abolished the detrimental effects of CA via upregulating the gene expression of the immunophilin protein (FKBP5), the oncogene (KRAS), the tumor suppressor gene (P53), and JAK2, which indicate DOX drug resistance via regulating cell differentiation, division and apoptosis. PEG-DOX restored renal function and resolved DOX resistance via KRAS, FKBP5, P53, and JAK2 signaling pathways manipulation; consequently, PEG-DOX may provide a useful adjunct treatment for chronic kidney disease. Full article

With the improvement of living standards in recent years, up to 90% of obese patients have nonalcoholic fatty liver disease (NAFLD). The number of nonalcoholic steatohepatitis (NASH)-related deaths will gradually increase, and NASH is expected to be the most common cause of liver-related deaths in the future. Therefore, there is an urgent need to find effective and reliable serum biomarkers to distinguish simple hepatic steatosis (SS) from NASH. Liver cell regeneration, oxidative stress-induced DNA methylation, and biliary epithelial cell proliferation were reported to increase serum alpha-fetoprotein (AFP) levels. AFP has long been used as a tool to monitor liver cancer. However, the function of AFP in NAFLD, especially NASH, has not been clarified. Moreover, whether an elevated AFP level indicates the occurrence of NASH or serves as a serum biomarker remains to be elucidated. The miRNA-122 pathway, DNA methylation and DNA damage, and activation of resident stem cells and/or progenitor cells in the liver, as well as necrosis, regeneration, and repair of liver cells, may contribute to slight increases in AFP levels in the development of NASH in patients with NAFLD. Furthermore, mildly elevated AFP levels may indicate the development of NASH. This review explores the role of elevated AFP levels in the development of NASH, with a specific focus on the underlying molecular mechanisms and the clinical significance. Full article

Diabetes mellitus (DM) is an established risk for biliary tract cancer (BTC). Metformin, an anti-diabetes medication, has been reported for its association with a reduced risk of BTC. However, the controversy about metformin’s benefit among epidemiological studies is unresolved. This study is to investigate metformin’s effects on the development and progression of BTC. Literature searches were performed, without language restriction, in Pubmed, Embase, and Web of Science, from their respective inceptions to February 28, 2023. All studies were screened by two researchers using Covidence. Quality assessment was performed using the Newcastle-Ottawa Scale. Meta-analyses were performed by a fixed and random-effect model using RevMan version 5.4. Nine observational studies met the inclusion criteria and were included in the meta-analysis. With pooled samples of 24,743,526 individuals from 4 case-control and 2 cohort studies, metformin was not associated with a decreased risk of BTC (pooled RR: 0.82, 95% CI: 0.42–1.59, p = 0.56). Sub-group analyses in each study design also revealed a null effect of metformin. Meta-analysis of 3 cohort studies reporting the association between metformin and survival of patients with BTC with a pooled sample of 1,163 patients showed a marginally significant effect of metformin on survival outcome improvement in both fixed effect models (pooled RR: 0.83, 95% CI: 0.68–1.00, p = 0.05), and random-effect model (pooled RR: 0.83, 95% CI: 0.68–1.01, p = 0.07). Meta-analyses of available observational studies showed that metformin was neither significantly associated with decreased risk nor, survival improvement for BTC patients who had DM. Full article

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common and important chronic liver diseases worldwide. Some chronic infectious diseases are associated with the risk of NAFLD. These can induce abnormal glucose and lipid metabolism, insulin resistance, inflammatory activation and other responses, which increase the risk of progression of liver fibrosis. The present study describes the pathogenesis and management of NAFLD with chronic infectious diseases, such as hepatitis B virus, hepatitis C virus, Helicobacter pylori, and human immunodeficiency virus infections. Full article

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the leading causes of hepatic fibrosis and liver-related mortality worldwide, despite efficient hepatitis B and C antiviral therapies that have dramatically lowered the disease load. Although significant efforts have been exerted to understand the molecular basis of disease pathogenesis, there are currently few therapeutic alternatives available for NAFLD-associated fibrosis. Thus, NAFLD prevention is critical before the development of disease-related complications. In this context, there is a tremendous substantial global burden on public health systems to actively search for effective preventive and therapeutic targets for NAFLD. In this review, we highlight the current strategies to prevent progression and poor outcomes of NAFLD and to avoid complications associated with disease fibrosis, notably cirrhosis, portal hypertension, and liver cancer. We discuss different nonpharmacological measures, such as lifestyle modifications (weight loss, exercise, healthy diet) and other pharmacological interventions that could prevent NAFLD. Full article

Today, medicinal plants and phytobiotics that contain flavonoids, alkaloids, and essential oils are widely used in animal feed. These additives have many benefits, including increasing liver function and preventing certain diseases. The liver is one of the organs that plays a key role in insulin-mediated regulation of metabolism as well as in glucose, whole-body, and lipid homeostasis. The aim of this study was to investigate the effect of fennel (Foeniculum vulgare) seed powder consumption on insulin-like growth factor 1 (IGF1) gene expression in the liver tissue of growing lambs. Three groups (including 0, 10, and 20 g/kg dry matter of fennel) of animals, with 10 animals in each group, were studied. The Pfaffl method was applied to assess the real-time polymerase chain reaction (qPCR) output. Mixing fennel into the feed of lambs increased the weights of their testis and gallbladder and decreased the weight of their liver in comparison to feed without fennel. It was also found that by increasing the fennel level in the feed, the expression level of IGF1 in the liver increased significantly (p < 0.05). Fennel had a useful effect on the expression of IGF1 in the liver tissue of sheep and may be applied to their diet to attain better liver function. Full article

The liver contributes substantially to the metabolic transformation and transport of lipids and lipoproteins. These bioactive substances represent a heterogeneous group of molecules with pivotal roles in diverse pathological processes as well as disease progression, the advent of complications, and the response to specific treatments in the context of cirrhosis. The present mini-review aims to summarize the underlying mechanisms regarding lipid changes across divergent circumstances. Recent evidence suggests the prognostic value of lipids/lipoproteins and their close relationship to an increased risk for morbidity and mortality among cirrhotic patients. However, more research regarding the development of risk stratification and therapeutic strategies based on altered lipid profiles in patients with cirrhosis is warranted. Full article