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Liver, an important regulator of metabolic homeostasis, is critical for healthy brain function. In particular, age‐related neurodegenerative diseases seriously reduce the quality of life for the elderly. As population aging progresses rapidly, unraveling the mechanisms that effectively delay aging has become critical. Appropriate exercise is reported to improve aging‐related cognitive impairment. Whereas current studies focused on exploring the effect of exercise on the aging brain itself, ignoring the persistent effects of peripheral organs on the brain through the blood circulation. The aim of this paper is to summarize the communication and aging processes of the liver and brain and to emphasize the metabolic mechanisms of the liver–brain axis about exercise ameliorating aging‐related neurodegenerative diseases. A comprehensive understanding of the potential mechanisms about exercise ameliorating aging is critical for improving adaptation to age‐related brain changes and formulating effective interventions against age‐related cognitive decline. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is the most common type of diabetes, and insulin resistance (IR) is its core pathological mechanism. Proteomics is an ingenious and promising Omics technology that can comprehensively describe the global protein expression profiling of body or specific tissue, and is widely applied to the study of molecular mechanisms of diseases. In this paper, we focused on insulin target organs: adipose tissue, liver, and skeletal muscle, and analyzed the different pathological processes of IR in these three tissues based on proteomics research. By literature studies, we proposed that the main pathological processes of IR among target organs were diverse, which showed unique characteristics and focuses. We further summarized the differential proteins in target organs which were verified to be related to IR, and discussed the proteins that may play key roles in the emphasized pathological processes, aiming at discovering potentially specific differential proteins of IR, and providing new ideas for pathological mechanism research of IR. [ABSTRACT FROM AUTHOR]

Obesity is a worldwide health problem and is directly associated with insulin resistance and type 2 diabetes. The liver is an important organ for the control of healthy glycemic levels, since insulin resistance in this organ reduces phosphorylation of forkhead box protein 1 (FOXO1) protein, leading to higher hepatic glucose production (HGP) and fasting hyperglycemia. Aerobic physical training is known as an important strategy in increasing the insulin action in the liver by increasing FOXO1 phosphorylation and reducing gluconeogenesis. However, little is known about the effects of strength training in this context. This study aimed to investigate the effects of short‐term strength training on hepatic insulin sensitivity and glycogen synthase kinase‐3β (GSK3β) and FOXO1 phosphorylation in obese (OB) mice. To achieve this goal, OB Swiss mice performed the strength training protocol (one daily session for 15 days). Short‐term strength training increased the phosphorylation of protein kinase B and GSK3β in the liver after insulin stimulus and improved the control of HGP during the pyruvate tolerance test. On the other hand, sedentary OB animals reduced FOXO1 phosphorylation and increased the levels of nuclear FOXO1 in the liver, increasing the phosphoenolpyruvate carboxykinase (PEPCK) and glucose‐6‐phosphatase (G6Pase) content. The bioinformatics analysis also showed positive correlations between hepatic FOXO1 levels and gluconeogenic genes, reinforcing our findings. However, strength‐trained animals reverted to this scenario, regardless of body adiposity changes. In conclusion, short‐term strength training is an efficient strategy to enhance the insulin action in the liver of OB mice, contributing to glycemic control by reducing the activity of hepatic FOXO1 and lowering PEPCK and G6Pase contents. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a reversible response to either acute or chronic cellular injury from a wide variety of etiologies, characterized by excessive deposition of extracellular matrix resulting in liver dysfunction and cirrhosis. Melatonin (N‐acetyl‐5‐methoxytryptamine), the main product secreted by the pineal gland, is a multitasking indolamine with important physiological functions such as anti‐inflammatory and antioxidant actions, modulation of circadian rhythms, and immune system enhancement. Among the numerous biological activities of melatonin, its antifibrotic effects have received increasingly more attention. In this study, we performed a systematic review of publications of the last 10 years evaluating the mechanisms of action of melatonin against liver fibrosis. The study protocol was registered at PROSPERO (CRD42022304744). Literature research was performed employing PubMed, Scopus, and Web of Science (WOS) databases, and after screening, 29 articles were included. Results from the selected studies provided denoted the useful actions of melatonin on the development, progression, and evolution of liver fibrosis. Melatonin antifibrotic effects in the liver involved the reduction of profibrogenic markers and modulation of several cellular processes and molecular pathways, mainly acting as an antioxidant and anti‐inflammatory agent. In addition, the indolamine influenced different molecular processes, such as hepatocyte apoptosis, modulation of autophagy and mitophagy, restoration of circadian rhythms, and modulation of microRNAs, among others. Although some limitations have been found regarding variability in the study design, the findings here summarized display the potential role of melatonin in ameliorating the development of liver fibrosis and its possible progression to liver cirrhosis and hepatocarcinoma. [ABSTRACT FROM AUTHOR]

Arsenic is an environmental toxicant. Its overdose can cause liver damage. Autophagy has been reported to be involved in arsenite (iAs3+) cytotoxicity and plays a dual role in cell proliferation and cell death. However, the effect and molecular regulative mechanisms of iAs3+ on autophagy in hepatocytes remains largely unknown. Here, we found that iAs3+ exposure lead to hepatotoxicity by inducing autophagosome and autolysosome accumulation. On the one hand, iAs3+ promoted autophagosome synthesis by inhibiting E2F1/mTOR pathway in L‐02 human hepatocytes. On the other, iAs3+ blocked autophagosome degradation partially via suppressing the expression of INPP5E and Rab7 as well as impairing lysosomal activity. More importantly, autophagosome and autolysosome accumulation induced by iAs3+ increased the protein level of E2F7a, which could further inhibit cell viability and induce apoptosis of L‐02 cells. The treatment of Ginkgo biloba extract (GBE) effectively reduced autophagosome and autolysosome accumulation and thus alleviated iAs3+‐induced hepatotoxicity. Moreover, GBE could also protect lysosomal activity, promote the phosphorylation level of E2F1 (Ser364 and Thr433) and Rb (Ser780) as well as suppress the protein level of E2F7a in iAs3+‐treated L‐02 cells. Taken together, our data suggested that autophagosome and autophagolysosome accumulation play a critical role for iAs3+‐induced hepatotoxicity, and GBE is a promising candidate for intervening iAs3+ induced liver damage by regulating E2F1‐autophagy‐E2F7a pathway and restoring lysosomal activity. [ABSTRACT FROM AUTHOR]

Organic selenium has antioxidation and disease treatment effects. To explore the mechanisms of how methionine selenium alleviates necroptosis in the liver and whether this process is related to microRNA (miRNA) and the mitogen‐activated protein kinase (MAPK) pathway, an animal model of methionine selenium and the lipopolysaccharide (LPS) interaction was established. The morphology, inflammatory factor (tumor necrosis factor‐α [TNF‐α]), necroptosis‐related genes (RIP1, RIP3, MLKL, and caspase 8), MAPK pathway‐related genes (JNK, ERK, and p38, p‐JNK, p‐ERK, and p‐p38), gga‐miR‐155, TRAF3 (predicted target of gga‐miR‐155), and oxidative stress‐related indicators (SOD, MDA, CAT, GSH, and GSH‐Px) were analyzed from the perspective of the miR‐155/TRAF3/MAPK axis to elucidate the mechanism of methionine selenium on the LPS‐induced necroptosis mechanism in the chicken liver. The current results suggested that methionine selenium antagonizes oxidative stress, inflammation, and the MAPK pathway, thereby antagonizing the occurrence of necroptosis through multiple mechanisms. At the same time, methionine selenium affects miR‐155/TRAF3/MAPK signaling, reduces miR‐155 expression, and upregulates TRAF3 expression to inhibit necroptosis. This information provided new ideas and a theoretical basis for the practical application of methionine selenium, and it also enriched the study of miRNAs in birds and provided a reference for comparative medicine. [ABSTRACT FROM AUTHOR]

Thymoquinone (TQ), the main active constituent of Nigella sativa seeds, has been shown to play a role in antioxidation, anti‐inflammation, and antitumor. Recent studies have demonstrated that TQ contributes to the suppression of liver fibrosis. Abnormal activated epithelial‐mesenchymal transition (EMT) promotes the activation of hepatic stellate cells (HSCs). However, whether the antifibrotic effects of TQ occur through inhibiting EMT is largely unknown. In this study, it was found that TQ ameliorated liver fibrosis and collagen accumulation in carbon tetrachloride (CCl4) mice. In vitro, TQ inhibited HSC activation including reduced proliferation, α‐smooth muscle actin, and collagen. In addition, TQ markedly suppressed the EMT process, with enhanced E‐cadherin and reduced desmin. Notably, snail family transcriptional repressor 1 (Snai1), the EMT master transcription factor, was obviously inhibited by TQ in vivo and in vitro. Further studies demonstrated that Snai1 was a target of microRNA‐30a (miR‐30a), which was upregulated by TQ. Interestingly, the effects of TQ on HSC activation and EMT were almost inhibited by miR‐30a inhibitor. Collectively, we demonstrate that TQ inhibits HSC activation, at least in part, via regulation of miR‐30a and Snai1. TQ upregulates miR‐30a expression, resulting in a reduced Snai1 level as well as EMT process inactivation, which contributes to the inhibition of HSC activation. TQ may be a potential therapeutic agent for liver fibrosis. [ABSTRACT FROM AUTHOR]

Liver fibrosis (LF) is the result of a vicious cycle between inflammation‐induced chronic hepatocyte injury and persistent activation of hepatic stellate cells (HSCs). Mesenchymal stem cell (MSC)‐based therapy may represent a potential remedy for treatment of LF. However, the fate of transplanted MSCs in LF remains largely unknown. In the present study, the fate and antifibrotic effect of MSCs were explored in a LF model induced by CCl4 in mouse. Additionally, MSCs were stimulated in vitro with LF‐associated factors, tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ), and transforming growth factor‐β1 (TGF‐β1), to mimic the LF microenvironment. We unveiled that MSCs exhibited autophagy in response to the LF microenvironment through Becn1 upregulation both in vivo and in vitro. However, autophagy suppression induced by Becn1 knockdown in MSCs resulted in enhanced antifibrotic effects on LF. The improved antifibrotic potential of MSCs may be attributable to their inhibitory effects on T lymphocyte infiltration, HSCs proliferation, as well as production of TNF‐α, IFN‐γ, and TGF‐β1, which may be partially mediated by elevated paracrine secretion of PTGS2/PGE2. Thus, autophagy manipulation in MSCs may be a novel strategy to promote their antifibrotic efficacy. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), an abundant nonpsychoactive constituent of marijuana, has been reported previously to protect against hepatic steatosis. In this study, we studied further the functions and mechanisms of CBD on liver inflammation induced by HFC diet. Mice feeding an HFC diet for 8 weeks were applied to test the protective effect of CBD on livers. RAW264.7 cells were incubated with LPS + ATP ± CBD to study the mechanisms of the effect of CBD against inflammasome activation. We found that CBD alleviated liver inflammation induced by HFC diet. CBD significantly inhibited the nuclear factor‐κappa B (NF‐κB) p65 nuclear translocation and the activation of nucleotide‐binding domain like receptor protein 3 (NLRP3) inflammasome both in vivo and in vitro studies, which lead to the reduction of the expression of inflammation‐related factors in our studies. In addition, Inhibitor of activation of NF‐κB partly suppressed the NLRP3 inflammasome activation, while adding CBD further inhibited NF‐κB activation and correspondingly suppressed the NLRP3 inflammasome activation in macrophages. In conclusion, the suppression of the activation of NLRP3 inflammasome through deactivation of NF‐κB in macrophages by CBD might be one mechanism of its anti‐inflammatory function in the liver. [ABSTRACT FROM AUTHOR]

The next‐generation RNA sequencing technologies expedite the discovery of a large number of novel transcripts and genes associated with various pathophysiological conditions. These technologies involve poly(A) enrichment, which in turn requires micrograms of high‐quality total RNA. Unfortunately, the available RNA isolation approaches produce poor quality total RNA from difficult‐to‐isolate animal tissues, such as the liver with high glycogen content. Moreover, the extraction efficiencies of these approaches vary significantly depending on the animal species. To address this challenge, we optimized a three‐step protocol for the extraction of high‐yield and high‐quality total RNA from the liver tissue (LT). The procedure effectively resolved the problem of glycogen coprecipitation by its stepwise removal. No signs of RNA degradation on gel electrophoresis analysis and RNA integrity number values ≥8.5 indicated that the extracted RNA is suitable for downstream processing, such as poly(A) enrichment and transcriptome profiling. To demonstrate the robustness of the novel protocol, a comparison was made with other currently available RNA extraction approaches from diverse resources. Whereas other protocols yielded partially degraded bands with either decreased or reversed ribosomal RNA (rRNA) ratio, our protocol yielded intact rRNA with a ratio of 2.0 ± 0.1. This optimized protocol was also successfully followed for other animal tissues, such as the bone and muscles. In conclusion, the study has described a highly efficient method for the next‐generation sequencing quality RNA isolation from LT across a broad range of animal species, with extended applicability to other difficult‐to‐isolate tissues. [ABSTRACT FROM AUTHOR]

Omega‐3 fatty acids are gaining attention as a therapeutic agent of many diseases. Their protective effect in a variety of diseases has been demonstrated. To the best of our knowledge, this is the first study on omega‐3 fatty acids related to acute cold‐restraint stress (CRS) induced hepatic dysfunction in rats. Forty adult male Sprague–Dawley albino rats were used and classified into: control, omega‐3 group, each rat was pretreated with omega‐3 fatty acids; CRS group, rats were subjected to acute CRS for 6 hr; and CRS group pretreated with omega‐3 fatty acids. Serum was obtained to determine corticosterone (CORT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor‐α (TNF‐α) levels. Hepatic malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were measured. Also, liver tissues were taken for histological examination and immunohistochemical assessment of the apoptotic marker, caspase‐3. Results showed that pretreatment of stressed rats with omega‐3 fatty acids led to significant decrease in hepatic MDA and increase in TAC levels. They reduced serum levels of CORT, ALT, AST, and TNF‐α. Also, they improved liver damage and suppressed hepatic caspase‐3 expression. In conclusion, pretreatment of stressed rats with omega‐3 fatty acids has ameliorated stress‐induced liver damage due to their antioxidant, anti‐inflammatory, and antiapoptotic effects. So, they can be used to minimize stress complications on the liver. Omega‐3 fatty acids are gaining attention as a therapeutic agent of many diseases. Their protective effect in a variety of diseases has been demonstrated. To the best of our knowledge, this is the first study on omega‐3 fatty acids related to acute cold‐restraint stress (CRS) induced hepatic dysfunction in rats. [ABSTRACT FROM AUTHOR]

Liver, as one of the most important organs involved in lipids and glucose metabolism, is perceived as a key tissue for pharmacotherapy of insulin resistance (IRes) and type 2 diabetes. Ceramides (Cer) are biologically active lipids, which accumulation is associated with the induction of muscle IRes. We sought to determine the role of intrahepatic bioactive lipids production on insulin action in liver of insulin‐resistant rats and after myriocin administration. The experiments were conducted on male Wistar rats divided into three groups: Control, fed high‐fat diet (HFD), and fed HFD and treated with myriocin (HFD/Myr). Before sacrifice, the animals were infused with a [U‐13C]palmitate to calculate lipid synthesis rate by means of tracer incorporation technique in particular lipid groups. Liver Cer, diacylglycerols (DAG), acyl‐carnitine concentration, and isotopic enrichment were analyzed by LC/MS/MS. Proteins involved in lipid metabolism and insulin pathway were analyzed by western blot analysis. An OGTT and ITT was also performed. HFD‐induced IRes and increased both the synthesis rate and the content of DAG and Cer, which was accompanied by inhibition of an insulin pathway. Interestingly, myriocin treatment reduced synthesis rate not only of Cer but also DAG and improved insulin sensitivity. We conclude that the insulin‐sensitizing action of myriocin in the liver is a result of the lack of inhibitory effect of lipids on the insulin pathway, due to the reduction of their synthesis rate. This is the first study showing how the synthesis rate of individual lipid groups in liver changes after myriocin administration. Hepatic insulin resistance induced by high‐fat diet resulted from an increase in synthesis rate of ceramide and diacylglycerol (DAG). Myriocin treatment improved insulin sensitivity, which was accompanied by a decrease in the synthesis rate and content of ceramide and DAG. [ABSTRACT FROM AUTHOR]

It is believed that oxidative stress is a key causing factor of liver damage induced by a variety of agents, and it is a major contributing factor in almost all conditions compromising liver function, including ischemia–reperfusion injury (IRI), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC). Liver is the organ that high concentration of melatonin (N‐acetyl‐5‐methoxytryptamine) accumulates, and it is the sole organ where circulating melatonin is metabolized. Melatonin is one of the best antioxidants that protects liver, and its metabolites also have antioxidative function. Melatonin exerts its antioxidative function directly through its radical scavenging ability and indirectly through stimulation of antioxidant enzymes. The antioxidative response from melatonin in liver affects from various factors, including its dosage, route, time and duration of administration, the type of oxidative‐induced agent and species aging. This indoleamine is also an effective and promising antioxidative choice for targeting liver IRI, NAFLD, NASH, fibrosis, cirrhosis, and HCC. [ABSTRACT FROM AUTHOR]

The “in vitro” establishment of a physiological model of bipotential liver progenitors would be useful for analyzing the molecular mechanisms involved in regulating growth and differentiation, as well as studying their potential role/s in liver physiology and pathology. The transforming growth factor-beta (TGF-β) induces de-differentiation of fetal rat hepatocytes (FH), concomitant with changes in morphology. The aim of this work was to isolate and characterize this population of TGF-β-treated fetal hepatocytes (TβT-FH) and test whether they can behave as liver progenitors. The TβT-FH isolated cell lines show high expression of Thy-1 and low expression of c-Kit. They express liver-specific proteins, such as albumin and alpha-fetoprotein, and mesenchymal markers, such as vimentin. TβT-FH maintain expression of the hnf3β gene, but lose expression of hnf1β, hnf4, and hnf6. They express c-met and show an increase in proliferation in response to HGF. Interestingly, the transdifferentiation process is coincident with changes in the expression of genes related to the oxidative metabolism. TβT-FH cultured in the presence of EGF + DMSO change morphology, towards epithelial cells, gaining expression of CK19 and c-Kit, markers found in hepatoblasts and bile duct cells. Furthermore, TβT-FH form duct-like structures when cultured on Matrigel. TβT-FH show also potential to revert to an hepatocyte phenotype when submitted to a long-term “in vitro” differentiation protocol towards hepatocytic lineage. In summary, our results support the hypothesis that hepatocytes can function as facultative liver stem cells and demonstrate that TGF-β might play an essential role in the transdifferentiation process. J. Cell. Physiol. 215: 846–855, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]