AGK2, a SIRT2 inhibitor, ameliorates D-galactose-induced liver fibrosis by inhibiting fibrogenic factors.

In our study, we aimed to investigate the effect of SIRT2 inhibition on function, fibrosis and inflammation in liver fibrosis induced by D-Galactose (D-Gal) administration. A total of 32 3-month-old Sprague Dawley rats were used in the study. Rats were divided into 4 groups as Control, d-Gal, Solvent+d-Gal, d-Gal+AGK2+Solvent. d-Gal (150 mg/kg/day), AGK-2 (10 µM/bw) as a specific SIRT2 inhibitor, 4%DMSO + PBS as a solvent was applied to the experimental groups and physiological saline was applied to the control group for 10 weeks. All applications were performed subcutaneously. Histological fibrotic changes were studied in the liver tissues by Masson's trichrome staining, hematoxylin and eosin staining and immunohistochemistry and the levels of selected factors were determined by quantitative reverse transcription-polymerase chain reaction, western blot analysis, and immunohistochemical analysis. Biochemical parameters and Paraoxonase levels were determined in the plasma. d-Galactose administration increased AST, AST-ALT Ratio, APRI, SIRT2 protein expression, IL1ß, TGF ß, ß-catenin, Type I collagen, Type III collagen and α-SMA, collagen fiber density and histopathological score. ALT and lipid panels were not changed and paraxonase plasma level was shown to decrease. These effects were largely blocked by the SIRT2 inhibitor AGK2. These findings suggest that SIRT2 inhibition attenuates d-Gal-induced liver injury and that this protection may be due to its antifibrotic and anti-inflammatory activities.

Naringenin ameliorates MASH fibrosis via regulating TAK1/MAPK/FoxO3a-mediated apoptosis in the activated hepatic stellate cells.

This study aims to explore the regulating effect and mechanism of naringenin (NGN) on the hepatic stellate cells (HSCs) apoptosis and its preventive effects on MASH fibrosis. C57BL/6 mice were subjected to either high-fat diet (HFD) plus carbon tetrachloride (CCl4) injection (HFD + CCl4) for 8 weeks to induce a MASH fibrosis model or bile duct ligation (BDL) to establish a liver fibrosis model, NGN was administered by gavage. LX2 cells were stimulated by oleic acid (OA) and lipopolysaccharide (LPS) (OA + LPS) to study the effects of NGN on activated hepatic stellate cell (HSC). Additionally, LO2 cells stimulated with OA + LPS were used to assess the protective effects of NGN on lipotoxicity of hepatocytes. Our in vivo results showed that NGN administration effectively inhibited mouse liver fibrosis in both of the MASH model and BDL model. The in vitro results indicate that NGN directly inhibited HSCs activation and promoted apoptosis of the activated HSCs, while it suppressed the apoptosis of LO2 cells induced by OA + LPS. The underlying mechanisms were mainly elucidated through the reduction of TAK1 phosphorylation, leading to the downregulation of p-JNK and p-ERK expression. This in turn, inhibited the phosphorylation of FoxO3a and promoted the nuclear localization of FoxO3a. Consequently, this may enhance the transcription of apoptosis-related genes, resulting in the apoptosis of activated HSCs. In conclusion, NGN ameliorates MASH fibrosis by enhancing apoptosis of the activated HSCs. The inhibitory effects of NGN on the TAK1/MAPK/FoxO3a pathway were demonstrated as its preventive mechanisms against MASH fibrosis.

A New Target for Hepatic Fibrosis Prevention and Treatment: The Warburg Effect.

Hepatic fibrosis is a major public health problem that endangers human wellbeing. In recent years, a number of studies have revealed the important impact of metabolic reprogramming on the occurrence and development of hepatic fibrosis. Among them, the Warburg effect, as an intracellular glucose metabolism reprogramming, can promote the occurrence and development of hepatic fibrosis by promoting the activation of hepatic stellate cells (HSCs) and inducing the polarization of liver macrophages (KC). Understanding the Warburg effect and its important role in the progression of hepatic fibrosis will assist in developing new strategies for the prevention and treatment of hepatic fibrosis. This review focuses on the Warburg effect and the specific mechanism by which it affects the progression of hepatic fibrosis by regulating HSCs activation and KC polarization. In addition, we also summarize and discuss the related experimental drugs and their mechanisms that inhibit the Warburg effect by targeting key proteins of glycolysis in order to improve hepatic fibrosis in the hope of providing more effective strategies for the clinical treatment of hepatic fibrosis.

Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease.

BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM: To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS: ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS: The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and ß-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION: EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

Hepatoprotective effect of astaxanthin against cholestasis liver fibrosis induced by bile duct ligation in adult Wistar rats.

In this study, we evaluated the hepatoprotective effects of astaxanthin, a natural carotenoid, against the cholestatic liver fibrosis induced by bile duct ligation (BDL). Toward this end, male rats were subjected to BDL and treated with astaxanthin for 35 days. Afterwards, their serum and liver biochemical factors were assessed. Also, histopathological and immunohistochemical analyses were performed to determine the fibrosis and the expression levels of alpha-smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-ß1) in the liver tissue. Based on the results, BDL caused a significant increase in liver enzyme levels, blood lipids, and bilirubin, while decreasing the activity of superoxide dismutase(SOD), catalase (CAT), and glutathione (GSH) enzymes. Also, in the BDL rats, hepatocyte necrosis, infiltration of inflammatory lymphocytes, and hyperplasia of bile ducts were detected, along with a significant increase in α-SMA and TGF-ß1 expression. Astaxanthin, however, significantly prevented the BDL's detrimental effects. In all, 10 mg/kg of this drug maintained the bilirubin and cholesterol serum levels of BDL rats at normal levels. It also reduced the liver enzymes' activity and serum lipids, while increasing the SOD, CAT, and GSH activity in BDL rats. The expression of α-SMA and TGF-ß1 in the BDL rats treated with 10 mg/kg of astaxanthin was moderate (in 34%-66% of cells) and no considerable cholestatic fibrosis was observed in this group. However, administrating the 20 mg/kg of astaxanthin was not effective in this regard. These findings showed that astaxanthin could considerably protect the liver from cholestatic damage by improving the biochemical features and regulating the expression of related proteins.

Tranilast Inhibits TRPV2 and Suppresses Fibrosis Progression and Weight Gain in a NASH Model Mouse.

BACKGROUND/AIM: This study aimed to investigate the role of transient receptor potential vanilloid 2 (TRPV2) in a mouse model with non-alcoholic steatohepatitis (NASH) and to examine the effects of tranilast on TRPV2 and fibrosis-related cytokines. MATERIALS AND METHODS: C57BL/6N mice were fed a Gubra-Amylin NASH (GAN) diet for 20 weeks to induce NASH. The tranilast groups received oral administration of tranilast at doses of 300, 400 and 500 mg/kg/day, five days per week for 20 weeks, in addition to the GAN diet. The effects of tranilast were assessed based on the dosage of food intake, changes in body weight, liver weight, blood biochemical parameters, histopathological examination, and expression of TRPV2 and inflammatory cytokines. RESULTS: Hepatic expression of TRPV2 was observed in the GAN-fed NASH mouse model. The tranilast groups showed significantly suppressed increases in body and liver weights. The development of intrahepatic fat deposition and liver fibrosis, assessed histopathologically, was inhibited. Tranilast administration improved the expression of TRPV2 and inflammatory cytokines in the liver. Additionally, blood tests indicated a reduction in elevated liver enzyme levels. CONCLUSION: In GAN diet NASH models, TRPV2 was up-regulated in the liver and tranilast inhibited TRPV2 and suppressed fibrosis. Therefore, it might prevent the incidence of hepatocellular carcinoma associated with NASH.

Bifidobacterium longum-Derived Extracellular Vesicles Prevent Hepatocellular Carcinoma by Modulating the TGF-ß1/Smad Signaling in Mice.

BACKGROUND: The involvement of gut microbiota in carcinogenesis has gradually been highlighted in past decades. Bacteria could play its role by the secretion of extracellular vesicles (EVs); however, interrelationship between bacterial EVs and hepatocellular carcinoma (HCC) development has not been investigated much. METHODS: Diethylnitrosamine (DEN) was utilized to produce HCC model in mice, of which fecal was collected for detecting Bifidobacterium longum (B.longum) with real-time polymerase chain reaction (PCR). EV isolated from B.longum (B.longum-EV) with ultracentrifugation were stained with PKH26 to investigate the cellular uptake of murine hepatocytes (AML12). After treatment with B.longum-EV, TGF-ß1-induced AML12 cells were subjected to morphological observation, fibrosis- and apoptosis-related marker detection with western blot, apoptotic ratio and reactive oxygen species (ROS) level analysis with flow cytometry, and oxidative stress biomarker assessment with enzyme-linked immunosorbent assay (ELISA); meanwhile, animal studies including liver function, tumor formation rate, and histological analysis, were also performed to investigate the role of B.longum-EV in the fibrosis, apoptosis, oxidative stress, and carcinogenesis of the liver in vivo. RESULTS: The levels of B.longum were significantly reduced in HCC model mice. B.longum-EV could enter AML12 cells and effectively attenuate TGF-ß1-induced fibrosis, apoptosis, and oxidative stress in AML12 cells. In vivo studies showed that B.longum-EV administration alleviated DEN-induced liver fibrosis, apoptosis, and oxidative stress at the early stage. Moreover, B.longum-EV administration also effectively reduced the tumor formation rate and liver function injury in DEN-induced mice and down-regulated TGF-ß1 expression and Smad3 phosphorylation of mouse liver. CONCLUSIONS: B.longum-EVs protect hepatocytes against fibrosis, apoptosis, and oxidative damage, which exert a potential of preventing HCC development.

Roflumilast ameliorates GAN diet-induced non-alcoholic fatty liver disease by reducing hepatic steatosis and fibrosis in ob/ob mice.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent progressive liver disease. Currently, there is only one drug for NAFLD treatment, and the options are limited. Phosphodiesterase-4 (PDE-4) inhibitors have potential in treating NAFLD. Therefore, this study aims to investigate the effect of roflumilast on NAFLD. Here, we fed ob/ob mice to induce the NAFLD model by GAN diet. Roflumilast (1 mg/kg) was administered orally once daily. Semaglutide (20 nmol/kg), used as a positive control, was injected subcutaneously once daily. Our findings showed that roflumilast has beneficial effects on NAFLD. Roflumilast prevented body weight gain and improved lipid metabolism in ob/ob-GAN NAFLD mice. In addition, roflumilast decreased hepatic steatosis by down-regulating the expression of hepatic fatty acid synthesis genes (SREBP1c, FASN, and CD36) and improving oxidative stress. Roflumilast not only reduced liver injury by decreasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, but also ameliorated hepatic inflammation by reducing the gene expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6). Roflumilast lessened liver fibrosis by inhibiting the expression of fibrosis mRNA (TGFß1, α-SMA, COL1a1, and TIMP-1). Collectively, roflumilast could ameliorate NAFLD, especially in reducing hepatic steatosis and fibrosis. Our findings suggested a PDE-4 inhibitor roflumilast could be a potential drug for NAFLD.

[Research progress on induced hepatic stellate cell ferroptosis in prevention and treatment of liver fibrosis].

Liver fibrosis is a key pathological stage in the progression of chronic liver disease. If the disease is mistreated, it can further deteriorate into liver failure, which seriously affects the quality of life of patients and brings heavy medical costs. Hepatic stellate cell(HSC) activation triggers extracellular matrix(ECM) deposition, which plays an important driving role in liver fibrosis, and ferroptosis is an effective strategy to clear or reverse the activation of HSCs into a deactivated phenotype. Therefore, inhibiting the activation and proliferation of HSCs by regulating ferroptosis is the key to the treatment of this disease, so as to derive the prospect of inducing ferroptosis of HSCs(including RNA-binding proteins, non-coding RNA, chemicals, and active components of traditional Chinese medicine) to intervene in liver fibrosis. On this basis, this paper started from the activation of HSCs to induce ECM deposition and focused on summarizing the mechanism of inducing HSC ferroptosis in delaying the progression of liver fibrosis, so as to continuously enrich the clinical practice of liver fibrosis and provide a reference for subsequent basic research.

Farnesoid X receptor modulator 12ß-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid represses liver fibrosis by inhibiting ERK/p38 signaling pathways.

Liver fibrosis is a common pathological process in the progression of several chronic liver diseases to cirrhosis and hepatocellular carcinoma. Therefore, the development of medications that can repress the progress of liver fibrosis is essential. We discovered that initially, 12ß-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid (12d-OA), a farnesoid X receptor (FXR) modulator, possessed potential anti-fibrotic properties. Through an in-depth study, we revealed that 12d-OA not only inhibited the expression of fibrogenic markers in the LX-2 cells and HSC-T6 cells but also exhibited significant protective effects against liver injury and liver fibrosis in bile duct ligation (BDL) rats. Further exploration of its molecular mechanism indicated that 12d-OA exerted antifibrotic activity by inhibiting the extracellular signal-regulated kinase (ERK)/stress-activated protein kinase (p38) signaling pathways. Consequently, the great effects of 12d-OA in vitro and in vivo suggest that it may be a good candidate for liver fibrosis.

Thymoquinone protects thioacetamide-induced chronic liver injury by inhibiting TGF-ß1/Smad3 axis in rats.

Chronic liver injury due to various etiological factors results in excess secretion and accumulation of extracellular matrix proteins, leading to scarring of liver tissue and ultimately to hepatic fibrosis. If left untreated, fibrosis might progress to cirrhosis and even hepatocellular carcinoma. Thymoquinone (TQ), an active compound of Nigella sativa, has been reported to exhibit antioxidant, anti-inflammatory and anticancer activities. Therefore, the effect of TQ against thioacetamide (TAA)-induced liver fibrosis was assessed in rats. Fibrosis was induced with intraperitoneal administration of TAA (250 mg/kg b.w.) twice a week for 5 weeks. TQ (20 mg/kg b.w.) and silymarin (50 mg/kg b.w.) were orally administered daily for 5 weeks separately in TAA administered groups. Liver dysfunction was reported by elevated liver enzymes, increased oxidative stress, inflammation and fibrosis upon TAA administration. Our study demonstrated that TQ inhibited the elevation of liver marker enzymes in serum. TQ administration significantly increased antioxidant markers, such as superoxide dismutase, catalase, glutathione, glutathione peroxidase and glutathione reductase in the liver tissue of rats. Further, TQ significantly attenuated liver fibrosis, as illustrated by the downregulation of TAA-induced interleukin-ß, tumour necrosis factor-α, inducible nitric oxide synthase and fibrosis markers like transforming growth factor-ß (TGF-ß), α-smooth muscle actin, collagen-1, Smad3 and 7. Therefore, these findings suggest that TQ has a promising hepatoprotective property, as indicated by its potential to effectively suppress TAA-induced liver fibrosis in rats by inhibiting oxidative stress and inflammation via TGF-ß/Smad signaling.

Empagliflozin attenuates liver fibrosis in high-fat diet/streptozotocin-induced mice by modulating gut microbiota.

The effects of SGLT2 inhibitors on hepatic fibrosis in diabetes remain unclear. This study aimed to investigate the effects of empagliflozin on liver fibrosis in high-fat diet/streptozotocin-induced mice and the correlation with gut microbiota. After the application of empagliflozin for 6 weeks, we performed oral glucose tolerance and intraperitoneal insulin tolerance tests to assess glucose tolerance and insulin resistance, and stained liver sections to evaluate histochemical and hepatic pathological markers of liver fibrosis. Moreover, 16S rRNA amplicon sequencing was performed on stool samples to explore changes in the composition of intestinal bacteria. We finally analysed the correlation between gut microbiome and liver fibrosis scores or indicators of glucose metabolism. The results showed that empagliflozin intervention improved glucose metabolism and liver function with reduced liver fibrosis, which might be related to changes in intestinal microbiota. In addition, the abundance of intestinal probiotic Lactobacillus increased, while Ruminococcus and Adlercreutzia decreased after empagliflozin treatment, and correlation analysis showed that the changes in microbiota were positively correlated with liver fibrosis and glucose metabolism. Overall, considering the contribution of the gut microbiota in metabolism, empagliflozin might have improved the beneficial balance of intestinal bacteria composition. The present study provides evidence and indicates the involvement of the gut-liver axis by SGLT2 inhibitors in T2DM with liver fibrosis.

Therapeutic implication of human placental extract to prevent liver cirrhosis in rats with metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is always accompanied with hepatic fibrosis that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Employing a rat model, we evaluated the role of human placental extract (HPE) to arrest the progression of hepatic fibrosis to cirrhosis in patients with MASH. SHRSP5/Dmcr rats were fed with a high-fat and high-cholesterol diet for 4 weeks and evaluated for the development of steatosis. The animals were divided into control and treated groups and received either saline or HPE (3.6 ml/kg body weight) subcutaneously thrice a week. A set of animals were killed at the end of 6th, 8th, and 12th weeks from the beginning of the experiment. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatic malondialdehyde (MDA), and glutathione content were measured. Immunohistochemical staining was performed for α-smooth muscle actin (α-SMA), 4-hydroxy-2-nonenal (4-HNE), collagen type I, and type III. Control rats depicted progression of liver fibrosis at 6 weeks, advanced fibrosis and bridging at 8 weeks, and cirrhosis at 12 weeks, which were significantly decreased in HPE-treated animals. Treatment with HPE maintained normal levels of MDA and glutathione in the liver. There was marked decrease in the staining intensity of α-SMA, 4-HNE, and collagen type I and type III in HPE treated rats compared with control animals. The results of the present study indicated that HPE treatment mediates immunotropic, anti-inflammatory, and antioxidant responses and attenuates hepatic fibrosis and early cirrhosis. HPE depicts therapeutic potential to arrest the progression of MASH towards cirrhosis.

Innovative prophylactic and therapeutic approaches in liver cirrhosis.

Liver cirrhosis is the consequence of chronicisation and of the evolution of untreated liver diseases. The complexity of the disease and the complications it can cause have been and are still intensively researched, aiming to discover new therapies or improve existing ones for the effective management of liver cirrhosis. Currently, the treatment used is directed against the cause that caused the disease, if it is known; in advanced cases, liver transplantation is the only valid therapeutic option. Hepatoprotectors that are currently on the market are numerous, having as common properties the antioxidant, anti-inflammatory, stabilizing properties of the hepatocytic membrane; A few examples: the ethanolic extract of Curcuma longa, the extract from the plant called Sophora flavescens, the extract of Glycyrrhiza glabra, silymarin (extracted from Sylibum marianum), the extract of Ganoderma lucidum, etc. Liver cirrhosis is accompanied by generalized hypovitaminosis, so supplementing the diet with hydro- and liposoluble vitamins is mandatory. Protein-caloric malnutrition can be prevented by a hyperprotein diet, especially beneficial being the supplementation with branched-chain amino acids, which are also applicable in the prophylaxis and treatment of hepatic encephalopathy. Nanoparticles are a state-of-the-art therapeutic option, proving increased bioavailability, for example polydopamine nanoparticles loaded with l-arginine have been tested as therapy in liver cirrhosis. Among the innovative treatment directions in liver cirrhosis are hybrid products (e.g. hybrid polymer nanoparticles loaded with caffeic acid), cell cultures and artificial or bioartificial liver support.

Virological, serological and clinical outcomes in chronic hepatitis B virus infection: development and validation of the HEPA-B simulation model.

OBJECTIVES: Detailed simulation models are needed to assess strategies for prevention and treatment of hepatitis B virus (HBV) infection, the world's leading cause of liver disease. We sought to develop and validate a simulation model of chronic HBV that incorporates virological, serological and clinical outcomes. METHODS: We developed a novel Monte Carlo simulation model (the HEPA-B Model) detailing the natural history of chronic HBV. We parameterised the model with epidemiological data from the Western Pacific and sub-Saharan Africa. We simulated the evolution of HBV DNA, 'e' antigen (HBeAg) and surface antigen (HBsAg). We projected incidence of HBeAg loss, HBsAg loss, cirrhosis, hepatocellular carcinoma (HCC) and death over 10-year and lifetime horizons. We stratified outcomes by five HBV DNA categories at the time of HBeAg loss, ranging from HBV DNA<300 copies/mL to >106 copies/mL. We tested goodness of fit using intraclass coefficients (ICC). RESULTS: Model-projected incidence of HBeAg loss was 5.18% per year over lifetime (ICC, 0.969 (95% CI: 0.728 to 0.990)). For people in HBeAg-negative phases of infection, model-projected HBsAg loss ranged from 0.78% to 3.34% per year depending on HBV DNA level (ICC, 0.889 (95% CI: 0.542 to 0.959)). Model-projected incidence of cirrhosis was 0.29-2.09% per year (ICC, 0.965 (95% CI: 0.942 to 0.979)) and HCC incidence was 0.06-1.65% per year (ICC, 0.977 (95% CI: 0.962 to 0.986)). Over a lifetime simulation of HBV disease, mortality rates were higher for people with older age, higher HBV DNA level and liver-related complications, consistent with observational studies. CONCLUSIONS: We simulated HBV DNA-stratified clinical outcomes with the novel HEPA-B Model and validated them to observational data. This model can be used to examine strategies of HBV prevention and management.

Functional Food Chemical Ingredient Strategies for Non-alcoholic Fatty Liver Disease (NAFLD) and Hepatic Fibrosis: Chemical Properties, Health Benefits, Action, and Application.

PURPOSE OF REVIEW: The liver is an important digestive gland in the body. Lifestyle and dietary habits are increasingly damaging our liver, leading to various diseases and health problems. Non-alcoholic fatty liver disease (NAFLD) has become one of the most serious liver disease problems in the world. Diet is one of the important factors in maintaining liver health. Functional foods and their components have been identified as novel sources of potential preventive agents in the prevention and treatment of liver disease in daily life. However, the effects of functional components derived from small molecules in food on different types of liver diseases have not been systematically summarized. RECENT FINDINGS: The components and related mechanisms in functional foods play a significant role in the development and progression of NAFLD and liver fibrosis. A variety of structural components are found to treat and prevent NAFLD and liver fibrosis through different mechanisms, including flavonoids, alkaloids, polyphenols, polysaccharides, unsaturated fatty acids, and peptides. On the other hand, the relevant mechanisms include oxidative stress, inflammation, and immune regulation, and a large number of literature studies have confirmed a close relationship between the mechanisms. The purpose of this article is to examine the current literature related to functional foods and functional components used for the treatment and protection against NAFLD and hepatic fibrosis, focusing on chemical properties, health benefits, mechanisms of action, and application in vitro and in vivo. The roles of different components in the biological processes of NAFLD and liver fibrosis were also discussed.

Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor.

Non-alcoholic fatty liver disease (NAFLD) is increasing globally, and seeking therapeutic molecule targets is urgent. Several studies have demonstrated that IL-33 plays an important role in the progression of Non-alcoholic steatohepatitis (NASH) with fibrosis and the proliferation of hepatocellular carcinoma (HCC). However, whether the inhibition of IL-33 signaling prevents NAFLD from progressing to NASH and HCC has not been clarified. We investigated the effects of a novel antibody, IL-33RAb, and luseogliflozin, a SGLT2 inhibitor, when administered to a model mouse for NASH and HCC, and their effects were compared to investigate the mechanisms of how IL-33 is involved in the pathogenesis of NASH progression. Compared with the positive control of luseogliflozin, inhibition of IL-33 signaling ameliorated decreasing hepatic fibrosis via decreasingαSMA and MCP-1, and also partially suppressed the progression of the HCC cell line in in vitro experiments. These findings suggest that inhibition of IL-33 possibly prevents progression from NASH to HCC, and their effect may be a newly arrived therapeutic agent.

Abordaje de la esteatosis hepática en atención primaria / Approach to hepatic steatosis in primary care

Desde fines de 2023, la denominación hígado graso no alcohólico cambió por esteatosis hepática asociada a disfunción metabólica (MASLD, por sus iniciales en inglés), ya que el nombre anterior era considerado estigmatizante para los pacientes. No está recomendado rastrear esta entidad en la población general. Sin embargo, si por algún motivo se solicitó una ecografía y esta informa esteatosis hepática, se recomienda evaluar el riesgo de progresión a fibrosis hepática mediante el puntaje FIB-4. Los pacientes con puntaje mayor a 1,3 requieren mayor evaluación y se les solicita una elastografía transicional (Fibroscan®). El tratamiento de esta entidad apunta, en general, al descenso de peso mediante la actividad física y la dieta hipocalórica. (AU)

Since the end of 2023, the name non-alcoholic fatty liver has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD), as the former denomination was considered stigmatizing for patients. It is not recommended to screen for this entity in the general population. However, if for some reason an ultrasound was performed and it reports hepatic steatosis, it is recommended to evaluate the risk of progression to liver fibrosis using the FIB-4 score. Patients with a score greater than 1.3 require further evaluation, and a transient elastography (FibroScan®) is requested. Treatment in general aims at weight loss through physical activity and a low-calorie diet. (AU)

Lactobacillus plantarum and Bifidobacterium longum Alleviate Liver Injury and Fibrosis in Mice by Regulating NF-κB and AMPK Signaling.

In a preliminary study, live biotherapeutic products (LBPs) Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 inhibited the secretion of alanine transaminase (ALT) and aspartate transaminase (AST) in LPS-stimulated HepG2 cells, while Escherichia coli K1 (Ec) increased ALT and ALT secretion. Therefore, we examined the effects of LC27 and LC67 on LPS-induced liver injury and fibrosis in mice and the correlation between their biomarkers in cell and animal experiments. Orally administered LC27 or LC67 significantly decreased blood ALT, AST, γ-glutamyl transferase (γGTP), TNF-α, triglyceride (TG), total cholesterol (TCh), total bile acid, and LPS levels, liver TNF-α, toll-like receptor-4 gene (Tlr4), α-smooth muscle actin (αSMA), and collagen-1 expression and αSMA+GFAP+ and NF-κB+F4/80+ cell populations, and colonic Tlr4, TNF-α, and IL-6 expression and NF-κB-positive cell population in LPS-treated mice. Furthermore, they increased AMPKa phosphorylation in the liver and colon. However, Ec increased the expression of TNF-α and IL-6 in blood, liver, and colon. The suppression of LPS-stimulated ALT and AST secretion in HepG2 cells by LBPs was positively correlated with their ameliorating effects on LPS-induced blood γGTP, ALT, and AST levels and liver αSMA and collagen-1 expression in mice. Based on these findings, LC27 and LC67 may improve liver injury and fibrosis by regulating NF-κB and AMPK signaling pathway and a protocol that can assay the inhibitory activity of LBPs on LPS-induced ALT and AST secretion in HepG2 may be useful for guessing their antihepatitic effects in the in vivo experiments.

Mechanisms and targeted reversion/prevention of hepatic fibrosis caused by the non-hereditary toxicity of benzo(a)pyrene.

The effect of long term exposure to low concentrations of environmental pollutants on hepatic disorders is a major public health concern worldwide. Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic pollutants. In recent years, an increasing number of studies have focused on the deleterious effects of low concentrations of PAHs in the initiation or exacerbation of the progression of chronic liver disease. However, the underlying molecular mechanisms and effective intervention methods remain unclear. Here, we found that in hepatocytes, a low concentration of benzo(a)pyrene (B[a]P, an indicator of PAHs) chronic exposure continuously activated 14-3-3η via an epigenetic accumulation of DNA demethylation. As a "switch like" factor, 14-3-3η activated its downstream PI3K/Akt signal, which in turn promoted vascular endothelial growth factor (VEGF) production and secretion. As the characteristic fibrogenic paracrine factor regulated by B[a]P/14-3-3η, VEGF significantly induced the neovascularization and activation of hepatic stellate cells, leading to the development of hepatic fibrosis. Importantly, targeted 14-3-3η by using its specific inhibitor invented by our lab could prevent B[a]P-induced hepatic fibrosis, and could even reverse existent hepatic fibrosis caused by B[a]P. The present study not only revealed novel mechanisms, but also proposed an innovative approach for the targeted reversion/prevention of the harmful effects of exposure to PAHs on chronic liver disease.