Innovative Molecular Targets and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 3.0.

The aim of this Special Issue is to provide an update on the diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD), which is the most prevalent liver disease worldwide; however, there are still no specific treatment agents [...].

Ticagrelor, but Not Clopidogrel, Attenuates Hepatic Steatosis in a Model of Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: Previous studies have suggested that platelets are associated with inflammation and steatosis and may play an important role in liver health. Therefore, we evaluated whether antiplatelet agents can improve metabolic disorder-related fatty liver disease (MASLD). METHODS: The mice used in the study were fed a high-fat-diet (HFD) and were stratified through liver biopsy at 18 weeks. A total of 22 mice with NAFLD activity scores (NAS) ≥ 4 were randomly divided into three groups (HFD-only, clopidogrel (CLO; 35 mg/kg/day), ticagrelor (TIC; 40 mg/kg/day) group). And then, they were fed a feed mixed with the respective drug for 15 weeks. Blood and tissue samples were collected and used in the study. RESULTS: The TIC group showed a significantly lower degree of NAS and steatosis than the HFD group (p = 0.0047), but no effect on the CLO group was observed. Hepatic lipogenesis markers' (SREBP1c, FAS, SCD1, and DGAT2) expression and endoplasmic reticulum (ER) stress markers (CHOP, Xbp1, and GRP78) only reduced significantly in the TIC treatment group. Inflammation genes (MCP1 and TNF-α) also decreased significantly in the TIC group, but not in the CLO group. Nile red staining intensity and hepatic lipogenesis markers were reduced significantly in HepG2 cells following TIC treatment. CONCLUSION: Ticagrelor attenuated NAS and hepatic steatosis in a MASLD mice model by attenuating lipogenesis and inflammation, but not in the CLO group.

Lactiplantibacillus plantarum ZDY2013 Inhibits the Development of Non-Alcoholic Fatty Liver Disease by Regulating the Intestinal Microbiota and Modulating the PI3K/Akt Pathway.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic hepatic condition whose impact on human health is increasingly significant. The imbalance of the gut microbiome, linked to insulin resistance, heightened intestinal permeability, and pro-inflammatory reactions, may be the linchpin in the development of NAFLD. In our research, the impact of Lactiplantibacillus plantarum ZDY2013 administration for 12 weeks on gut microbiota dysbiosis induced by a high-fat, high-fructose, high-cholesterol (FHHC) diet in male C57BL/6n mice was investigated. Research results presented that the intervention of L. plantarum ZDY2013 in mice fed with the FHHC diet could restore their liver function and regulate oxidative stress. Compared to mice in the model group, the intervention of L. plantarum ZDY2013 significantly regulated the gut microbiota, inhibited the LPS/NF-κB pathway, and led to a lower level of colonic inflammation in the mice administered with L. plantarum ZDY2013. It also improved insulin resistance to regulate the PI3K/Akt pathway and lipid metabolism, thereby resulting in reduced fat accumulation in the liver. The above results suggest that the intervention of L. plantarum ZDY2013 can hinder the progression of diet-induced NAFLD by reducing inflammation to regulate the PI3K/Akt pathway and regulating gut microbiota disturbance.

Huanglian-Hongqu herb pair improves nonalcoholic fatty liver disease via NF-κB/NLRP3 pathway in mice: network pharmacology, molecular docking and experimental validation.

The Huanglian-Hongqu herb pair (HH) is a carefully crafted traditional Chinese herbal compound designed to address disorders related to glucose and lipid metabolism. Its primary application lies in treating hyperlipidemia and fatty liver conditions. This study explored the potential mechanism of HH in treating non-alcoholic fatty liver disease (NAFLD) through network pharmacology, molecular docking, and in vivo animal experiments. Ultrahigh performanceliquid chromatography-quadrupole/orbitrapmass spectrometry (UPLC-Q-TOF-MS) was employed to identify the chemical composition of HH. Network pharmacology was used to analyze the related signaling pathways affected by HH. Subsequently, the prediction was verified by animal experiment. Finally, we identified 29 components within HH. Network pharmacology unveiled interactions between HH and 153 NAFLD-related targets, highlighting HH's potential to alleviate NAFLD through NF-κB signaling pathway. Molecular docking analyses illuminated the binding interactions between HH components and key regulatory proteins, including NF-κB, NLRP3, ASC, and Caspase-1. In vivo experiments demonstrated that HH alleviated NAFLD by reducing serum and liver lipid levels, improving liver function, and lowering inflammatory cytokine levels in the serum. Moreover, HH administration downregulated mRNA and protein levels of the NF-κB/NLRP3 pathway. In conclusion, our findings demonstrated that HH has potential therapeutic benefits in ameliorating NAFLD by targeting the NF-κB/NLRP3 pathway, facilitating the broader application of HH in the field of NAFLD.

Advances in management of metabolic dysfunction-associated steatotic liver disease: from mechanisms to therapeutics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease that affects over 30% of the world's population. For decades, the heterogeneity of non-alcoholic fatty liver disease (NAFLD) has impeded our understanding of the disease mechanism and the development of effective medications. However, a recent change in the nomenclature from NAFLD to MASLD emphasizes the critical role of systemic metabolic dysfunction in the pathophysiology of this disease and therefore promotes the progress in the pharmaceutical treatment of MASLD. In this review, we focus on the mechanism underlying the abnormality of hepatic lipid metabolism in patients with MASLD, and summarize the latest progress in the therapeutic medications of MASLD that target metabolic disorders.

Design, synthesis, and biological evaluation of first-in-class FABP1 inhibitors for the treatment of NASH.

The fatty acid-binding protein 1 (FABP1) is a fatty acid transporter protein that is considered as an emerging target for metabolic diseases. Despite forceful evidence that the inhibition of FABP1 is essential for ameliorating NASH, pharmacological control and validation of FABP1 are hindered by a lack of relevant inhibitors as pharmacological tool. Therefore, the development of effective FABP1 inhibitors is a current focus of research. Herein, we firstly reported the comprehensive structure-activity relationship (SAR) study of novel FABP1 inhibitors derived from high throughput screening of our in-house library, which resulting in the identification of the optimal compound 44 (IC50 = 4.46 ± 0.54 µM). Molecular docking studies revealed that 44 forms stable hydrogen bonds with amino acids around the active pocket of FABP1. Moreover, 44 alleviated the typical histological features of fatty liver in NASH mice, including steatosis, lobular inflammation, ballooning and fibrosis. Additionally, 44 has been demonstrated to have lipid metabolism regulating, anti-oxidative stress and hepatoprotective properties. This study might be provided a promising insight into the field of NASH and inspiration for the development of FABP1 inhibitors.

Semaglutide alters gut microbiota and improves NAFLD in db/db mice.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease associated with type 2 diabetes mellitus (T2D). NAFLD can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and even cancer, all of which have a very poor prognosis. Semaglutide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist, has been recognized as a specific drug for the treatment of diabetes. In this study, we used a gene mutation mouse model (db/db mice) to investigate the potential liver-improving effects of semaglutide. The results showed that semaglutide improved lipid levels and glucose metabolism in db/db mice. HE staining and oil red staining showed alleviation of liver damage and reduction of hepatic lipid deposition after injection of semaglutide. In addition, semaglutide also improved the integrity of gut barrier and altered gut microbiota, especially Alloprevotella, Alistpes, Ligilactobacillus and Lactobacillus. In summary, our findings validate that semaglutide induces modifications in the composition of the gut microbiota and ameliorates NAFLD, positioning it as a promising therapeutic candidate for addressing hepatic steatosis and associated inflammation.

Hammerhead-type FXR agonists induce an enhancer RNA Fincor that ameliorates nonalcoholic steatohepatitis in mice.

The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (Fincor). We show that Fincor is specifically induced by the hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown of Fincor in dietary NASH mice reduced the beneficial effects of tropifexor, an FXR agonist currently in clinical trials for NASH and primary biliary cholangitis (PBC), indicating that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by Fincor. Overall, our findings highlight that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, Fincor, contributing to the amelioration of NASH in mice. Fincor may represent a new drug target for addressing metabolic disorders, including NASH.

Non-alcoholic steatohepatitis, also known as NASH, is a severe condition whereby fat deposits around the liver lead to inflammation, swelling, scarring and lasting damage to the organ. Despite being one of the leading causes of liver-related deaths worldwide, the disease has no approved treatment. A protein known as Farnesoid X receptor (or FXR) is increasingly being recognized as a promising drug target for non-alcoholic steatohepatitis. Once activated, FXR helps to regulate the activity of DNA regions which are coding for proteins important for liver health. However, less is known about how FXR may act on non-coding regions, the DNA sequences that do not generate proteins but can be transcribed into RNA molecules with important biological roles. In response, Chen et al. investigated whether FXR activation of non-coding RNAs could be linked to the clinical benefits of hammerhead FXR agonists, a type of synthetic compounds that activates this receptor. To do so, genetic analyses of mouse livers were performed to identify non-coding RNAs generated when FXR was activated by the agonist. These experiments revealed that agonist-activated FXR induced a range of non-coding RNAs transcribed from DNA sequences known as enhancers, which help to regulate gene expression. In particular, hammerhead FXR agonists led to the production of a liver-specific enhancer RNA called Fincor. Additional experiments using tropifexor, a hammerhead FXR agonist currently into clinical trials, showed that this investigational new drug had reduced benefits in a mouse model of non-alcoholic steatohepatitis with low Fincor levels. This suggested that this enhancer RNA may play a key role in mediating the clinical benefits of hammerhead FXR agonists, encouraging further research into its role and therapeutic value.

[Effect of Zuogui Jiangtang Qinggan Formula on lipid metabolism in db/db mouse model of type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease].

This study aims to explore the effect of Zuogui Jiangtang Qinggan Formula(ZGJTQGF) on the lipid metabolism in the db/db mouse model of type 2 diabetes mellitus(T2DM) complicated with non-alcoholic fatty liver disease(NAFLD) via the insulin receptor(INSR)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/sterol-regulatory element-binding protein 2(SREBP-2) signaling pathway. Twenty-four db/db mice were randomized into positive drug(metformin, 0.067 g·kg~(-1)) and low-(7.5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) ZGJTQGF groups. Six C57 mice were used as the blank group and administrated with an equal volume of distilled water. The mice in other groups except the blank group were administrated with corresponding drugs by gavage for 6 consecutive weeks. At the end of drug administration, fasting blood glucose(FBG) and blood lipid levels were measured, and oral glucose tolerance test was performed. Compared with the blank group, the mice treated with ZGJTQGF showed decreased body mass and liver weight coefficient, lowered levels of FBG, total cholesterol(TC), triglyceride(TG), and low-density lipoprotein(LDL), and weakened liver function. The pathological changes and lipid accumulation in the liver tissue were examined. Western blot was employed to measure the protein levels of INSR, AMPK, p-AMPK, and SREBP-2. Compared with the blank group, the model group showed down-regulated protein levels of INSR and p-AMPK/AMPK and up-regulated protein level of SREBP-2. Compared with the model group, high-dose ZGJTQGF up-regulated the protein levels of INSR and p-AMPK/AMPK and down-regulated the protein level of SREBP-2. Low-dose ZGJTQGF slightly up-regulated the protein levels of INSR and p-AMPK/AMPK and down-regulated the protein level of SREBP-2, without significant differences. The results suggested that ZGJTQGF may alleviate insulin resistance and improve lipid metabolism in db/db mice by activating the INSR/AMPK/SREBP-2 signaling pathway.

[Tanshinone â ¡_A inhibits ferroptosis via Nrf2 signaling pathway to protect liver in rats of non-alcoholic fatty liver disease].

This study investigated the protective effect of tanshinone Ⅱ_A(TSⅡ_A) on the liver in the rat model of non-alcoholic fatty liver disease(NAFLD) and the mechanism of TSⅡ_A in regulating ferroptosis via the nuclear factor E2-related factor 2(Nrf2) signaling pathway. The rat model of NAFLD was established with a high-fat diet for 12 weeks. The successfully modeled rats were assigned into model group, low-and high-dose TSⅡ_A groups, and inhibitor group, and normal control group was set. Enzyme-linked immunosorbent assay was employed to determine the content of superoxide dismutase(SOD) and malondialdehyde(MDA) in the serum of rats in each group. A biochemical analyzer was used to measure the content of aspartate aminotransferase(AST), alaninl aminotransferase(ALT), total cholesterol(TC), and triglycerides(TG). Hematoxylin-eosin(HE) staining was used to detect pathological damage in liver tissue. Terminal-deoxynucleoitidyl transferase-mediated nick end labeling(TUNEL) was employed to examine the apoptosis of the liver tissue. Oil red O staining, MitoSOX staining, and Prussian blue staining were conducted to reveal lipid deposition, the content of reactive oxygen species(ROS), and iron deposition in liver tissue. Western blot was employed to determine the expression of Nrf2, heme oxygenase-1(HO-1), glutathione peroxidase 4(GPX4), ferroptosis suppressor protein 1(FSP1), B cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) in the liver tissue. The result showed that TSⅡ_A significantly reduced the content of MDA, AST, ALT, TC, and TG in the serum, increased the activity of SOD, decreased the apoptosis rate, lipid deposition, ROS, and iron deposition in the liver tissue, up-regulated the expression of Nrf2, HO-1, FSP1, GPX, and Bcl-2, and inhibited the expression of Bax in the liver tissue of NAFLD rats. However, ML385 partially reversed the protective effect of TSⅡ_A on the liver tissue. In conclusion, TSⅡ_A could inhibit ferroptosis in the hepatocytes and decrease the ROS and lipid accumulation in the liver tissue of NAFLD rats by activating the Nrf2 signaling pathway.

Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients.

OBJECTIVE: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients. METHODS: This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated. RESULTS: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease. CONCLUSION: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

Administration of silymarin in NAFLD/NASH: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide and poses serious harm to human health. There is growing evidence suggesting that the administration of specific supplements or nutrients may slow NAFLD progression. Silymarin is a hepatoprotective extract of milk thistle, but its efficacy in NAFLD remains unclear. MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrails.gov, and China National Knowledge Infrastructure and were screened according to the eligibility criteria. Data were analyzed using Revman 5.3. Continuous values and dichotomous values were pooled using the standard mean difference (SMD) and odds ratio (OR). Heterogeneity was evaluated using the Cochran's Q test (I2 statistic). A P<0.05 was considered statistically significant. RESULTS: A total of 26 randomized controlled trials involving 2,375 patients were included in this study. Administration of silymarin significantly reduced the levels of TC (SMD[95%CI]=-0.85[-1.23, -0.47]), TG (SMD[95%CI]=-0.62[-1.14, -0.10]), LDL-C (SMD[95%CI]=-0.81[-1.31, -0.31]), FI (SMD[95%CI]=-0.59[-0.91, -0.28]) and HOMA-IR (SMD[95%CI]=-0.37[-0.77, 0.04]), and increased the level of HDL-C (SMD[95%CI]=0.46[0.03, 0.89]). In addition, silymarin attenuated liver injury as indicated by the decreased levels of ALT (SMD[95%CI]=-12.39[-19.69, -5.08]) and AST (SMD[95% CI]=-10.97[-15.51, -6.43]). The levels of fatty liver index (SMD[95%CI]=-6.64[-10.59, -2.69]) and fatty liver score (SMD[95%CI]=-0.51[-0.69, -0.33]) were also decreased. Liver histology of the intervention group revealed significantly improved hepatic steatosis (OR[95%CI]=3.25[1.80, 5.87]). CONCLUSIONS: Silymarin can regulate energy metabolism, attenuate liver damage, and improve liver histology in NAFLD patients. However, the effects of silymarin will need to be confirmed by further research.

Anti-osteoporotic treatments in the era of non-alcoholic fatty liver disease: friend or foe.

Over the last years non-alcoholic fatty liver disease (NAFLD) has grown into the most common chronic liver disease globally, affecting 17-38% of the general population and 50-75% of patients with obesity and/or type 2 diabetes mellitus (T2DM). NAFLD encompasses a spectrum of chronic liver diseases, ranging from simple steatosis (non-alcoholic fatty liver, NAFL) and non-alcoholic steatohepatitis (NASH; or metabolic dysfunction-associated steatohepatitis, MASH) to fibrosis and cirrhosis with liver failure or/and hepatocellular carcinoma. Due to its increasing prevalence and associated morbidity and mortality, the disease-related and broader socioeconomic burden of NAFLD is substantial. Of note, currently there is no globally approved pharmacotherapy for NAFLD. Similar to NAFLD, osteoporosis constitutes also a silent disease, until an osteoporotic fracture occurs, which poses a markedly significant disease and socioeconomic burden. Increasing emerging data have recently highlighted links between NAFLD and osteoporosis, linking the pathogenesis of NAFLD with the process of bone remodeling. However, clinical studies are still limited demonstrating this associative relationship, while more evidence is needed towards discovering potential causative links. Since these two chronic diseases frequently co-exist, there are data suggesting that anti-osteoporosis treatments may affect NAFLD progression by impacting on its pathogenetic mechanisms. In the present review, we present on overview of the current understanding of the liver-bone cross talk and summarize the experimental and clinical evidence correlating NAFLD and osteoporosis, focusing on the possible effects of anti-osteoporotic drugs on NAFLD.

Network pharmacological analysis on the mechanism of Linggui Zhugan decoction for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), represents a chronic progressive disease that imposes a significant burden on patients and the healthcare system. Linggui Zhugan decoction (LGZGD) plays a substantial role in treating NAFLD, but its exact molecular mechanism is unknown. Using network pharmacology, this study aimed to investigate the mechanism of action of LGZGD in treating NAFLD. Active ingredients and targets were identified through the integration of data from the TCMSP, GEO, GeneCards, and OMIM databases. Cytoscape 3.9.1 software, in conjunction with the STRING platform, was employed to construct network diagrams and screen core targets. The enrichment analysis of gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathways were conducted by using the R. Molecular docking of the active ingredients and core targets was performed with AutoDock Vina software. We obtained 93 and 112 active ingredients and potential targets using the bioinformatic analysis of LGZGD in treating NAFLD. The primary ingredients of LGZGD included quercetin, kaempferol, and naringenin. The core targets were identified AKT1, MYC, HSP90AA1, HIF1A, ESR1, TP53, and STAT3. Gene ontology function enrichment analysis revealed associations with responses to nutrient and oxygen levels, nuclear receptor activity, and ligand-activated transcription factor activity. Kyoto Encyclopedia of Genes and Genomes signaling pathway analysis implicated the involvement of the PI3K-Akt, IL-17, TNF, Th17 cell differentiation, HIF-1, and TLR signaling pathways. Molecular docking studies indicated strong binding affinities between active ingredients and targets. LGZGD intervenes in NAFLD through a multi-ingredient, multi-target, and multi-pathway approach. Treatment with LGZGD can improve insulin resistance, oxidative stress, inflammation, and lipid metabolism associated with NAFLD.

Ginsenoside Rg5 Activates the LKB1/AMPK/mTOR Signaling Pathway and Modifies the Gut Microbiota to Alleviate Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet.

The primary objective of this investigation was to elucidate the manner in which ginsenoside Rg5 (Rg5) ameliorates nonalcoholic fatty liver disease (NAFLD) via the modulation of the gut microbiota milieu. We administered either a standard diet (ND) or a high-fat diet (HFD), coupled with 12-week treatment employing two distinct doses of Rg5 (50 and 100 mg/kg/d), to male C57BL/6J mice. In comparison to the HFD cohort, the Rg5-treated group demonstrated significant enhancements in biochemical parameters, exemplified by a substantial decrease in lipid concentrations, as well as the reduced expression of markers indicative of oxidative stress and liver injury. This signifies a mitigation of hepatic dysfunction induced by an HFD. Simultaneously, Rg5 demonstrates the capacity to activate the LKB1/AMPK/mTOR signaling pathway, instigating energy metabolism and consequently hindering the progression of NAFLD. Furthermore, we underscored the role of Rg5 in the treatment of NAFLD within the gut-microbiota-liver axis. Analysis via 16S rRNA sequencing unveiled that Rg5 intervention induced alterations in gut microbiota composition, fostering an increase in beneficial bacteria, such as Bacteroides and Akkermansia, while concurrently reducing the relative abundance of detrimental bacteria, exemplified by Olsenella. Furthermore, employing fecal microbiota transplantation (FMT) experiments, we observed analogous outcomes in mice subjected to fecal bacterial transplants, providing additional verification of the capacity of Rg5 to mitigate NAFLD in mice by actively participating in the restoration of gut microbiota via FMT. Drawing from these data, the regulation of the gut microbiota is recognized as an innovative strategy for treating or preventing NAFLD and metabolic syndrome. Consequently, these research findings suggest that Rg5 holds promise as a potential therapeutic agent for NAFLD management.

Potential Hepatoprotective Effect of Matricaria Pubescens on High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Rats.

This study aimed to identify the phytochemical compounds of Matricaria pubescens by LC-MS/MS and evaluate the potential protective effect of its supplementation in high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in adult rats through modulation of oxidative stress and histopathological changes. Twenty-four male rats were randomly divided into four groups. The first group served as control and received the standard diet. The second group (HFD) received a high-fat diet only (30 % of sheep fat). The third group's (control+MP) animals received a standard diet supplemented with 5 % M. pubescens (w/w). The fourth group (HFD+MP) received a high-fat diet supplemented with 5 % M. pubescens for 16 weeks. LC-MS/MS analysis showed that M. pubescens contains many phytochemical compounds. It was observed that the ethanolic extract of M. pubescens has a higher phenolic content than the aqueous extract. The supplementation of M. pubescens (5 % w/w) to HFD rats decreased significantly (p<0.01) body weight, liver and epididymal adipose tissue relative weights, glycemia, triglycerides (TG), insulin resistance, liver markers, TNF-α, malondialdehyde (MDA), protein carbonyl (PCO), advanced oxidation protein products (AOPP) level, and increased reduced glutathione (GSH) level, glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), and catalase activities as well as ameliorated histological alterations through the reduction hepatic lipid deposition and adipocytes hypertrophy compared to the HFD group. We conclude that M. pubescens powder may be effective for correcting hyperglycemia, hypertriglyceridemia, insulin resistance, and liver markers while decreasing inflammation and oxidative stress in the liver of high-fat diet-fed rats.

Natural Products in the Modulation of Farnesoid X Receptor Against Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with a high prevalence and increasing economic burden, but official medicine remains unavailable. Farnesoid X receptor (FXR), a nuclear receptor member, is one of the most promising drug targets for NAFLD therapy that plays a crucial role in modulating bile acid, glucose, and lipid homeostasis, as well as inhibits hepatic inflammation and fibrosis. However, the rejection of the FXR agonist, obecholic acid, by the Food and Drug Administration for treating hepatic fibrosis raises a question about the functions of FXR in NAFLD progression and the therapeutic strategy to be used. Natural products, such as FXR modulators, have become the focus of attention for NAFLD therapy with fewer adverse reactions. The anti-NAFLD mechanisms seem to act as FXR agonists and antagonists or are involved in the FXR signaling pathway activation, indicating a promising target of FXR therapeutic prospects using natural products. This review discusses the effective mechanisms of FXR in NAFLD alleviation, and summarizes currently available natural products such as silymarin, glycyrrhizin, cycloastragenol, berberine, and gypenosides, for targeting FXR, which can facilitate development of naturally targeted drug by medicinal specialists for effective treatment of NAFLD.

Peroxisome Proliferator-Activated Receptor agonists and antagonists: an updated patent review (2020-2023).

INTRODUCTION: The search for novel compounds targeting Peroxisome Proliferator-Activated Receptors (PPARs) is currently ongoing, starting from the previous successfully identification of selective, dual or pan agonists. In last years, researchers' efforts are mainly paid to the discovery of PPARγ and δ modulators, both agonists and antagonists, selective or with a dual-multitarget profile. Some of these compounds are currently under clinical trials for the treatment of primary biliary cirrhosis, nonalcoholic fatty liver disease, hepatic, and renal diseases. AREAS COVERED: A critical analysis of patents deposited in the range 2020-2023 was carried out. The novel compounds discovered were classified as selective PPAR modulators, dual and multitarget PPAR agonists. The use of PPAR ligands in combination with other drugs was also discussed, together with novel therapeutic indications proposed for them. EXPERT OPINION: From the analysis of the patent literature, the current emerging landscape sees the necessity to obtain PPAR multitarget compounds, with a balanced potency on three subtypes and the ability to modulate different targets. This multitarget action holds great promise as a novel approach to complex disorders, as metabolic, inflammatory diseases, and cancer. The utility of PPAR ligands in the immunotherapy field also opens an innovative scenario, that could deserve further applications.

Lian-Mei-Yin formula alleviates diet-induced hepatic steatosis by suppressing Yap1/FOXM1 pathway-dependent lipid synthesis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

Isolation, purification, and structural characterization of polysaccharides from Codonopsis pilosula and its therapeutic effects on non-alcoholic fatty liver disease in vitro and in vivo.

Codonopsis pilosula is a famous edible and medicinal plants, in which polysaccharides are recognized as one of the important active ingredients. A neutral polysaccharide (CPP-1) was purified from C. pilosula. The structure was characterized by HPSEC-MALLS-RID, UV, FT-IR, GC-MS, methylation analysis, and NMR. The results showed that CPP-1 was a homogeneous pure polysaccharide, mainly containing fructose and glucose, and a small amount of arabinose. Methylation analysis showed that CPP-1 composed of →1)-Fruf-(2→, Fruf-(1→ and Glcp-(1→ residues. Combined the NMR results the structure of CPP-1 was confirmed as α-D-Glcp-(1 â†’ [2)-ß-D-Fruf-(1 â†’ 2)-ß-D-Fruf-(1]26 â†’ 2)-ß-D-Fruf with the molecular weight of 4.890 × 103 Da. The model of AML12 hepatocyte fat damage was established in vitro. The results showed that CPP-1 could increase the activity of SOD and CAT antioxidant enzymes and reduce the content of MDA, thus protecting cells from oxidative damage. Subsequently, the liver protective effect of CPP-1 was studied in the mouse model of nonalcoholic fatty liver disease (NAFLD) induced by the high-fat diet. The results showed that CPP-1 significantly reduced the body weight, liver index, and body fat index of NAFLD mice, and significantly improved liver function. Therefore, CPP-1 should be a potential candidate for the treatment of NAFLD.