Chronic Liver Condition Research Articles

Carbon monoxide as a negative feedback mechanism on HIF-1α in the progression of metabolic-associated fatty liver disease

Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α–HO–1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.

NPRC promotes hepatic steatosis via USP30-mediated deubiquitination of C/EBPβ

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition characterised by dysregulated lipid metabolism. The role of Natriuretic Peptide Receptor C (NPRC), a receptor responsible for clearing natriuretic peptides, in MAFLD remains elusive. Therefore, the aim of the present study was to elucidate the role of NPRC in MAFLD progression. Approach and resultsThis study demonstrated that NPRC enhanced lipid metabolism reprogramming and accelerated MAFLD progression. Mechanistic investigations, including proteomic and ubiquitination analyses, revealed that elevated NPRC levels stabilized the C/EBPβ protein, leading to excessive lipid accumulation. The DNA-binding domain (DBD) of C/EBPβ interacted with the deubiquitinase USP30, a key regulator that inhibited K149-specific K48-linked polyubiquitination of C/EBPβ. Importantly, the ANPR region of NPRC bound to USP30, facilitating the deubiquitination of C/EBPβ. Furthermore, virtual screening identified punicalin, a natural compound, as a potential inhibitor of NPRC expression, which may reduce hepatic lipid accumulation, inflammation and fibrosis. ConclusionsOur findings indicate that NPRC recruits USP30 to mediate the deubiquitination of C/EBPβ, driving lipid metabolism reprogramming. Targeting NPRC could represent a promising therapeutic approach for MAFLD.

Interleukin-17 Gene Polymorphisms and Hepatitis B Virus Infection in a Sample of Iraqi Patients

Hepatitis B, a chronic inflammatory liver condition, constitutes a significant global health issue, with 3 million new cases and over 1 million deaths annually (when combined with hepatitis C). The infection may be acute or chronic, and it transmits horizontally by contact with biological fluids such saliva, blood, semen, tears, vaginal secretions, or perinatal fluids following childbirth, which are transferred from mother to infant. Infections can be easily prevented with immunization, typically administered shortly after birth; nevertheless, if neglected, chronic hepatitis B may lead to severe outcomes, including liver cancer or cirrhosis. Interleukin-17A, a pro-inflammatory cytokine, is essential in the immune response to many infections and is implicated in autoimmune diseases. The cytokine interleukin-17 (IL-17A) is only secreted by activated T cells. cDNA of IL-17 has been isolated and cloned from murine hybridomas (cytotoxic T lymphocyte antigen 8 (CTLA-8)). Cytokine imbalance is a crucial factor in the progression and growth of the hepatitis B virus (HBV). A cross-sectional study was conducted including 180 patients with HBV infection at the Digestive and Liver Diseases Teaching Hospital in Baghdad province, from December 14, 2022, to February 15, 2023. This study comprised two groups: the first group consisted of 40 HBV antibody-positive patients, while the second group included 40 HBV antibody-negative patients, along with a control group of 20 individuals. A blood sample of 5 ml was collected from each patient, divided into 2 ml in an anticoagulated EDTA tube and 3 ml in a gel tube. Whole blood with anticoagulated samples was utilized under optimal conditions for DNA extraction, while serum was isolated from blood for biochemical tests. The study comprised 180 patients, categorized into three groups: HBV Positive, HBV Cleared, and Control. The HBV Positive cohort consists of 99 individuals, comprising 54 males (54.45%) and 45 females (45.45%). The average age in this cohort is 42.52 years, accompanied by a standard deviation of 15.13 years. Of these individuals, 84 (84.85%) are wed. The HBV Cleared group has 45 individuals, including 24 males (53.34%) and 21 females (46.67%). The average age in this cohort is 48.43 years, with a standard deviation of 13.98 years. A predominant 39 persons (86.67%) are wed. The Control group comprises 36 individuals, primarily male, consisting of 24 men (66.67%) and 12 females (33.34%). Genotype distribution for two genetic markers, rs2275913 and rs10484879, among three groups: HBV Positive, HBV Negative, and Control. In the HBV Positive group for the rs2275913 marker, the AA genotype is present in 30 patients, the AG genotype in 36 patients, and the GG genotype in 36 patients. In the HBV Negative group, the AA genotype is observed in 9 patients, the AG genotype in 12 patients, and the GG genotype in 21 patients. Multiple research investigations have concentrated on the role of SNPs in the IL17A gene, particularly rs2275913 and rs10484879, in the susceptibility to chronic HBV infection. The polymorphisms were specifically examined for their possible impact on immune response and disease progression in patients infected with HBV. A study of the Han Chinese population demonstrated a significant correlation between the GG genotype and G allele of rs2275913 and an increased risk of HBV infection, suggesting a causal relationship with heightened susceptibility to viral infection.

Identification of neutrophil extracellular trap-related biomarkers in non-alcoholic fatty liver disease through machine learning and single-cell analysis

Non-alcoholic Fatty Liver Disease (NAFLD), noted for its widespread prevalence among adults, has become the leading chronic liver condition globally. Simultaneously, the annual disease burden, particularly liver cirrhosis caused by NAFLD, has increased significantly. Neutrophil Extracellular Traps (NETs) play a crucial role in the progression of this disease and are key to the pathogenesis of NAFLD. However, research into the specific roles of NETs-related genes in NAFLD is still a field requiring thorough investigation. Utilizing techniques like AddModuleScore, ssGSEA, and WGCNA, our team conducted gene screening to identify the genes linked to NETs in both single-cell and bulk transcriptomics. Using algorithms including Random Forest, Support Vector Machine, Least Absolute Shrinkage, and Selection Operator, we identified ZFP36L2 and PHLDA1 as key hub genes. The pivotal role of these genes in NAFLD diagnosis was confirmed using the training dataset GSE164760. This study identified 116 genes linked to NETs across single-cell and bulk transcriptomic analyses. These genes demonstrated enrichment in immune and metabolic pathways. Additionally, two NETs-related hub genes, PHLDA1 and ZFP36L2, were selected through machine learning for integration into a prognostic model. These hub genes play roles in inflammatory and metabolic processes. scRNA-seq results showed variations in cellular communication among cells with different expression patterns of these key genes. In conclusion, this study explored the molecular characteristics of NETs-associated genes in NAFLD. It identified two potential biomarkers and analyzed their roles in the hepatic microenvironment. These discoveries could aid in NAFLD diagnosis and management, with the ultimate goal of enhancing patient outcomes.

Exogenous S1P via S1P receptor 2 induces CTGF expression through Src-RhoA-ROCK-YAP pathway in hepatic stellate cells.

Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial. In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmacological inhibitors, siRNAs, and Rho activity assays were adopted to address the molecular mechanisms of S1P mediated YAP activation. Serum and exogenous S1P significantly increased the expression of YAP target genes in HSCs. Pharmacologic inhibitors and siRNA-mediated knockdowns of S1P receptors showed S1P receptor 2 (S1PR2) as the primary mediator for S1P-induced CTGF expression in HSCs. Results using siRNA-mediated knockdown, Verteporfin, and Phospho-Tag immunoblots showed that S1P-S1PR2 signaling effectively suppressed the Hippo kinases cascade, thereby activating YAP. Furthermore, S1P increased RhoA activities in cells and ROCK inhibitors effectively blocked CTGF induction. Cytoskeletal-perturbing reagents were shown to greatly modulate CTGF induction, suggesting the important role of actin cytoskeleton in S1P-induced YAP activation. Exogeneous S1P treatment was enough to increase the expression of COL1A1 and α-SMA, that were blocked by YAP specific inhibitor. Our data demonstrate that S1P/S1PR2-Src-RhoA-ROCK axis leads to Hippo-YAP activation, resulting in the up-regulation of CTGF, COL1A1 and α-SMA expression in HSCs. Therefore, S1PR2 may represent a potential therapeutic target for hepatic fibrosis.

Comparison of blood-based liver fibrosis scores in the Mount Sinai Health System, MASLD Registry, and NHANES 2017-2020 study.

Liver fibrosis is a critical public health concern, necessitating early detection to prevent progression. This study evaluates the recently developed LiverRisk score and steatosis-associated Fibrosis Estimator (SAFE) score against established indices for prognostication and/or fibrosis prediction in 4diverse cohorts, including participants with metabolic dysfunction-associated steatotic liver disease (MASLD). We used data from the Mount Sinai Data Warehouse (32,828 participants without liver disease diagnoses), the Mount Sinai MASLD/MASH Longitudinal Registry (422 participants with MASLD), and National Health and Nutrition Examination Survey 2017-2020 (4133 participants representing the general population) to compare LiverRisk score, FIB-4 index, APRI, and SAFE score. Analyses included Cox proportional hazards regressions, Kaplan-Meier estimates, and classification metrics to evaluate performance in prognostication and fibrosis prediction. In Mount Sinai Data Warehouse, LiverRisk score was significantly associated with future liver-related outcomes but did not significantly outperform FIB-4 or APRI for predicting any of the outcomes. In the general population, LiverRisk score and SAFE score outperformed FIB-4 and APRI in identifying fibrosis, but LiverRisk score underperformed among participants who were non-White or had type 2 diabetes. Among participants with MASLD, SAFE score outperformed FIB-4 and APRI in 1 of 2 cohorts, but there were generally few significant performance differences between all 4 scores. LiverRisk score does not consistently outperform existing predictors in diverse populations, and further validation is needed before adoption in settings with significant differences from the original derivation cohorts. It remains necessary to replicate the ability of these scores to predict liver-specific mortality, as well as to develop diagnostic tools for liver fibrosis that are accessible and substantially better than current scores, especially among patients with MASLD and other chronic liver conditions.

Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis

ObjectiveMetabolic-associated fatty liver disease (MAFLD) represents one of the most prevalent chronic liver conditions worldwide, but its precise pathogenesis remains unclear. This research endeavors to elucidate the involvement and molecular mechanisms of polyribonucleotide nucleotidyltransferase 1 (PNPT1) in the progression of MAFLD. MethodsThe study employed western blot and qRT-PCR to evaluate PNPT1 levels in liver specimens from individuals diagnosed with MAFLD and in mouse models subjected to a high-fat diet. Cellular studies investigated the effects of PNPT1 on lipid metabolism, apoptosis, and mitochondrial stability in hepatocytes. Immunofluorescence was utilized to track the subcellular movement of PNPT1 under high lipid conditions. RNA immunoprecipitation and functional assays were conducted to identify interactions between PNPT1 and Mcl-1 mRNA. The role of PPARα as an upstream transcriptional regulator of PNPT1 was investigated. Recombinant adenoviral vectors were utilized to modulate PNPT1 expression in vivo. ResultsPNPT1 was found to be markedly reduced in liver tissues from MAFLD patients and HFD mice. In vitro, PNPT1 directly regulated hepatic lipid metabolism, apoptosis, and mitochondrial stability. Under conditions of elevated lipids, PNPT1 relocated from mitochondria to cytoplasm, modifying its physiological functions. RNA immunoprecipitation revealed that the KH and S1 domains of PNPT1 bind to and degrade Mcl-1 mRNA, which in turn affects mitochondrial permeability. The transcriptional regulator PPARα was identified as a significant influencer of PNPT1, impacting both its expression and subsequent cellular functions. Alterations in PNPT1 expression were directly correlated with the progression of MAFLD in mice. ConclusionsThe study confirms the pivotal function of PNPT1 in the development of MAFLD through its interactions with Mcl-1 and its regulatory effects on lipid metabolism and mitochondrial stability. These insights highlight the intricate association between PNPT1 and MAFLD, shedding light on its molecular pathways and presenting a potential new therapeutic avenue for MAFLD management.

The Constellation of Risk Factors and Paraneoplastic Syndromes in Cholangiocarcinoma: Integrating the Endocrine Panel Amid Tumour-Related Biology (A Narrative Review).

Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe. Thus, awareness represents the key operating factor. Our purpose was to overview the field of CCAs following a double perspective: the constellation of the risk factors, and the presence of the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. This is a narrative review. A PubMed-based search of English-language original articles offered the basis of this comprehensive approach. Multiple risk factors underlying different levels of statistical evidence have been listed such as chronic biliary diseases and liver conditions, inflammatory bowel disease, parasitic infections (e.g., Opisthorchis viverrini, Clonorchis sinensis), lifestyle influence (e.g., alcohol, smoking), environmental exposure (e.g., thorotrast, asbestos), and certain genetic and epigenetic interplays. With regard to the endocrine panel, a heterogeneous spectrum should be taken into consideration: non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and potential connections with vitamin D status, glucagon-like peptide 1 receptor, or the galanin system, respectively, with exposure to sex hormone therapy. Amid the numerous dermatologic, hematologic, renal, and neurologic paraneoplastic manifestations in CCAs, the endocrine panel is less described. Humoral hypercalcaemia of malignancy stands as the most frequent humoral paraneoplastic syndrome in CCAs, despite being exceptional when compared to other paraneoplastic (non-endocrine) manifestations and to its reported frequency in other (non-CCAs) cancers (it accompanies 20-30% of all cancers). It represents a poor prognosis marker in CCA; it may be episodic once the tumour relapses. In addition to the therapy that targets the originating malignancy, hypercalcaemia requires the administration of bisphosphonates (e.g., intravenous zoledronic acid) or denosumab. Early detection firstly helps the general wellbeing of a patient due to a prompt medical control of high serum calcium and it also provides a fine biomarker of disease status in selected cases that harbour the capacity of PTHrP secretion. The exact molecular biology and genetic configuration of CCAs that display such endocrine traits is still an open matter, but humoral hypercalcaemia adds to the overall disease burden.

Prevalence of nonalcoholic fatty liver disease in Pakistan: a systematic review and meta-analysis

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver condition globally and the leading cause of liver-related death and morbidity. The goal of this study was to collect current data in order to calculate the pooled prevalence of NAFLD in Pakistan. We conducted a comprehensive literature search on four electronic databases until March 2024 to find studies on the prevalence of NAFLD in Pakistan. Pooled prevalence estimates of NAFLD were obtained using random-effects meta-analytic models. The chi-square test was used to account for study heterogeneity, whereas the I2 statistic was used to assess inconsistency. The data were stratified by the general population (average risk) and individuals with metabolic diseases (high risk). Two reviewers thoroughly and independently screened, reviewed, and assessed all studies. In total, 468 studies were reviewed, and 34 were included. The pooled NAFLD prevalence in the general population was 29.82% (95% CI 21.39–39.01%; prediction interval: 2.98–68.92%) based on 13 studies. In individuals with metabolic disorders, the prevalence of NAFLD in patients with diabetes, hypertension, and obesity, was 58.47% (95% CI 54.23–62.64%; prediction interval: 38.16–77.40%), 74.08% (95% CI 60.50–85.70%), and 47.43% (95% CI 30.49–64.66%), respectively. There was no evidence of publication bias, although a statistically significant level of heterogeneity was seen among the studies (I2 ranged from 57.5 to 98.69%). The findings of this study indicate a substantial prevalence of NAFLD in the population of Pakistan. The Pakistani government must formulate a comprehensive approach and plan aimed at augmenting awareness, control, prevention, and treatment of fatty liver disease.Prospero Registration no: CRD42022356607.

Co-exposure of polyvinyl chloride microplastics with cadmium promotes nonalcoholic fatty liver disease in female ducks through oxidative stress and glycolipid accumulation

A recently discovered environmental contaminant, microplastics (MPs) are capable of amassing within the body and pose a grave threat to the health of both humans and animals. It is widely acknowledged that the combination of cadmium (Cd), a hazardous heavy metal, and microplastics produces synergistic deleterious effects. Nevertheless, the mechanism by which co-exposure to polyvinyl chloride microplastics (PVC-MPs) and Cd damages the liver of avian females is unknown. Globally prevalent and the subject of extensive research in mammals, non-alcoholic fatty liver disease (NAFLD) is a chronic liver condition. However, the mechanisms underlying injury to the avian digestive system caused by NAFLD remain unknown. Two months of co-exposure to Cd and PVC-MPs, pure water, solitary Cd exposure, single microplastics exposure, and pure water were administered to female Muscovy ducks in this study. The objective of this research was to examine whether the co-exposure of duck liver to PVC-MPs and Cd-induced oxidative stress resulted in NAFLD and subsequent apoptosis of hepatic cells. The study's findings showed that hepatocyte shape and functional activity were negatively impacted by PVC-MP and Cd buildup in liver tissues. Reduced liver organ coefficients, increased alanine aminotransferase (ALT) content, and ultrastructural damage to hepatocyte nuclei and mitochondria are indicators of this. These results point to a possible impairment in liver function. phosphoenolpyruvate carboxykinase 1 (PCK1) deficiency activates the protein kinase B/phosphatidylinositol 3-kinase (PI3K/AKT) pathway in the livers of female reproductive ducks that have been damaged by oxidative stress. This stimulation induces lipid deposition, fibrosis, and glycogen accumulation, which ultimately results in hepatocyte apoptosis. In summary, our research provides evidence that PVC-MPs cause oxidative harm to the liver, which subsequently results in fibrosis of liver tissue, hepatic glucolipid metabolism, and ultimately apoptosis.

Silymarin as an Antioxidant Therapy in Chronic Liver Diseases: A Comprehensive Review.

Chronic liver diseases (CLDs) such as chronic hepatitis, cirrhosis, and non-alcoholic fatty liver disease (NAFLD) present significant global health challenges due to their high morbidity and mortality rates. Silymarin, a flavonoid complex derived from the seeds of the milk thistle plant (Silybum marianum), has been extensively studied for its hepatoprotective properties. This review aims to evaluate the role of silymarin as an antioxidant therapy in managing CLDs. We explore its efficacy, safety, and mechanisms of action through a comprehensive analysis of clinical trials and scientific studies. Silymarin offers protective effects on the liver and shows promise in improving liver function and histological outcomes in various chronic liver conditions. Despite the promising results, further research is needed to fully elucidate the optimal dosing regimens, long-term safety, and potential drug interactions of silymarin. This review underscores the therapeutic potential of silymarin in CLDs and provides a foundation for future studies aimed at enhancing its clinical application.

Research on the function of epigenetic regulation in the inflammation of non-alcoholic fatty liver disease

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition, characterized by a spectrum that progresses from simple hepatic steatosis to nonalcoholic steatohepatitis, which may eventually lead to cirrhosis and hepatocellular carcinoma. The precise pathogenic mechanisms underlying NAFLD and its related metabolic disturbances remain elusive. Epigenetic modifications, which entail stable transcriptional changes without altering the DNA sequence, are increasingly recognized as pivotal. The principal forms of epigenetic modifications include DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. These alterations participate in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial injury, oxidative stress response, and release of inflammatory cytokines, all of which are associated with the onset and progression of NAFLD. This review discussed recent advances in understanding the potential epigenetic regulation of inflammation in NAFLD. Unraveling these epigenetic mechanisms may facilitate the identification of early diagnostic biomarkers and the development of targeted therapeutic strategies for NAFLD.

Bacteroides acidifaciens drives a liver detox program

Alcohol-associated liver disease is a leading cause of chronic liver conditions, yet there are limited effective therapies. In this issue of Cell Host & Microbe, Shen etal. demonstrate that soluble dietary fiber enhances intestinal Bacteroides acidifaciens, which ameliorates alcohol-associated liver injury in mice by activating hepatic ornithine aminotransferase.

Jiawei Taohe Chengqi Decoction attenuates CCl4 induced hepatic fibrosis by inhibiting HSCs activation via TGF-β1/CUGBP1 and IFN-γ/Smad7 pathway

BackgroundHepatic fibrosis (HF) is an essential stage in the progression of different chronic liver conditions to cirrhosis and even hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) plays a crucial role in the progression of HF. IFN- γ/Smad7 pathway can inhibit HSCs activation, while TGF-β1/CUGBP1 pathway can inhibit IFN-γ/Smad7 pathway transduction and promote HSCs activation. Thus, inhibiting the TGF-β1/CUGBP1 pathway and activating the IFN-γ/Smad7 pathway reverses HSCs activation and inhibits HF. Jiawei Taohe Chengqi Decoction (JTCD) was derived from the Taohe Chengqi Tang in the ancient Chinese medical text titled “Treatise on Febrile Diseases”. We found several anti-HF components in JTCD including ginsenoside Rb1 and others, but the specific mechanism of anti-HF in JTCD is not clear. PurposeTo elucidate the specific mechanism by which JTCD reverses HF by inhibiting the activation of HSCs, and to establish a scientific foundation for treating HF with Traditional Chinese medicine (TCM). MethodsWe constructed a CCl4-induced mice HF model in vivo and activated human hepatic stellate cell line (LX-2) with TGF-β1 in vitro, after which they were treated with JTCD and the corresponding inhibitors. We examined the expression of pivotal molecules in the two pathways mentioned above by immunofluorescence staining, Western blotting and RT-PCR. ResultsJTCD attenuated liver injury and reduced serum ALT and AST levels in mice. In addition, JTCD attenuated CCl4-induced HF by decreasing the expression of α-SMA, COL1A1 and other markers of HSCs activation in mice liver tissue. Moreover, JTCD effectively suppressed the levels of TGF-β1, p-Smad3, p-p38MAPK, p-ATF2, and CUGBP1 in vivo and in vitro and upregulated the levels of IFN-γ, p-STAT1, and Smad7. Mechanically, after using the inhibitors of both pathways in vitro, we found that JTCD inhibited the activation of HSCs by restoring the balance of the TGF-β1/CUGBP1 and IFN-γ/Smad7 pathways. ConclusionWe demonstrated that JTCD inhibited HSCs activation and reversed HF by inhibiting the TGF-β1/CUGBP1 signalling pathway and upregulating the IFN-γ/Smad7 signalling pathway. Moreover, we have identified specific links where JTCD interferes with both pathways to inhibit HSCs activation. JTCD is an effective candidate for the clinical treatment of HF.

Circular RNA RRM2 alleviates metabolic dysfunction-associated steatotic liver disease by targeting miR-142-5p to increase NRG1 expression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition worldwide, demanding further investigation into its pathogenesis. Circular RNAs (circRNAs) are emerging as pivotal regulators in MASLD processes, yet their pathological implications in MASLD remain poorly understood. This study focused on elucidating the role of circular RNA ribonucleotide reductase subunit M2 (circRRM2) in MASLD progression. In this study, we used both in vitro and in vivo MASLD models using long-chain-free fatty acid (FFA)-treated hepatocytes and high-fat diet (HFD)-induced MASLD in mice, respectively. We determined the expression patterns of circRRM2, microRNA-142-5p (miR-142-5p), and neuregulin 1 (NRG1) in livers of MASLD-afflicted mice and MASLD hepatocytes by RT-qPCR. Dual-luciferase reporter assays verified the binding relationships among circRRM2, miR-142-5p, and NRG1. We conducted further analyses of their roles in MASLD hepatocytes and modulated circRRM2, miR-142-5p, and NRG1 expression in vitro by transfection. Our findings were validated in vivo. The results demonstrated reduced levels of circRRM2 and NRG1, along with elevated miR-142-5p expression in MASLD livers and hepatocytes. Overexpression of circRRM2 downregulated lipogenesis-related genes and decreased triglycerides accumulation in livers of MASLD mice. MiR-142-5p, which interacts with circRRM2, effectively counteracted the effects of circRRM2 in MASLD hepatocytes. Furthermore, NRG1 was identified as a miR-142-5p target, and its overexpression mitigated the regulatory impact of miR-142-5p on MASLD hepatocytes. In conclusion, circRRM2, via its role as a miR-142-5p sponge, upregulating NRG1, possibly influenced triglycerides accumulation in both in vitro and in vivo MASLD models.NEW & NOTEWORTHY CircRRM2 expression was downregulated in free fatty acid (FFA)-challenged hepatocytes and high-fat diet (HFD) fed mice. Overexpressed circular RNA ribonucleotide reductase subunit M2 (circRRM2) attenuated metabolic dysfunction-associated steatotic liver disease (MASLD) development by suppressing FFA-induced triglycerides accumulation. CircRRM2 targeted microRNA-142-5p (miR-142-5p), which served as an upstream inhibitor of neuregulin 1 (NRG1) and collaboratively regulated MASLD progression.

Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

The Protective Activity of Kaempferol Glycosides from Soya Leaf Extract for Experimentally Induced Non-alcoholic Fatty Liver Disease in Wistar Rats

Non-alcoholic fatty liver disease (NAFLD) ranks as one of the most important chronic liver conditions globally, characterized by excessive fat deposition in the liver, central obesity, insulin resistance and in general with characteristics of the metabolic syndrome. Thus, it is vital to treat NAFLD as well as its accompanying metabolic disorders. The present study is to evaluate Kaempferol glycosides activity from Glycine.max leaves extract in experimentally induced NAFLD in rats. The study evaluated the KG activity of G.max extract from leaves on a the HFD and Fructose induced rat model, utilizing Albino Wistar rats with daily doses of 200-250g. Parameters included body weight, liver weight, fasting blood glucose, fasting insulin, insulin resistance, lipid profiles, and histopathological investigations. The doses for KGE were 300mg/kg as medium and 400mg/kg as high. From the research results it was determined that medium dose (300mg/kg) and high dose (400mg/kg) demonstrated a substantial effect when compared to HFD and fructose induced positive control. The study demonstrated that Kaempferol glycosides from Glycine.max leaves extract can prevent and cure HFD and fructose-induced non-alcoholic fatty liver in Albino Wistar rats. The extract's action was substantial at medium and high doses, compared to HFD and fructose-induced positive controls. This shows that Kaempferol glycosides could be a promising natural therapeutic agent against NAFLD, hyperlipidaemic diseases, and metabolic syndromes with less adverse effects compared to conventional medications.

The Association of Serum Ferritin with Disease Severity in Non-alcoholic Fatty Liver Disease

Abstract Background NONALCOHOLIC FATTY LIVER DISEASE is emerging as the most common chronic liver condition in the Western world. It is associated with insulin resistance and frequently occurs with features of the metabolic syndrome. Disease presentation ranges from asymptomatic elevated liver enzyme levels to cirrhosis with complications of liver failure and hepatocellular carcinoma. Current treatment recommendations are limited to weight loss and exercise, although several promising medications are on the horizon. Aim of the Work The aim of this study is to evaluate the association of serum ferritin with non- alcoholic fatty liver disease. Patients and Methods The study was cross sectional study which conducted at Ain Shams University Hospital. This study was conducted on 80 patients both sexes, with age (18years old - 60 years), duration of study will be 6 months. All study patients approved to participate in this study. Patients were divided in to 2 groups as following: Results Our study reveals that patients with non alcoholic steatohepatitis (NASH) have significantly higher median serum ferritin levels, compared to those with non alcohoholic fatty liver disease (NAFLD). Also ROC curve shows that the best cutoff point of serum ferritin to differentiate between normal lipid profile group and elevated lipid profile group was found > 80 with sensitivity of 82.5%, specificity of 60.0% and AUC of 69.5% while the best cutoff point of fatty liver index to differentiate between normal lipid profile group and elevated lipid profile group was found > 89 with sensitivity of 67.5%, specificity of 80.0% and AUC of 76.8%. Conclusion Elevated serum ferritin may reflect increased disease severity in NAFLD either because of increased ongoing hepatic or systemic inflammation or increased body iron stores or a combination of these factors. Our study also reveals that patients with non alcoholic steatohepatitis (NASH) have significantly higher median serum ferritin levels, compared to those with non alcohoholic fatty liver disease (NAFLD).

Mairin from Huangqi Decoction Mitigates Liver Cirrhosis through Suppression of Pro-inflammatory Signaling Pathways: A Network Pharmacology and Experimental Study

Background:: Liver cirrhosis is a consequence of various chronic liver conditions and may lead to liver failure and cancer. Huangqi Decoction (HQD) is a Traditional Chinese Medicine (TCM) effective for treating liver conditions, including cirrhosis. Therefore, both the active ingredients and the pharmacological actions of HQD deserve further exploration. The active components and pharmacological actions of HQD in preventing and treating liver cirrhosis were investigated using network pharmacology. The actions of the principal active ingredient, Mairin, were investigated empirically. Methods:: Using network pharmacology, the critical components of HQD were identified from multiple databases, and UPLC screening and targets were investigated using Swiss Target Prediction. Targets associated with liver cirrhosis were identified using the GeneCards database. GO and KEGG enrichment analysis of targets that overlapped between HQD and cirrhosis were analyzed in DAVID, and a “component-target-pathway” network for HQD was created in Cytoscape 3.7.2. The biological functions of the key active component, Mairin, were investigated using in silico docking, cell experiments, and evaluation in a carbon-tetrachloride (CCl4)-induced mouse model of liver cirrhosis. CCK-8 and F-actin assays were used to measure cell viability and hepatic stellate cell (HSC) activation, respectively; fibrosis was measured by histological and immunohistochemical evaluations, and the levels of the cirrhosis-related protein α-SMA and predicted essential target proteins in the PI3KAKT, NFκB-IκBα, and NLRP3-IL18 pathways were determined by western blotting. Results:: Fourteen active HQD components, 72 targets, and 10 pathways common to HQD and cirrhosis were identified. Network analysis indicated the association of Mairin with most targets and with inflammation through the PI3K/Akt, NF-κB, and NLRP3 pathways. Dose-dependent reductions in the activation and proliferation of LX-2 cells after Mairin treatment were observed. Mairin reversed the histopathological changes in the livers of cirrhosis model mice. Mairin also significantly reduced the α-SMA, NF-κB, IκBα, NLRP3, and IL-18 protein levels while increasing those of p- PI3K and p-Akt, suggesting that Mairin mitigates liver cirrhosis through modulation of the PI3KAKT, NFκB-IκBα, and NLRP3-IL18 pathways. Conclusions:: Using a comprehensive investigative process involving network pharmacology, bioinformatics, and experimental verification, it was found that Mairin, an active component of HQD, may be useful for developing specific treatments for preventing and treating liver cirrhosis.

Dissecting the causal role of immunophenotypes in primary sclerosing cholangitis risk: A Mendelian randomization study.

Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the "microbiota" and "gut lymphocyte homing" hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828-0.986, P = .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823-0.969, P = .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013-1.157, P = .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012-1.118, P = .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835-0.986, P = .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864-0.994, P = .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630-0.833, P = 5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001-1.112, P = .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.