Search Results (503)

Liver fibrosis is a common pathological result of chronic hepatic injury caused by various factors, such as viral hepatitis, alcohol-induced liver disease, and metabolic dysfunction-associated steatohepatitis (MASH). It is characterized by an excessive deposition of extracellular matrix, which disrupts the architecture of the liver and can lead to cirrhosis, liver failure, and hepatocellular carcinoma. Globally, nearly 10% of the population has significant fibrosis, with its prevalence increasing with age, obesity, and metabolic syndrome. Despite its significant clinical impact, early detection of liver fibrosis is still limited due to insufficient diagnostic technologies and low public awareness. The increasing burden of MASH emphasizes the urgent need for scalable therapeutic strategies. Currently, liver transplantation is the only definitive treatment, but it is limited by donor shortages and the need for lifelong immunosuppression. However, fibrosis is now recognized as a dynamic and potentially reversible process if the underlying cause is addressed. This shift in understanding has prompted efforts to develop pharmacological agents that target hepatic stellate cell activation, immune system interactions, and metabolic dysfunction. Advances in organoid platforms, multi-omics, and non-invasive diagnostics are accelerating translational research in this area. This review aims to synthesize current knowledge about the molecular drivers of fibrosis, bottlenecks in the current anti-fibrotic drug discovery process, and emerging therapeutic approaches to inform precision medicine strategies and reduce the global burden of chronic liver disease. Full article

Background/Objectives: Patients with rheumatic immune-mediated inflammatory diseases (R-IMID) require latent tuberculosis infection screening and, in case of positivity, chemoprophylaxis. Isoniazid INH remains the standard regimen, but hepatotoxicity is an underrecognized concern. To describe the characteristics of R-IMID patients developing hepatotoxicity during INH therapy and identify potential risk factors through clinical analysis and literature review. Methods: Retrospective study of 64 R-IMID who developed hepatotoxicity with INH. Mean age was 53.4 ± 10.5 years; 70.3% female. Diagnoses included spondyloarthritis/psoriatic arthritis (56.3%), rheumatoid arthritis (32.8%), systemic sclerosis (4.7%), connective tissue diseases (4.7%), and other IMIDs (3.2%). All patients showed ≥ 2 × upper limit of normality (ULN) liver enzyme elevation, 34.4% ≥ 3 ULN, 20.3% ≥ 4 ULN. Literature review (19 studies) revealed INH-related hepatotoxicity rates of 1–41%, exacerbated by concurrent methotrexate, sulfasalazine, TNF inhibitors, and prior drug-induced liver injury. Results: Hepatotoxicity was frequent when INH was combined with other hepatotoxic drugs, especially methotrexate. Conclusions: INH prophylaxis in R-IMID patients carries substantial hepatotoxic risk. Careful hepatic monitoring and individualized risk stratification are essential to prevent liver injury in immunosuppressed populations. Full article

Microalgae are sustainable sources of bioactive compounds with broad hepato-protective potential. This review synthesizes evidence for five major classes—carotenoids such as astaxanthin and fucoxanthin, polysaccharides such as paramylon and fucoidan, phycobiliproteins such as phycocyanin, omega-3 fatty acids, and phenolic extracts—linking their actions to key liver injury mechanisms. Preclinically, these compounds enhance antioxidant defenses, improve mitochondrial function, suppress inflammatory signaling, regulate lipid metabolism, modulate the gut–liver axis, and inhibit hepatic stellate cell activation, thereby attenuating fibrosis. Consistent benefits are observed in models of non-alcoholic and alcoholic fatty liver disease, drug-induced injury, ischemia–reperfusion, and fibrosis, with marked improvements in liver enzymes, oxidative stress, inflammation, steatosis, and collagen deposition. Emerging evidence also highlights their roles in regulating endoplasmic reticulum stress and ferroptosis. Despite their promise, translational challenges include compositional variability, a lack of standardized quality control, limited safety data, and few rigorous human trials. To address these challenges, we propose a framework integrating multi-omics and AI-assisted strain selection with specification-driven quality control and formulation-aware designs—such as lipid carriers for carotenoids or rational combinations like fucoxanthin with low-molecular-weight fucoidan. Future priorities include composition-defined randomized controlled trials in non-alcoholic fatty liver disease, alcoholic liver disease, and drug-induced liver injury; harmonized material specifications; and multi-constituent interventions that synergistically target oxidative, inflammatory, metabolic, and fibrotic pathways. Full article

Background: Recent studies have shown that plant-based dietary extracts can prevent the formation of lipid droplets (LDs) and oxidized lipid droplets (oxLDs) in liver cells. These results indicate that these extracts might be useful in addressing metabolic dysfunction-associated fatty liver disease (MAFLD) and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). In our ongoing study, we evaluated the potential of various food extracts to inhibit the accumulation and oxidation of LDs in liver cells to prevent metabolic MAFLD and MASH. Methods: The antioxidant activity index was determined using the DPPH assay, cell viability was assessed via cytotoxicity and lipotoxicity, and lipid droplet accumulation inhibition (LDAI) assays were performed. Metabolome analysis was performed using 1D-NMR [¹H, ¹³C, DEPT 90, and 135] techniques. Results: Dietary clove (Syzygium aromaticum) extract exhibited antioxidant properties and inhibited linoleic acid-induced lipid droplet (LD) accumulation (LDA) and oxidized LDA (oxLDA) in HepG2 cells. Additionally, an analysis of the metabolome of dietary clove bioactive LDAI using 1D-NMR showed that clove extract (CE) mainly consists of hydroxybenzoic acids (HBAs) and hydroxycinnamic acids (HCAs), along with minor amounts of carbohydrates, coumarins, polyphenolic compounds, and small quantities of polyols, fatty acyls, small peptides, and amino acids. This suggests that CE could be a promising resource for developing functional foods and nutraceuticals and discovering drugs for treating MAFLD, MASH, and related conditions. Full article

Background: Two natural steroids derived from cholesterol pathways are testosterone and progesterone, androgen and antiandrogen receptor binding. Steroid androgen antagonists can be prescribed to treat an array of diseases and disorders such as gender dysphoria. In men, androgen antagonists are frequently used to treat prostate cancer and hyperplasia. Sex hormones regulate the expression of the viral receptors in COVID-19 progression, and these hormones may act as a metabolic signal-mediating response to changes in glucose and Reactive Oxygen Species (ROS). The objective of the present study is to use artificial intelligence (AI) applications in healthcare to predict the targets and to assess biological assays of novel steroid derivatives prepared in house from the commercially available 16-dehydropregnenolone acetate (DPA^®) aimed at achieving the metabolic stability of glucose and steroid brain homeostasis. This suggests the introduction of aromatic or aliphatic structures in the steroid B-ring and D-ring. This is important since the roles of 5α-reductase and ROS in brain control of glucose and novel steroids homeostasis remain unclear. Methods: A tool prediction was used as a tuned algorithm, with the novel steroid derivatives data in web interface to carry out their pharmacological evaluation. The new steroidal derivatives were determined with neuroprotection effect using the select biomarkers of oxidative stress on induced hypoglycemic male rat brain and liver. The enzyme kinetics was established by the inhibition of the 5α-reductase enzyme on the brain myelin. Results: We used novel chemical structures to order the information of a Swiss data bank that allow target predictions. Biological assays suggest that steroid derivatives with an electrophilic center can interact more efficiently with the 5α-reductase enzyme, and by this way, induce neuroprotection in hypoglycemia model. All compounds were synthesized with a yield of 30–80% and evaluated with tool target prediction to understand the molecular mechanisms underlying a given phenotype or bioactivity and to rationalize possible favorable or unfavorable side effects, as well as to predict off-targets of known molecules and to clear the way for drug repurposing. Apart, they turned out to be good inhibitors for the 5α-reductase enzyme. Conclusions: The probed efficacy of these novel steroids with respect to spironolactone control appears to be a promising compound for future hormonal therapy with neuroprotection activity in glucose disorder status. However, further research with clinically meaningful endpoints is needed to optimize the use of androgen antagonists in these hormonal therapies in COVID-19 progression. Full article

The absence of a unifying pathogenetic mechanism in metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has significantly hindered therapeutic progress. Appreciation that the delivery of excessive amounts of calories to the liver via the portal circulation might be a key parallel between MASLD and the twin steatotic liver disease, alcohol-related liver disease (ALD), establishes a consolidated framework that could guide rational drug design and precise therapeutic approaches. This review contends that, in both ALD and MASLD, the unique dual blood supply to the liver, from both portal vein and hepatic artery as well as the distinctive blood flow control physiology, prevents hepatic arterial oxygen delivery from adequately compensating for the increased metabolic demands induced by excess caloric intake—alcohol in ALD and food in MASLD—resulting in hepatocellular injury. Over four decades ago, Lautt postulated that this ‘oxygen-nutrient mismatch’ could play a role in ALD. We have extended this paradigm to MASLD, theorizing that analogous mechanisms may be involved in both conditions. Evidence that comorbidities, which are associated with recurrent episodes of hypoxemia, such as obstructive sleep apnea (OSA), exacerbate MASLD progression, supports this. ALD is less strongly linked to metabolic syndrome than MASLD. This may be due to inherent differences in hepatic substrate processing. Carbohydrates, lipids, and proteins undergo diverse and flexible cytosolic metabolic pathways, especially under metabolic stress. In contrast, hepatic ethanol metabolism is predominantly linear and obligately oxidative, providing limited metabolic adaptability. Future perspectives could focus on rectifying the imbalance between hepatic oxygen delivery and nutrient availability. This might be accomplished by attenuating hepatic caloric excess using emerging pharmacotherapies for weight reduction, augmenting hepatic oxygenation through hyperbaric oxygen therapy, or increasing hepatic arterial blood flow with agents such as obeticholic acid. Furthermore, enhancement of hepatic basal metabolic activity with thyroid hormone receptor-β agonists, like resmiritom may confer similar therapeutic effects. Full article

Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed with improved efficacy. Methods: (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic acid derivatives 1a–g and 2a–g were synthesized as potential multitarget antidiabetic agents. They were tested in vitro as inhibitors of both human recombinant AKR1B1 and PTP1B, and kinetic studies and molecular docking simulations for both enzymes were performed. Their effects on cellular glucose uptake, insulin signalling, and mitochondrial potential were assayed in cultures of murine C2C12 myocytes. A lipid accumulation assay was performed in HepG2 liver cells. The effects on high glucose-induced sorbitol accumulation were evaluated in lens HLE and retinal MIO-M1 cells. Results: All compounds displayed excellent AKR1B1 inhibitory activity (IC₅₀ 0.03–0.46 μM 1a–g; IC₅₀ 0.48–6.30 μM 2a–g); 1g and 2e–g also appreciably inhibited PTP1B at micromolar concentrations. Propanoic derivatives 2e–g significantly stimulated glucose uptake in C2C12 myocytes, in an insulin-independent way, reduced lipid accumulation in HepG2 liver cells, and caused hyperpolarization of C2C12 mitochondria at 10 μM concentration. Derivative 2e significantly reduced sorbitol accumulation in both HLE and MIO-M1 cells at a 5 μM concentration. Conclusions: The results reported here provided new insights into the mechanisms of action and structure/activity relationships of 4-thiazolidinone derivatives, underscoring the capability of compounds 2e–g of eliciting insulin-mimetic effects independent of hormone signalling. Among them, compound 2e also proved to inhibit AKR1B1-dependent sorbitol accumulation and, thus, emerged as a promising multitarget agent that can be considered for further investigations. Full article

Lipotoxicity and oxidative stress are key pathogenic drivers in the development of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). The underlying mechanisms of MASLD are not fully understood, and approved pharmacotherapies remain elusive. Thus, exploring therapeutic targets and potential drugs for MASLD is still a major challenge. In our previous study, a new cuspidatyl ferulate (2,3-dihydroxy-4-carboxylic butyl (E)-4-[3-(4-hydroxy-3-methoxyphenyl)-2-propenoate], CuF) was first isolated and identified from Hyssopus cuspidatus Boriss (H. cuspidatus). Here, we investigated the effects of this novel phenolic acid on free fatty acid (FFA)-induced oxidative stress and lipid accumulation in HepG2 cells. Exposure to FFA significantly increased intracellular reactive oxygen species (ROS) levels and lipid accumulation. Notably, CuF treatment effectively reversed FFA-induced suppression of key antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT), and attenuated lipid accumulation, as evidenced by reduced total cholesterol (TC) and triglyceride (TG) levels. Mechanistically, molecular docking and capillary electrophoresis analyses revealed that CuF directly interacts with Kelch-like ECH-associated protein 1 (Keap1), disrupting the Keap1-Nrf2 protein complex, thereby promoting nuclear translocation of Nrf2 and activating the antioxidant response pathway. In summary, our findings demonstrate that this novel phenolic acid exhibits strong antioxidant and anti-lipotoxic activities in vitro, offering a potential natural product-based drug candidate for MASLD therapy. Full article

Nonalcoholic fatty liver disease (NAFLD) associated with high-fat diet (HFD) intake involves oxidative stress, inflammation, apoptosis, and genotoxicity. Carvacrol, a natural monoterpenoid phenol, exhibits potent antioxidant, anti-inflammatory, and cytoprotective properties, but its clinical application is limited by poor solubility and bioavailability. Chitosan nanoparticles, known for their biocompatibility and ability to enhance drug delivery, offer a promising nanotherapeutic platform for carvacrol delivery in NAFLD. Given the limited therapeutic options for NAFLD, there is a growing interest in nanotherapeutic strategies to enhance the delivery and efficacy of natural antioxidants. This study examined carvacrol-loaded chitosan nanoparticles (CRV-CNPs) in HFD-induced NAFLD. Sixty rats were assigned to six groups: control, CRV-treated (100 mg/kg), CRV-CNP-treated (100 mg/kg), HFD-fed, and two combination groups receiving HFD with either CRV or CRV-CNPs (100 mg/kg) for six weeks after 14 weeks on HFD. Liver function, metabolic markers, oxidative stress parameters, antioxidant enzyme levels, inflammatory and fibrotic mediators, apoptotic gene expression, genotoxicity indices, and histopathological changes were evaluated. CRV-CNPs showed greater efficacy than free carvacrol in ameliorating hepatic dysfunction and metabolic disturbances in HFD-fed rats. CRV-CNPs significantly reduced malondialdehyde, upregulated Nrf2, and elevated hepatic glutathione peroxidase, superoxide dismutase, catalase, and reduced glutathione. Inflammatory markers (NF-κB, iNOS, IL-1β, CRP) and transforming growth factor-beta were suppressed. Pro-apoptotic genes (Bax, Caspase-3) were downregulated, while antiapoptotic Bcl-2 was upregulated. CRV-CNPs also reduced DNA fragmentation and 8-hydroxy-2′-deoxyguanosine levels, indicating strong antigenotoxic effects. Histopathological and ultrastructural assessments revealed mitigated steatosis, preserved hepatic architecture, and maintained mitochondrial integrity. In conclusion, CRV-CNPs provide potent hepatoprotection by targeting oxidative stress, inflammation, apoptosis, and genotoxicity in NAFLD, demonstrating enhanced bioavailability, solubility, and sustained release, which support their potential as an advanced nanotherapeutic strategy for NAFLD management. Full article

Sleep disturbances and liver diseases have a bidirectional relationship. Unhealthy sleep habits promote liver diseases, such as steatotic liver disease, and impact the prognosis, promoting progression to liver cirrhosis and liver-related mortality. Sleep accounts for 20% of the association between lifestyle and steatotic liver disease, indirectly by promoting obesity and metabolic syndrome and through direct effects in the liver. Conversely, liver diseases can affect sleep. Patients with liver cirrhosis complain of sleep disturbances five times more than the general population, with a profound impact on their quality of life. Common drugs used to treat sleep disorders, such as hypnotics and benzodiazepines, must be used very carefully in patients with cirrhosis due to altered hepatic metabolism and the potential to induce hepatic encephalopathy, making sleep disorders particularly challenging to manage in these patients. This review summarizes the available knowledge on the interplay between sleep and liver diseases. Full article

Inflammatory bowel disease (IBD) management traditionally focuses on intestinal inflammation, yet extraintestinal manifestations can substantially impair patient quality of life. In this perspective, we emphasize the broad systemic impact of IBD—from highly prevalent conditions such as anemia, metabolic dysfunction-associated steatotic liver disease, or fatigue to rare but severe complications like interstitial lung disease and drug-induced glomerulonephritis. We review underlying mechanisms linking gut inflammation to distant organs, including immune dysregulation, microbial translocation, and metabolic derangements. Advances in diagnostics—such as biomarker panels, high-resolution imaging, and genomic/microbiome profiling—enable early detection and risk stratification. Emerging therapies, including targeted biologics (anti-TNF, anti-integrin, anti-IL-23), JAK and S1P modulators, precision nutrition, and microbiome modulation, offer new opportunities to address systemic inflammation. A multidisciplinary framework integrating gastroenterology with hepatology, hematology, neurology, nephrology, endocrinology, dermatology, pulmonology, and cardiology is essential to recognize hidden complications, facilitate timely intervention, and deliver personalized, comprehensive care for IBD. Full article

The liver is the primary metabolic organ in the body, metabolizing nutrients and drugs. Advanced liver diseases result in compromised metabolic function of the liver. These diseases are often difficult to treat with drugs because of inability of the liver to generate effective drug metabolites and/or to properly inactivate the drugs resulting in high drug-induced toxicity with subsequent reduced patient compliance. Hepatocellular carcinoma (HCC) is a disease that develops on a fibrotic/cirrhotic liver and is mostly diagnosed at an advanced stage. Current protocol for treating advanced HCC includes a combination of immunotherapy or tyrosine kinase inhibitors (TKIs), which provides a survival benefit of only ~2 years. In addition, immunotherapy is effective in only 27% of HCC patients and patients treated with TKIs invariably develop drug resistance within 6 months. In this scenario gene therapy serves as an alternative approach that might bring significant benefits to HCC patients. Although gene therapy approaches for HCC or other liver diseases have yet to obtain approval from the Food and Drug Administration (FDA), a significant advancement has been made over the years in this field. In this review article, we highlight very recent literature showing the promise of gene therapy in managing HCC patients, extending survival benefits and providing improved quality of life. Full article

Inflammation drives the development of multiple inflammatory enterohepatic diseases. The recruitment of immune cells to inflammatory tissues is essential for maintaining immune homeostasis, mediating immune responses and regulating inflammation. MAdCAM-1/α4β7 is a pair of homing ligand and receptor that plays important roles in lymphocyte migration. Their binding induces lymphocytes to cross endothelial structures into corresponding lymphoid tissues, contributing to the inflammatory response. Aberrant lymphocyte migration due to excessive binding is closely related to the occurrence and development of inflammatory bowel disease and liver inflammation. In this review, we focus on the activation of α4β7 and binding to MAdCAM-1 how to induce the migration of multiple kinds of lymphocytes. Additionally, we describe the intestinal microbiota and its metabolites associated with MAdCAM-1/α4β7 in inflammatory enterohepatic diseases. We also discuss the current status of the development of monoclonal antibodies and small molecule drugs targeting MAdCAM-1/α4β7 for the remission and treatment of inflammatory enterohepatic disease. Future research should focus on enhancing hepatic specificity and conducting well-designed clinical trials for inflammatory liver diseases to confirm therapeutic efficacy. Full article

Intestinal homeostasis disorders (IHDs), driven by food safety issues, pollution, and drug-resistant pathogens, threaten global health. Key factors in intestinal and metabolic diseases (like IBD, obesity, and liver disease) include barrier dysfunction, gut microbiota imbalance, and excessive immune activation. Transcription factors in intestinal epithelial cells are crucial regulators. ELF4, an ETS family transcription factor, plays vital roles in transcriptional regulation, impacting tumorigenesis, the DNA damage response, and the cell cycle. ELF4 deficiency exacerbates alcoholic liver disease (ALD). Significantly, ELF4 is a novel IFN-I transcription factor with antiviral capabilities. Its regulation of the type I IFN response offers new avenues for developing antiviral and anticancer strategies and managing IFN-induced autoimmune disorders. Thus, ELF4 emerges as a promising target for preventing and treating IHD-related diseases. Mechanistic studies could help identify diets or antimicrobials that activate intestinal ELF4 to combat pathogen/virus-induced intestinal diseases. Full article

Steatotic liver disease (SLD) has become one of the most prevalent chronic liver diseases, representing a significant health burden worldwide. The complex pathogenesis of SLD results in a lack of specific therapeutic targets and effective drug treatment modalities. Copper (Cu) is a trace element that plays a critical role in various physiological processes, particularly hepatic metabolism. Meanwhile, Cu overload can induce cellular toxicity, which is generally explained by its capacity to induce oxidative damage. In 2022, a novel form of programmed cell death, designated as cuproptosis, was identified. In essence, excess Cu ions bind to the lipoylated components of the tricarboxylic acid cycle, resulting in proteotoxic stress and subsequent cell death. The role of cuproptosis in the pathologies of Cu overload-induced diseases has gained considerable attention. However, the association between SLD and Cu overload, particularly cuproptosis, remains to be elucidated. This review provides a concise overview of cuproptosis. The significance of Cu overload in SLD, as well as the potential association between cuproptosis and SLD, is explored. This review aims to offer insights into the potential of cuproptosis as a therapeutic target for SLD. Full article