Search Results (493)

Background/Objectives: Primary liver cancer (PLC), encompassing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), constitutes a growing global health concern. Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) and Type 2 diabetes mellitus (T2DM) represent a recurrent epidemiological overlap. Individuals with MASLD and T2DM (MASLD-T2DM) are at a higher risk of PLC. This scoping review highlights the epidemiological burden, the classic and novel pathogenetic frontiers, and the potential strategies optimizing the management of PLC in MASLD-T2DM. Methods: A systematic search of the PubMed, Medline, and SCOPUS electronic databases was conducted to identify evidence investigating the pathogenetic mechanisms linking MASLD and T2DM to hepatic carcinogenesis, highlighting the most relevant targets and the relatively emerging therapeutic strategies. The search algorithm included in sequence the filter words: “MASLD”, “liver steatosis”, “obesity”, “metabolic syndrome”, “body composition”, “insulin resistance”, “inflammation”, “oxidative stress”, “metabolic dysfunction”, “microbiota”, “glucose”, “immunometabolism”, “trained immunity”. Results: In the MASD-T2DM setting, insulin resistance (IR) and IR-induced mechanisms (including chronic inflammation, insulin/IGF-1 axis dysregulation, and autophagy), simultaneously with the alterations of gut microbiota composition and functioning, represent crucial pathogenetic factors in hepatocarcinogenesis. Besides, the glucose-related metabolic reprogramming emerged as a crucial pathogenetic moment contributing to cancer progression and immune evasion. In this scenario, lifestyle changes, simultaneously with antidiabetic drugs targeting IR-related effects and gut-liver axis, in parallel with novel approaches modulating immunometabolic pathways, represent promising strategies. Conclusions: Metabolic dysfunction, classically featuring MASLD-T2DM, constitutes a continuously expanding global issue, as well as a critical driver in PLC progression, demanding integrated and personalized interventions to reduce the future burden of disease. Full article

Background: Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Full article

(1) Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by liver damage similar to alcoholic fatty liver disease, including triglyceride infiltration of hepatocytes, regardless of alcohol consumption. It leads to progressive liver damage, such as loss of liver function, cirrhosis, and liver cancer, and the response rate of drugs under clinical research is less than 50%. There is an urgent need for biomarkers to evaluate the efficacy of these drugs. (2) Methods: MASLD was induced in mice using a High-Fat diet (HF), Western diet (WD), and Methionine/Choline-Deficient diet (MCD) for 20 weeks (4 weeks for MCD). Liver tissue biopsies were performed, and the treatment effects of saponin and non-saponin feeds were evaluated. Fat accumulation and hepatic inflammation were measured, and mRNA sequencing analysis was conducted. The therapeutic effects were validated using patient-derived liver organoids. (3) Results: The NAFLD Activity Score (NAS) significantly increased in all MASLD models compared with controls. Saponin treatment decreased NAS in the HF and WD groups but not in the MCD group. RNA sequencing and PCA analysis showed that the HF saponin response samples were similar to normal controls. DAVID analysis revealed significant changes in lipid, triglyceride, and fatty acid metabolic processes. qRT-PCR confirmed decreased fibrosis markers in the HF saponin response group, and GSEA analysis showed reduced HAMP1 gene expression. (4) Conclusions: Among the diets, red ginseng was most effective in the HF diet, with significant effects in the saponin-treated group. The therapeutic efficacy was better when HAMP1 expression was increased. Therefore, we propose HAMP1 as a potential exploratory biomarker to assess the saponin response in a preclinical setting. In addition, the reduction of inflammation and hepatic iron accumulation suggests that saponins may exert antioxidant effects through modulation of oxidative stress. Full article

This study aimed to investigate the effect of gender on the pharmacokinetics of meloxicam in goats following intravenous (IV, 0.5 mg/kg) and oral (PO, 1.0 mg/kg) administration. A crossover design was used with 12 clinically healthy Saanen goats (six females and six males). Plasma samples were collected up to 96 h post-administration and analyzed with an HPLC for meloxicam concentrations. Pharmacokinetic parameters were calculated and statistically compared between genders and administration routes. The results show that male goats exhibited significantly longer terminal half-life (T_1/2λz), a greater mean residence time (MRT_0–∞), and higher systemic exposure (AUC_0–∞) than females, particularly after oral administration. Oral bioavailability was calculated as 77.43% in females and 104.73% in males. These differences may be linked to gender-based variations in hepatic metabolism, enterohepatic recirculation, and the hormone-mediated modulation of cytochrome P450 activity. The findings are consistent with previous research demonstrating that gender can influence drug disposition through hormonal and enzymatic mechanisms. This study underscores the importance of considering gender as a biological variable in pharmacokinetic assessments of veterinary drugs, especially those used in food-producing animals, to optimize dosing strategies and ensure both therapeutic efficacy and food safety. Full article

Pregnancy introduces significant physiological changes that alter the pharmacokinetics (PK) of antiretroviral therapy (ART), impacting its safety and efficacy in HIV-positive women. Optimizing ART during pregnancy is critical to maintaining maternal virological suppression and preventing mother-to-child transmission (MTCT) of HIV. This review evaluates the impact of pregnancy-induced PK changes on ART and proposes strategies for tailored regimens to improve outcomes. A comprehensive review of published literature was conducted, focusing on PK adaptations during pregnancy and their implications for different ART classes, including protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). Key studies were analyzed to assess drug exposure, efficacy, and safety. Pregnancy significantly alters the PK of antiretrovirals, with increased hepatic metabolism, renal clearance, and changes in plasma protein binding leading to reduced drug exposure. For example, drugs like lopinavir and atazanavir require dose adjustments, while dolutegravir maintains efficacy despite reduced plasma levels. Integrase inhibitors demonstrate favorable virological suppression, although cobicistat-boosted regimens show subtherapeutic levels. Tailored approaches, such as therapeutic drug monitoring (TDM), optimize ART efficacy while minimizing toxicity. Pregnancy-specific PK changes necessitate evidence-based ART adjustments to ensure virological suppression and reduce MTCT risk. Incorporating TDM, leveraging pharmacogenomic insights, and prioritizing maternal and neonatal safety are critical for personalized ART management. Further research into long-acting formulations and global guideline harmonization is needed to address disparities in care and improve outcomes for HIV-positive pregnant women. Full article

Sulfotransferase (SULT) enzymes contribute significantly to drug metabolism in pediatric patients. The purpose of this study was to develop a PBPK model for acetaminophen (APAP) in pediatric populations that accounts for the ontogeny of SULT isozymes that play a critical role in APAP metabolism. PBPK modeling and simulation were performed using the Simcyp^® Simulator. The model incorporated the developmental ontogeny of three key hepatic SULT enzymes: SULT1A1, SULT1A3, and SULT2A1 using “best-fit” ontogeny equations for each isozyme as determined by nonlinear regression analysis of enzyme abundance versus age. PBPK model-simulated pharmacokinetic profiles for APAP captured observed clinical data for systemic exposure (Cmax, AUC) in neonates, infants, and children. SULTS accounted for ~60% APAP metabolism in neonates, with decreased contributions to infants and children. Model sensitivity analysis highlighted the potential for APAP metabolic DDIs, primarily through SULT1A1. The study demonstrates that the impact of SULT enzymes on drug metabolism is significant in neonates, which is an important clinical consideration for APAP. A PBPK model that incorporates SULT ontogeny has the potential to help inform dosing decisions in this special patient population. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD, is the most prevalent chronic liver disease worldwide. Strongly linked to obesity, type 2 diabetes, and metabolic syndrome, MASLD poses a growing health burden. Despite its high prevalence and risk of progression, no pharmacological treatment is currently approved. This narrative review provides an overview of emerging pharmacological treatments under clinical investigation, with a particular focus on agents recently evaluated in randomized clinical trials. A systematic search of the ClinicalTrials.gov database through to April 2025 was conducted to identify relevant studies. Investigational drugs were categorized by their molecular mechanisms, and data on efficacy, safety, and clinical development phases were summarized. The most extensively studied drug classes include GLP-1 receptor agonists, PPAR agonists, and FXR agonists, as well as inhibitors of ACC and DGAT. These therapies have shown promising effects on hepatic steatosis, liver enzyme levels, and metabolic markers and may be introduced into clinical practice in the near future. Full article

Artemisia absinthium L. contributes to ecological stabilization in arid regions through its deep root system for sand fixation and soil microenvironment modulation, thereby effectively mitigating desertification. Total terpenoids have been extracted from A. absinthium (AATP) and found to have antioxidant and anti-inflammatory activities. Terpenoids are a class of natural products derived from methyl hydroxypropanoic acid, for which their structural units consist of multiple isoprene (C5) units. They are one of the largest and most structurally diverse classes of natural compounds. However, there are still large gaps in knowledge regarding their exact biological activities and effects. Atherosclerosis (AS) is a prevalent cardiovascular disease marked by the chronic inflammation of the vascular system, and lipid metabolism plays a key role in its pathogenesis. This study determined the extraction and purification processes of AATP through single-factor experiments and response surface optimization methods. The purity of AATP was increased from 20.85% ± 0.94 before purification to 52.21% ± 0.75, which is 2.5 times higher than before purification. Studies have shown that the total terpenoids of A. absinthium significantly reduced four indices of serum lipids in atherosclerosis (AS) rats, thereby promoting lipid metabolism, inhibiting inflammatory processes, and hindering aortic wall thickening and hepatic fat accumulation. It is known from network pharmacology studies that AATP regulates the Janus kinase/signal transducer (JAK/STAT) signaling axis. Molecular docking studies have indicated that the active component of AATP effectively binds to Janus kinase (JAK2) and signal transducer (STAT3) target proteins. The results indicate that AATP can inhibit the release of pro-inflammatory mediators (such as reactive oxygen species (ROS)) in LPS-induced RAW264.7 macrophages. It also inhibits the M1 polarization of RAW264.7 macrophages. Protein immunoblotting analysis revealed that it significantly reduces the phosphorylation levels of Janus kinase (JAK2) and the signal transducer and activator of transcription 3 (STAT3). Research indicates that the active components in A. absinthium may exert anti-atherosclerotic effects by regulating lipid metabolism and inhibiting inflammatory responses. It holds potential value for development as a functional food or drug for the prevention and treatment of atherosclerosis. Full article

The liver is a vital organ responsible for a broad range of metabolic functions, including glucose and lipid metabolism, detoxification, and protein synthesis. Its structural complexity, characterized by hexagonal hepatic lobules composed of diverse parenchymal and non-parenchymal cell types, supports its broad spectrum of physiological activities. Traditional in vitro liver models have contributed significantly to our understanding of hepatic biology and the development of therapies for liver-related diseases. However, static culture systems fail to replicate the dynamic in vivo microenvironment, particularly the continuous blood flow and shear stress that are critical for maintaining hepatocyte function and metabolic zonation. Recent advances in microphysiological systems (MPS) incorporating dynamic fluid flow have addressed these limitations by providing more physiologically relevant platforms for modeling liver function. These systems offer improved fidelity for applications in drug screening, toxicity testing, and disease modeling. Furthermore, the integration of liver MPS with other organ models in multi-organ-on-chip platforms has enabled the investigation of inter-organ crosstalk, enhancing the translational potential of in vitro systems. This review summarizes recent progress in the development of dynamic liver MPS, highlights their biomedical applications, and discusses future directions for creating more comprehensive and predictive in vitro models. Full article

Background: In order to address complex scenarios in anti-doping science, especially in cases where an unintentional exposure of athletes to prohibited substances and a corresponding contamination of doping control samples at the collection event are argued, an understanding of tissue-specific drug metabolism is essential. Hence, in this study, the metabolic capacity of the seminal vesicle using in vitro assays was investigated. Methods: The aim was to assess whether selected doping-relevant substances—stanozolol, LGD-4033, GW1516, trimetazidine, and anastrozole—are metabolised in seminal vesicle cellular fractions (SV-S9) and how that metabolism compares to biotransformations induced by human liver S9 fractions (HL-S9). Liquid chromatography coupled to high-resolution/accurate mass spectrometry (LC HRAM MS) enabled the sensitive detection and identification of metabolites, revealing a limited metabolic activity of SV-S9. Results: For LGD-4033, GW1516, and trimetazidine, minor metabolic transformations were observed, whereas no metabolites of stanozolol or anastrozole were detected. Gene expression analysis using digital polymerase chain reaction (dPCR) confirmed transcripts of CYP2D6, CYP2E1, and CYP2C9 in SV-S9, though no enzymatic activity was detected. Gene expression and enzymatic activity in CYP3A4 and CYP1A2—major hepatic enzymes—were absent in SV-S9. Conclusions: Overall, these pilot study results suggest that the seminal vesicle has only a low capacity for xenobiotic metabolism, which translates into a limited role in the biotransformation of drugs and, hence, the metabolic pattern. Full article

Recently, China has become a hotspot for farming golden pompano (Trachinotus ovatus), a commercially valuable marine fish. The genetic mechanisms underlying ovarian development, particularly those regulated by insulin-like growth factors (IGFs), remain poorly understood. Existing research on T. ovatus has focused primarily on growth metrics, developmental stages, and immune responses, leaving a critical gap in knowledge regarding the hepatic regulatory pathways activated by IGFs. In this study, differentially expressed genes (DEGs) were detected through RNA sequencing (RNA-Seq) and associated pathways in response to IGF treatment. Comparisons between the IGF1, IGF2, and IGF3 treated groups and the control revealed 113 (46 upregulated, 67 downregulated), 637 (567 upregulated, 70 downregulated), and 587 DEGs (273 upregulated, 314 downregulated), respectively. KEGG enrichment analysis highlighted key pathways that may be linked to ovarian growth and development, including biotin metabolism, biosynthesis of amino acids, drug-cytochrome p450 pathways, MAPK signaling, estrogen signaling pathways, ECM receptor interaction, steroid biosynthesis, and ovarian steroidogenesis. These findings advance our understanding of hepatic metabolic regulation in golden pompano via the IGF system and provide actionable insights for optimizing aquaculture practices and selective breeding programs for this species. Full article

Background/Objectives: Hepatic clearance is important in determining clinical drug administration strategies. Achieving accurate hepatic clearance predictions through in vitro-to-in vivo extrapolation (IVIVE) relies on appropriate model selection, which is a critical step. Although numerous models have been developed to estimate drug dosage, some may fail to predict liver drug clearance owing to inappropriate hepatic clearance models during IVIVE. To address this limitation, an in silico-based model selection approach for optimizing hepatic clearance predictions was introduced in a previous study. The current study extends this strategy by verifying the accuracy of the selected models using ex situ experimental data, particularly for drugs whose model choices are influenced by protein binding. Methods: Commonly prescribed drugs were classified according to their hepatic extraction ratios and protein-binding properties. Building on previous studies that employed multinomial logistic regression analysis for model selection, a three-phase classification method was implemented to identify five representative drugs: diazepam, diclofenac, rosuvastatin, fluoxetine, and tolbutamide. Subsequently, an isolated perfused rat liver (IPRL) system was used to evaluate the accuracy of the in silico method. Results: As the unbound fraction increased for diazepam and diclofenac, the most suitable predictive model shifted from the initially preferred well-stirred model (WSM) to the modified well-stirred model (MWSM). For rosuvastatin, the MWSM provided a more accurate prediction. These three capacity-limited, binding-sensitive drugs conformed to the outcomes predicted by the multinomial logistic regression analysis. Fluoxetine was best described by the WSM, which is consistent with its flow-limited classification. For tolbutamide, a representative capacity-limited, binding-insensitive drug, no significant differences were observed among the various models. Conclusions: These findings demonstrate the accuracy of an in silico-based model selection approach for predicting liver metabolism and highlight its potential for guiding dosage adjustments. Furthermore, the IPRL system serves as a practical tool for validating the accuracy of the results derived from this approach. Full article

Nuclear receptors are proteins located in the nucleus that are involved in gene transcription and play an important role in regulating metabolism and inflammation. Systemic metabolic abnormalities and chronic inflammation in diabetic patients are associated with gene expression and activity of bile acid metabolism, lipid and carbohydrate metabolism, energy expenditure, and inflammation regulated by nuclear receptors. As a major metabolic organ, the nuclear receptor regulation signal of the liver is the key to regulating the dialog between the liver and other organs. In this review, we discuss the newly discovered role of hepatic nuclear receptor signaling in diabetes metabolism and inflammation and focus on recent advances in drug research targeting nuclear receptors in diabetes, including the use of traditional Chinese medicine. Full article

Background/Objectives: Early diagnosis and oral or, in severe cases, intravenous antibiotics are usually effective for Lyme disease, but some patients have persistent symptoms unresponsive to standards of care, requiring alternative therapies. Disulfiram (DIS), a drug for alcoholism, is under investigation as a potential adjunctive treatment, but its low bioavailability, rapid metabolism, and safety concerns urge the development of improved formulations for clinical translation. Methods: Screening dissolution and permeation studies were investigated for vehicle and excipient selection, following the pharmacopeia perspectives to develop and optimize the low-dose DIS rectal suppository intended for application in post-treatment Lyme disease syndrome (PTLDS). Further characterizations were carried out by differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy. Results: Cyclodextrin (CD) encapsulation was investigated to improve the aqueous solubility of the hydrophobic drug. The dissolution of DIS from fatty base suppository was very slow; it was remarkably improved by the molecular encapsulation of the drug with CDs. The dissolution of DIS from a water-soluble base was more favorable, but incomplete. In the polyethylene glycol (PEG) based suppositories, the addition of CDs already in a physical mixture ensured the dissolution of the drug. The presented drug delivery system relates to a novel preparation for rectal administration comprising a low-dose disulfiram with improved solubility and permeability by the PEG and hydroxypropyl-β-cyclodextrin (HPBCD) synergistic matrix. Conclusions: The rectal dosage form containing the drug and CD in the physical mixture is advantageous, avoiding the hepatic first-pass effect, minimizing dose-limiting toxicity, simplifying production, and fasting the availability of the repositioned drug. Full article

CYP2C9 and CYP2C19 are major CYP450 enzymes that heavily influence the hepatic metabolism and bioactivation of many medications, including over-the-counter and narrow therapeutic index drugs. Compared to the wild-type alleles, genetic variants in either gene could potentially alter the pharmacokinetics of widely used medications, affect the desired therapeutic outcomes of a drug therapy, or increase the risk of undesired adverse events. The frequency of genetic polymorphisms associated with CYP450 enzymes can widely differ across and between racial and ethnic groups. This narrative review highlights the differences in CYP2C9 and CYP2C19 allele frequencies among European and Asian population subgroups, using published literature. Identifying the substantial differences across European and Asian populations, as well as within Asian subgroups, indicates the need to further scrutinize general population data. Clinical scientists and healthcare providers should advocate for more inclusive clinical pharmacogenomic data and racially and ethnically diverse pharmacogenomic databases. Clinical trials of limited racial and geographical diversity may not necessarily have strong external generalizability for all populations. Furthermore, clinical trials that designate an all-inclusive Asian population consisting of multiple ethnicities may not be adequate due to the perceived genetic differences among Asian subgroups. Gravitating towards a more comprehensive approach to utilizing pharmacogenomic data necessitates granular population-level genetic information which can be leveraged to improve how drug therapies are prescribed, achieve health equity, and advance the future of precision medicine. Full article