Comput Methods Programs Biomed. 2025 Feb 18;263:108672. doi: 10.1016/j.cmpb.2025.108672. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Metabolomic interaction networks provide critical insights into the dynamic relationships between metabolites and their regulatory mechanisms. This study introduces MInfer, a novel computational framework that integrates outputs from MetaboAnalyst, a widely used metabolomic analysis tool, with Jacobian analysis to enhance the derivation and interpretation of these networks.

METHODS: MInfer combines the comprehensive data processing capabilities of MetaboAnalyst with the mathematical modeling power of Jacobian analysis. This framework was applied to various metabolomic datasets, employing advanced statistical tests to construct interaction networks and identify key metabolic pathways.

RESULTS: The application of MInfer revealed significant metabolic pathways and potential regulatory mechanisms across multiple datasets. The framework demonstrated high precision, sensitivity, and specificity in identifying interactions, enabling robust network interpretations.

CONCLUSIONS: MInfer enhances the interpretation of metabolomic data by providing detailed interaction networks and uncovering key regulatory insights. This tool holds significant potential for advancing the study of complex biological systems.

PMID:39999596 | DOI:10.1016/j.cmpb.2025.108672

Hepatology. 2025 Feb 25. doi: 10.1097/HEP.0000000000001281. Online ahead of print.

ABSTRACT

Drug-induced liver injury (DILI) is rare in clinical practice but when it occurs it can lead to acute liver failure and death. Drug developers and regulators undertake a series of steps to identify the DILI potential of a medication before it is approved for marketing. Preclinical testing by drug developers typically involves a multitude of in vitro assays and in vivo animal experiments before a compound is moved into first-in-human phase 1 testing. Over the last two decades, there have been a number of advances in preclinical screening for DILI potential of a new chemical entity, but these approaches tend to be overly sensitive with insufficient positive predictive value. Once in clinical trials, the DILI potential of an investigational agent and risks to a participant are carefully managed through patient selection, DILI monitoring paradigms, and drug interruption and discontinuation criteria, in close concert with the regulators. Recent developments in Quantitative Systems Toxicology offer promising and complementary in silico approaches to predict the compound's risk for DILI via multifaceted systems biology. When a drug developer submits a New Drug Application (NDA) for marketing approval, regulators review the preclinical and clinical trial data in a structured fashion to assess the DILI risk. While these approaches have been successful in dramatically reducing the marketing approval of medications eventually associated with hepatotoxicity, many challenges remain in identifying the risk for DILI during preclinical and early-to-late clinical development stages for genetic medicines, biological agents, and immunotherapies. In this review, we discuss current preclinical, in-silico, and clinical development approaches to screen for DILI potential of an investigational agent and provide a high-level description of regulators' approach for assessing DILI risk in an NDA.

PMID:39999469 | DOI:10.1097/HEP.0000000000001281

Proc Natl Acad Sci U S A. 2025 Mar 4;122(9):e2415933122. doi: 10.1073/pnas.2415933122. Epub 2025 Feb 25.

ABSTRACT

Atherosclerosis and vessel wall trauma induce vascular smooth muscle cell (VSMC) phenotypic modulation, leading to plaque cap growth and postintervention restenosis. Our systems biology approach identified RNA binding protein, mRNA processing factor (RBPMS) as a conserved, VSMC-specific gene associated with VSMC modulation in atherosclerosis. RBPMS gene expression positively correlates with VSMC contractile markers in human and murine atherosclerotic arteries as well as in two vascular injury models during the postinjury intimal hyperplasia phase. RBPMS promotes contractile VSMC differentiation, reduces plaque cap development in high-fat diet-fed apolipoprotein E-null (ApoE-/-) murine atherosclerotic arteries, and inhibits intimal hyperplasia. Mechanistically, the RBPMS protein interacts with the myocardin (MYOCD) pre-mRNA and enhances MYOCD_v3/MYOCD_v1 transcript balance through alternative exon 2a splicing. RBPMS promotes the VSMC contractile phenotype and reduces their fibroproliferative activity in a MYOCD_v3a-dependent manner. RBPMS enhances Myocd_v3/Myocd_v1 transcript balance in both atherosclerotic and injured vessels. RBPMS may inhibit VSMC-driven plaque cap development and intervention-induced restenosis.

PMID:39999164 | DOI:10.1073/pnas.2415933122

Tissue Eng Regen Med. 2025 Feb 25. doi: 10.1007/s13770-025-00705-0. Online ahead of print.

ABSTRACT

BACKGROUND: Autotaxin (ATX), an ENPP2 enzyme, regulates lipid signaling by converting lysophosphatidylcholine to lysophosphatidic acid (LPA). Dysregulation of the ATX/LPA axis promotes inflammation and disease progression. BMP-22, a lipid ATX inhibitor, effectively reduces LPA production. However, its clinical utility is hampered by limitations in solubility and pharmacokinetics. To overcome these limitations, we developed BMP-22-incorporated lipid nanoparticles (LNP-BMP) to improve utility while maintaining ATX inhibition efficacy.

METHODS: LNP-BMP was synthesized by incorporating DOTAP, DOPE, cholesterol, 18:0 PEG2000-PE, and together with BMP-22. The formulation of LNP-BMP was optimized and characterized by testing different molar ratios of BMP-22. The autophagy recovery and anti-inflammatory effects of LNP-BMP via ATX inhibition were evaluated in both macrophage cell line and mouse-derived primary macrophages.

RESULTS: LNP-BMP was shown to retain its functionality as an ATX inhibitor and maintain the physical characteristics upon BMP-22 integration. Synthesized LNP-BMP exerted superior ability to inhibit ATX activity. When applied to M1-induced macrophages, LNP-BMP exhibited substantial anti-inflammatory effects and successfully restored autophagy activity.

CONCLUSION: The results demonstrate that LNP-BMP effectively inhibits ATX, achieving both anti-inflammatory effects and autophagy restoration, highlighting its potential as a standalone immunotherapeutic agent. Furthermore, the capacity to load therapeutic drugs into this formulation offers promising opportunities for further therapeutic strategies.

PMID:39998744 | DOI:10.1007/s13770-025-00705-0

Brief Bioinform. 2024 Nov 22;26(1):bbaf070. doi: 10.1093/bib/bbaf070.

ABSTRACT

With the exponential growth of biomedical literature, leveraging Large Language Models (LLMs) for automated medical knowledge understanding has become increasingly critical for advancing precision medicine. However, current approaches face significant challenges in reliability, verifiability, and scalability when extracting complex biological relationships from scientific literature using LLMs. To overcome the obstacles of LLM development in biomedical literature understating, we propose LORE, a novel unsupervised two-stage reading methodology with LLM that models literature as a knowledge graph of verifiable factual statements and, in turn, as semantic embeddings in Euclidean space. LORE captured essential gene pathogenicity information when applied to PubMed abstracts for large-scale understanding of disease-gene relationships. We demonstrated that modeling a latent pathogenic flow in the semantic embedding with supervision from the ClinVar database led to a 90% mean average precision in identifying relevant genes across 2097 diseases. This work provides a scalable and reproducible approach for leveraging LLMs in biomedical literature analysis, offering new opportunities for researchers to identify therapeutic targets efficiently.

PMID:39998433 | DOI:10.1093/bib/bbaf070

mBio. 2025 Feb 25:e0401524. doi: 10.1128/mbio.04015-24. Online ahead of print.

ABSTRACT

The gastrointestinal (GI) tract is a site of replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and GI symptoms are often reported by patients. SARS-CoV-2 cell entry depends upon heparan sulfate (HS) proteoglycans, which commensal bacteria that bathe the human mucosa are known to modify. To explore human gut HS-modifying bacterial abundances and how their presence may impact SARS-CoV-2 infection, we developed a task-based analysis of proteoglycan degradation on large-scale shotgun metagenomic data. We observed that gut bacteria with high predicted catabolic capacity for HS differ by age and sex, factors associated with coronavirus disease 2019 (COVID-19) severity, and directly by disease severity during/after infection, but do not vary between subjects with COVID-19 comorbidities or by diet. Gut commensal bacterial HS-modifying enzymes reduce spike protein binding and infection of authentic SARS-CoV-2, suggesting that bacterial grooming of the GI mucosa may impact viral susceptibility.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019, can infect the gastrointestinal (GI) tract, and individuals who exhibit GI symptoms often have more severe disease. The GI tract's glycocalyx, a component of the mucosa covering the large intestine, plays a key role in viral entry by binding SARS-CoV-2's spike protein via heparan sulfate (HS). Here, using metabolic task analysis of multiple large microbiome sequencing data sets of the human gut microbiome, we identify a key commensal human intestinal bacteria capable of grooming glycocalyx HS and modulating SARS-CoV-2 infectivity in vitro. Moreover, we engineered the common probiotic Escherichia coli Nissle 1917 (EcN) to effectively block SARS-CoV-2 binding and infection of human cell cultures. Understanding these microbial interactions could lead to better risk assessments and novel therapies targeting viral entry mechanisms.

PMID:39998226 | DOI:10.1128/mbio.04015-24

mBio. 2025 Feb 25:e0399724. doi: 10.1128/mbio.03997-24. Online ahead of print.

ABSTRACT

Campylobacter jejuni is a common foodborne pathogen worldwide that is associated with high rates of morbidity and mortality among infants in low- to middle-income countries (LMICs). Human milk provides infants with an important source of nutrients and contains antimicrobial components for protection against infection. However, recent studies, including our own, have found significantly higher levels of Campylobacter in diarrheal stool samples collected from breastfed infants compared to non-breastfed infants in LMICs. We hypothesized that C. jejuni has unique strategies to resist the antimicrobial properties of human milk. Transcriptional profiling found human milk exposure induces genes associated with ribosomal function, iron acquisition, and amino acid utilization in C. jejuni strains 81-176 and 11168. However, unidentified proteinaceous components of human milk prevent bacterial growth. Evolving both C. jejuni isolates to survive in human milk resulted in mutations in genes encoding the acyl carrier protein (AcpP) and the major outer membrane porin (PorA). Introduction of the PorA/AcpP amino acid changes into the parental backgrounds followed by electron microscopy showed distinct membrane architectures, and the AcpP changes not only significantly improved growth in human milk, but also yielded cells surrounded with outer membrane vesicles. Analyses of the phospholipid and lipooligosaccharide (LOS) compositions suggest an imbalance in acyl chain distributions. For strain 11168, these changes protect both evolved and 11168∆acpPG33R strains from bacteriophage infection and polymyxin killing. Taken together, this study provides insights into how C. jejuni may evolve to resist the bactericidal activity of human milk and flourish in the hostile environment of the gastrointestinal tract.

IMPORTANCE: In this study, we evolved C. jejuni strains which can grow in the presence of human milk and found that cell membrane alterations may be involved in resistance to the antimicrobial properties of human milk. These bacterial membrane changes are predominantly linked to amino acid substitutions within the acyl carrier protein, AcpP, although other bacterial components, including PorA, are likely involved. This study provides some insights into possible strategies for C. jejuni survival and propagation in the gastrointestinal tract of breastfed infants.

PMID:39998218 | DOI:10.1128/mbio.03997-24

Microbiol Resour Announc. 2025 Feb 25:e0113424. doi: 10.1128/mra.01134-24. Online ahead of print.

ABSTRACT

Rhodococcus sp. strain DK17 degrades various alkylbenzenes, including o-xylene, making it a potential biocatalyst for the production of fine chemicals. DK17 carries the degradative genes on linear mega-plasmids. Here, we present the refined DK17 genome and analyze the genetic variations in UV-induced mutants DK176 and DK180.

PMID:39998182 | DOI:10.1128/mra.01134-24

Sports (Basel). 2025 Jan 21;13(2):28. doi: 10.3390/sports13020028.

ABSTRACT

The present study aimed to verify the (1) differences between players' roles in relation to technical and tactical and time-motion indicators, and the (2) relationships between individual time-motion and technical and tactical indicators for each role in a men's Italian football Serie A team. A total of 227 performances were analyzed (28 players: 8 forwards, FWs; 11 midfielders, MDs; 9 defenders, DFs). Technical and tactical indicators, such as ball possession (played balls, successful passes, successful playing patterns, lost balls, ball possession time), offensive play (total and successful dribbles, crosses, assists), and shooting (total shots, shots on target) were obtained by means of Panini Digital (DigitalSoccer Project S.r.l). In addition, a time-motion analysis included the total distance, distances covered at intensities of 16.0-19.8 km/h, 19.8-25.2 km/h, and over 25.2 km/h, the average recovery time between metabolic power peaks, and burst occurrence, the latter of which was performed by means of a 18 Hz GPS device (GPexe Pro2 system tool) worn by the players. Results showed role-specific differences: MDs covered more distance, while DFs had better ball possession. MDs and DFs had more successful playing patterns, and MDs and FWs performed more dribbles and shots. Strong correlations (p < 0.01, ρ > 0.8) were found between bursts and assists for FWs, high-intensity running and ball possession for MDs, and distance, dribbling, and shots for DFs. These findings highlight the importance of individual and tailored training programs to optimize role-specific performance demands.

PMID:39997959 | DOI:10.3390/sports13020028

Toxics. 2025 Feb 19;13(2):142. doi: 10.3390/toxics13020142.

ABSTRACT

Chemical exposure in the environment can adversely affect the biodiversity of living organisms, particularly when persistent chemicals accumulate over time and disrupt the balance of microbial populations. In this study, we examined how chemical contaminants influence microorganisms in sediment and overlaying water samples collected from the Kinnickinnic, Milwaukee, and Menomonee Rivers near Milwaukee, Wisconsin, USA. We characterized these samples using shotgun metagenomic sequencing to assess microbiome diversity and employed chemical analyses to quantify more than 200 compounds spanning 16 broad classes, including pesticides, industrial products, personal care products, and pharmaceuticals. Integrative and differential comparative analyses of the combined datasets revealed that microbial density, approximated by adjusted total sequence reads, declined with increasing total chemical concentrations. Protozoan, metazoan, and fungal populations were negatively correlated with higher chemical concentrations, whereas certain bacterial (particularly Proteobacteria) and archaeal populations showed positive correlations. As expected, sediment samples exhibited higher concentrations and a wider dynamic range of chemicals compared to water samples. Varying levels of chemical contamination appeared to shape the distribution of microbial taxa, with some bacterial, metazoan, and protozoan populations present only at certain sites or in specific sample types (sediment versus water). These findings suggest that microbial diversity may be linked to both the type and concentration of chemicals present. Additionally, this study demonstrates the potential roles of multiple microbial kingdoms in degrading environmental pollutants, emphasizing the metabolic versatility of bacteria and archaea in processing complex contaminants such as polyaromatic hydrocarbons and bisphenols. Through functional and resistance gene profiling, we observed that multi-kingdom microbial consortia-including bacteria, fungi, and protozoa-can contribute to bioremediation strategies and help restore ecological balance in contaminated ecosystems. This approach may also serve as a valuable proxy for assessing the types and levels of chemical pollutants, as well as their effects on biodiversity.

PMID:39997957 | DOI:10.3390/toxics13020142

Metabolites. 2025 Feb 6;15(2):101. doi: 10.3390/metabo15020101.

ABSTRACT

Background/Objectives: Determining appropriate cellular objectives is crucial for the system-scale modeling of biological networks for metabolic engineering, cellular reprogramming, and drug discovery applications. The mathematical representation of metabolic objectives can describe how cells manage limited resources to achieve biological goals within mechanistic and environmental constraints. While rapidly proliferating cells like tumors are often assumed to prioritize biomass production, mammalian cell types can exhibit objectives beyond growth, such as supporting tissue functions, developmental processes, and redox homeostasis. Methods: This review addresses the challenge of determining metabolic objectives and trade-offs from multiomics data. Results: Recent advances in single-cell omics, metabolic modeling, and machine/deep learning methods have enabled the inference of cellular objectives at both the transcriptomic and metabolic levels, bridging gene expression patterns with metabolic phenotypes. Conclusions: These in silico models provide insights into how cells adapt to changing environments, drug treatments, and genetic manipulations. We further explore the potential application of incorporating cellular objectives into personalized medicine, drug discovery, tissue engineering, and systems biology.

PMID:39997726 | DOI:10.3390/metabo15020101

Metabolites. 2025 Jan 26;15(2):76. doi: 10.3390/metabo15020076.

ABSTRACT

Background: Elevated choline kinase alpha (ChoK) levels are observed in most solid tumors, including glioblastomas (GBM), and ChoK inhibitors have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with resistance to GBM therapy, we hypothesized that tumor hypoxia could be responsible for the limited response. Therefore, we evaluated the effects of hypoxia on the function of JAS239, a potent ChoK inhibitor in four GBM cell lines. Methods: Rodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 h of hypoxic conditioning and treated with JAS239 for 24 h. NMR metabolomic measurements and analyses were performed to evaluate the signaling pathways involved. In addition, cell proliferation, cell cycle progression, and cell invasion parameters were measured in 2D cell monolayers as well as in 3D cell spheroids, with or without JAS239 treatment, in normoxic or hypoxic cells to assess the effect of hypoxia on JAS239 function. Results: Hypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways, associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, effects from JAS239 were variable depending on the cell line, reflecting the inherent heterogeneity of GBMs. Conclusions: Our findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit cell proliferation, and alter cell invasion. These results may be useful for designing new therapeutic strategies based on ChoK inhibition, which can act on multiple pro-tumorigenic features.

PMID:39997701 | DOI:10.3390/metabo15020076

Healthcare (Basel). 2025 Feb 10;13(4):376. doi: 10.3390/healthcare13040376.

ABSTRACT

Background: The risk of dying from chronic liver diseases (CLDs) is two to three times higher for patients with diabetes (DM). Nonalcoholic fatty liver disease (NAFLD) is the primary cause of this increased risk, which has an etiology unrelated to alcohol or viruses. Previous research reported that diabetes and CLD are related, since they influence each other. Aim: Estimation of the impact of diabetes (DM) on liver diseases (LD), and of the impact of liver diseases on DM among Egyptian and Saudi patients. It is a descriptive and prospective analytical study design. The investigation was carried out in Saudi Arabia and Egypt at gastroenterology outpatient clinics. Methods: Prospective data were collected through face-to-face patient interviews during clinic visits between June 2021 and June 2023. The interviews covered the patients' basic characteristics and information on DM and LD. Certain laboratory tests were conducted on these patients, such as liver function, glucose level, lipid profile, INR, and prothrombin time. Results: The total of 2748 participants in this study included 1242 diabetic patients of both genders from Saudi Arabia and 1506 from Egypt. Most Saudis had between 10 and 20 years' duration of DM (35.5%), with HbA1c (7-10%) values of 47.8%, while the Egyptian patients had >20 years' duration of DM (39.8%), with HbA1c (7-10%) values of 49.8%. Regarding the impact of DM on the development of liver diseases, about 35.5% (Saudis) vs. 23.5% (Egyptians) had liver diseases due to DM, a significant difference (p-value = 0.011). Liver enzymes were increased in many of the Egyptian and Saudi patients (41.4% vs. 33%), while the presence of fatty liver (28.2% vs. 35.7%) and hepatocellular carcinoma (13.7% vs. 6.1%) were also significantly different (p-value = 0.047). While the impact of liver diseases on DM was observed more among Egyptian (59%) than among Saudi (46.4%) patients because of liver cirrhosis (HCV or HBV), known to be a reason for diabetes in Egyptians (27.9%) vs. Saudis (8.0%), a higher incidence of fatty liver leading to DM was observed in Saudis than in Egyptians (15.9% vs. 11.6%) (p-value = 0.000. Obesity was more prevalent among Saudi patients (63.8%) than among Egyptian patients (48.6%) (p-value = 0.019). Fewer Egyptians (about 65%) suffered from dyslipidemia than Saudis (about 80%). Higher INR and longer prothrombin times were observed in Egyptians (29.9% and 29.1%, respectively) than in Saudis (20.3% and 18.8%, respectively), with a significant difference between the two nations (p-value < 0.050). Conclusions: We may conclude that diabetes in most patients has a negative impact on the development of liver diseases (particularly fatty liver in Saudi patients). In addition, most liver diseases (liver cirrhosis) have a negative influence on the development of DM (more so in Egyptian patients). There is a link between DM and liver disease. In particular, liver cirrhosis and diabetes were found to influence each other. Therefore, correct medication, adherence to treatment, lifestyle modifications, successful cirrhosis control (in patients with liver diseases), and diabetic control (in diabetic patients) could lead to effective management of both diseases. The negative fallouts in the two cases were prompted by obesity, morbid eating, and poor quality of life.

PMID:39997251 | DOI:10.3390/healthcare13040376

Cells. 2025 Feb 12;14(4):266. doi: 10.3390/cells14040266.

ABSTRACT

Liver fibrosis, a consequence of chronic liver injury, represents a major global health burden and is the leading cause of liver failure, morbidity, and mortality. The pathological hallmark of this condition is excessive extracellular matrix deposition, driven primarily by integrin-mediated mechanotransduction. Integrins, transmembrane heterodimeric proteins that serve as primary ECM receptors, orchestrate complex mechanosignaling networks that regulate the activation, differentiation, and proliferation of hepatic stellate cells and other ECM-secreting myofibroblasts. These mechanical signals create self-reinforcing feedback loops that perpetuate the fibrotic response. Recent advances have provided insight into the roles of specific integrin subtypes in liver fibrosis and revealed their regulation of key downstream effectors-including transforming growth factor beta, focal adhesion kinase, RhoA/Rho-associated, coiled-coil containing protein kinase, and the mechanosensitive Hippo pathway. Understanding these mechanotransduction networks has opened new therapeutic possibilities through pharmacological manipulation of integrin-dependent signaling.

PMID:39996739 | DOI:10.3390/cells14040266

Cells. 2025 Feb 11;14(4):257. doi: 10.3390/cells14040257.

ABSTRACT

Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the "diffusion penalty" on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand.

PMID:39996730 | DOI:10.3390/cells14040257

J Exp Bot. 2025 Feb 25;76(4):899-903. doi: 10.1093/jxb/erae411.

NO ABSTRACT

PMID:39996292 | DOI:10.1093/jxb/erae411

JHEP Rep. 2024 Nov 12;7(3):101267. doi: 10.1016/j.jhepr.2024.101267. eCollection 2025 Mar.

ABSTRACT

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a chronic heterogenous cholangiopathy with unknown etiology where chronic inflammation of the bile ducts leads to multifocal biliary strictures and biliary fibrosis with consecutive cirrhosis development. We here aimed to identify a PSC-specific gene signature associated with biliary fibrosis development.

METHODS: We performed RNA-sequencing of 47 liver biopsies from people with PSC (n = 16), primary biliary cholangitis (PBC, n = 15), and metabolic dysfunction-associated steatotic liver disease (MASLD, n = 16) with different fibrosis stages to identify a PSC-specific gene signature associated with biliary fibrosis progression. For validation, we compared an external transcriptome data set of liver biopsies from people with PSC (n = 73) with different fibrosis stages (baseline samples from NCT01672853).

RESULTS: Differential gene expression analysis of the liver transcriptome from patients with PSC with advanced vs. early fibrosis revealed 431 genes associated with fibrosis development. Of those, 367 were identified as PSC-associated when compared with PBC or MASLD. Validation against an external data set of 73 liver biopsies from patients with PSC with different fibrosis stages led to a condensed set of 150 (out of 367) differentially expressed genes. Cell type specificity assignment of those genes by using published single-cell RNA-Seq data revealed genetic disease drivers expressed by cholangiocytes (e.g. CXCL1, SPP1), fibroblasts, innate, and adaptive immune cells while deconvolution along fibrosis progression of the PSC, PBC, and MASLD samples highlighted an early involvement of macrophage- and neutrophil-associated genes in PSC fibrosis.

CONCLUSIONS: We reveal a PSC-attributed gene signature associated with biliary fibrosis development that may enable the identification of potential new biomarkers and therapeutic targets in PSC-related fibrogenesis.

IMPACT AND IMPLICATIONS: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease that is characterized by multifocal inflammation of bile ducts and subsequent biliary fibrosis. Herein, we identify a PSC-specific gene set of biliary fibrosis progression attributing to a uniquely complex milieu of different cell types, including innate and adaptive immune cells while neutrophils and macrophages showed an earlier involvement in fibrosis initiation in PSC in contrast to PBC and metabolic dysfunction-associated steatotic liver disease. Thus, our unbiased approach lays an important groundwork for further mechanistic studies for research into PSC-specific fibrosis.

PMID:39996122 | PMC:PMC11848773 | DOI:10.1016/j.jhepr.2024.101267

iScience. 2025 Jan 27;28(2):111808. doi: 10.1016/j.isci.2025.111808. eCollection 2025 Feb 21.

ABSTRACT

Intracrinology-wherein hormones are synthesized in the organ where they exert their effect without release into circulation-has been described. However, molecular mechanisms of hormone deactivation within intracrine tissue are still largely unknown. The meibomian glands in the eyelids produce oil (meibum) to the ocular surface to prevent dehydration (dry eye). Androgens are generated inside this gland and are crucial for its tissue-homeostasis. However, there is no data showing the presence of androgens in meibum, implying local conversion/deactivation into unknown metabolites. Here, we performed radioactive tracer studies in combination with pharmacological enzyme inhibition, followed by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and found three androgen metabolites-androstanedione, androsterone, and epiandrosterone-in mouse and human meibomian glands. Accounting for the enzymatic conversion, we show tissue-endogenous 3α/3β-ketosteroid reductase expression. We therefore reinforce the idea that androgens are metabolically inactivated within the glands. These metabolite markers may help to assess meibomian local androgen activity using meibum.

PMID:39995859 | PMC:PMC11848505 | DOI:10.1016/j.isci.2025.111808

Int J Cardiol Heart Vasc. 2025 Feb 5;57:101621. doi: 10.1016/j.ijcha.2025.101621. eCollection 2025 Apr.

ABSTRACT

BACKGROUND: Atrial fibrillation Better Care (ABC) pathway is recommended by guidelines on atrial fibrillation (AF) and exerts a protective role against adverse outcomes of AF patients. But the possible differences in its effectiveness across the diverse range of patients in China have not been systematically evaluated. We aim to comprehensively evaluate multiple clinical characteristics of patients, and probe clusters of ABC criteria efficacy in patients with AF.

METHODS: We used data from an observational cohort that included 2,016 patients with AF. We utilized 45 baseline variables for cluster analysis. We evaluated the management patterns and adverse outcomes of identified phenotypes. We assessed the effectiveness of adherence to the ABC criteria at reducing adverse outcomes of phenotypes.

RESULTS: Cluster analysis identified AF patients into three distinct groups. The clusters include Cluster 1: old patients with the highest prevalence rates of atherosclerotic and/or other comorbidities (n = 964), Cluster 2: valve-comorbidities AF in young females (n = 407), and Cluster 3: low comorbidity patients with paroxysmal AF (n = 644). The clusters showed significant differences in MACNE, all-cause death, stroke, and cardiovascular death. All clusters showed that full adherence to the ABC pathway was associated with a significant reduction in the risk of MACNE (all P < 0.05). For three clusters, adherence to the different 'A'/'B'/'C' criterion alone showed differential clinic impact.

CONCLUSION: Our study suggested specific optimization strategies of risk stratification and integrated management for different groups of AF patients considering multiple clinical, genetic and socioeconomic factors.

PMID:39995811 | PMC:PMC11848476 | DOI:10.1016/j.ijcha.2025.101621

Rep Biochem Mol Biol. 2024 Jul;13(2):281-300. doi: 10.61186/rbmb.13.2.281.

ABSTRACT

BACKGROUND: Gastric cancer (GC) is a prevalent malignancy with high recurrence. Advances in systems biology have identified molecular pathways and biomarkers. This study focuses on discovering gene and miRNA biomarkers for diagnosing and predicting survival in GC patients.

METHODS: Three sets of genes (GSE19826, GSE81948, and GSE112369) and two sets of miRNA expression (GSE26595, GSE78775) were obtained from the Gene Expression Omnibus (GEO), and subsequently, differentially expressed genes (DEGs) and miRNAs (DEMs) were identified. Functional pathway enrichment, DEG-miR-TF-protein-protein interaction network, DEM-mRNA network, ROC curve, and survival analyses were performed. Finally, qRT-PCR was applied to validate our results.

RESULTS: From the high-throughput profiling studies of GC, we investigated 10 candidate mRNA and 7 candidate miRNAs as potential biomarkers. Expression analysis of these hubs revealed that 5 miRNAs (including miR-141-3p, miR-204-5p, miR-338-3p, miR-609, and miR-369-5p) were significantly upregulated compared to the controls. The genes with the highest degree included 6 upregulated and 4 downregulated genes in tumor samples compared to controls. The expression of miR-141-3p, miR-204-5p, SESTD1, and ANTXR1 were verified in vitro from these hub DEMs and DEGs. The findings indicated a decrease in the expression of miR-141-3p and miR-204-5p and increased expression of SESTD1 and ANTXR1 in GC cell lines compared to the GES-1 cell line.

CONCLUSIONS: The current investigation successfully recognized a set of prospective miRNAs and genes that may serve as potential biomarkers for GC's early diagnosis and prognosis.

PMID:39995653 | PMC:PMC11847593 | DOI:10.61186/rbmb.13.2.281