Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic dr Show more
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4β>β0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC. Show less
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiolo Show more
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. To comprehensively identify the metabolic causal factors and potential drug targets for PCOS. This genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. The PCOS cohort included 10,074 PCOS cases (mean age 28 to 45Β years) and 103,164 controls (mean age 27 to 60Β years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95Β % CI, 2.65-4.36]), triglyceride (TG) (OR = 1.54 [95Β % CI, 1.17-2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95Β % CI, 1.07-1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95Β % CI, 1.09-1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95Β % CI, 0.47-0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. This study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings. Show less
Jia Min Chen, Yan Wang, Yan Shi Β· 2025 Β· Clinical, cosmetic and investigational dermatology Β· added 2026-04-24
Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known Show more
Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known as Mendelian randomization (MR), we sought to determine the causal impact of PUFAs on the likelihood of developing skin diseases among individuals of European ancestry. We integrated GWAS data from the CHARGE consortium and UK Biobank to identify genetic instruments for omega-3 PUFAs and desaturase activity, using two-sample MR to assess their associations with six skin diseases. Elevated levels of omega-3 fatty acids were found to substantially lower the probability of experiencing atopic dermatitis (0.92, [0.85,0.98]), while increased DPA levels correlated with a substantial increase in the probability of squamous cell carcinoma occurrence (2.25, [1.29,3.92]). Increased DHA levels were also associated with a reduced risk of atopic dermatitis (0.90, [0.84,0.96]) but increased the risk of solar dermatitis (1.38, [1.09,1.73]). In addition, tissue-type specific MR analysis revealed that elevated FADS1 expression in fibroblasts significantly inhibited atopic dermatitis development (Ξ² = -0.181, [-0.276,-0.0853]), while elevated FADS2 expression in non-sun-exposed skin tissues was associated with a reduced risk of squamous cell carcinoma (Ξ² = -0.562, [-0.833,-0.029]). Conversely, heightened FADS2 expression was strongly linked to a greater likelihood of developing atopic dermatitis in both sun-exposed and sun-protected skin areas (Ξ² = 0.107, [0.0348,0.179]; Ξ² = 0.192, [0.114,0.0270], respectively). This study reveals the causal role of omega-3 PUFAs and FADS expression in specific tissues and blood in skin diseases. These findings underscore the potential of PUFA biosynthesis pathways as therapeutic targets for skin disease interventions. Show less
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether c Show more
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether causal relationships exist among these associations remains unclear, as traditional observational studies are susceptible to confounding factors. To evaluate causal relationships between kidney cancer, kidney fibrosis, and inflammatory factors using Mendelian randomization, and explore tumor microenvironment heterogeneity through single-cell analysis. Based on large-scale GWAS data, bidirectional Mendelian randomization analysis was performed to assess causal relationships between kidney cancer and kidney fibrosis, using MR Egger, inverse variance weighted (IVW), and weighted mode methods. Causal associations between kidney cancer and inflammatory factors including Axin-1, C-C motif chemokine 28, and interleukin-10 receptor subunit were analyzed. Single-cell RNA sequencing data from the GEO database (GSM4819725) was integrated for tumor microenvironment analysis. Bidirectional Mendelian randomization analysis revealed no significant causal relationship between kidney cancer and kidney fibrosis [kidney cancerβkidney fibrosis: IVW OR=0.992(95%CI: 0.913-1.077, P=0.842); kidney fibrosisβkidney cancer: IVW OR=0.922(95%CI: 0.824-1.030, P=0.151)]. However, significant positive causal associations were identified between kidney cancer and multiple inflammatory factors: Axin-1 levels [OR=1.448(95%CI: 1.107-1.894, P=0.007)], C-C motif chemokine 28 [OR=1.287(95%CI: 1.076-1.540, P=0.006)], and interleukin-10 receptor subunit [OR=1.135(95%CI: 1.032-1.248, P=0.009)]. Sensitivity analyses confirmed the robustness of results. Single-cell analysis revealed cellular heterogeneity in the tumor microenvironment, including various cell types such as immune cells, T cells, and NK cells, with pseudotime analysis demonstrating cell differentiation trajectories and dynamic gene expression changes. Mendelian randomization analysis provides genetic evidence for causal relationships between kidney cancer and inflammatory factors, while excluding direct causal associations between kidney cancer and kidney fibrosis. Show less
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu Show more
Intramuscular fat (IMF) content in beef cattle is a critical determinant of beef meat quality, as it positively influences juiciness, tenderness, and palatability. In China, the crossbreeding of Wagyu and Angus is a prevalent method for achieving a better marbling level. However, the molecular mechanisms governing IMF regulation in these crossbreeds remain poorly understood. To elucidate the mechanism of IMF deposition in these crossbred cattle, we conducted a comparative transcriptomic analysis of Show less
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate Show more
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less
As inflammatory processes may be involved in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), the first aim of the present study was to determine the clinical characteristics of Show more
As inflammatory processes may be involved in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), the first aim of the present study was to determine the clinical characteristics of type 2 diabetes mellitus (T2DM) with distal sensorimotor polyneuorpathy (DSPN). Next goal was to investigate inflammatory biomarkers, insulin-like growth factor- 1 and lipid profile in these patients. Finally, we aimed to compare the renal function in these patients. In a cross-sectional study, we included 160 patients diagnosed with T2DM. The control group was included 22 non-diabetic healthy subjects (HC). The patients with diabetes were divided into four groups, absent (nβ=β74), mild (nβ=β38), moderate (nβ=β24), and severe (nβ=β24) using a nomogram based on the MNSI features for a DSPN severity grading probability. Patients with moderate and severe DSPN were a little older and had longer duration of diabetes compared to patients with absent and mild DSPNS (pβ<β0.05). Serum levels of interferon-gamma (INF-Ξ³), interleukin (IL)-1Ξ², IL-4, IL- 6 levels in patients with severe DSPN were significantly higher than HC, absent, mild and moderate of DSPN (pβ<β0.05). The circulating levels of insulin-like growth factor-1 (IGF-1) were significantly lower in patients with severe DSPN (pβ<β0.05) compared to absent, mild and moderate of DSPN and HC. Diabetic patients with moderate DSPN showed increased circulating levels of TC, LDL-C, APOB (pβ<β0.05) compared to HC and patients with absent, mild and severe DSPN. Moreover, APO-A1/APOB was significantly lower in patients with diabetes compared to HC. In addition, patients with severe DSPN showed increased Cystatin C (pβ<β0.05) compared to HC and absent, mild, and moderate DSPN. Multivariate ordered logistic regression analysis showed that the levels of IL-6 (ORβ=β3.166, 95%CI 1.461-6.860, pβ=β0.003, IL-1Ξ²(ORβ=β1.148, 95%CI 1.070-2.232; pβ=β0.000), TC (ORβ=β1.174, 95%CI 1.011-1.364; pβ=β0.035), LDL-C (ORβ=β1.246, 95%CI 1.098-3.618; pβ=β0.003), Cystatin C (ORβ=β1.867, 95%CI 1.245-3.434; pβ=β0.004), ages (ORβ=β1.043, 95%CI 1.009-1.078; pβ=β0.012), and duration of diabetes (ORβ=β1.157, 95%CI 1.049-1.277; pβ=β0.004) were positively associated with increasing the odds ration of DSPN in T2DM. Conversely, the level of IGF-1 (ORβ=β0.922, 95%CI 0.961-0.982; pβ=β0.000) and ratio of APO-A1/APOB (ORβ=β0.212, 95%CI 0.078-0.567; pβ=β0.002) were significantly associated with decreasing the odds ratio of DSPN in T2DM. The levels of inflammatory biomarkers such as INF-Ξ³, IL-1Ξ², IL-4, IL- 6 were increased in patients with severe DSPN in T2DM. Ages, duration of diabetes as well as high circulating levels of IL-6, IL-1Ξ², TC, LDL-C and Cystatin C were positively associated with DSPN in T2DM. Conversely, the level of IGF-1 and the ratio of APOA1/APOB were independent protective factors for DSPN in T2DM. Our results emphasize the importance of addressing issues related to inflammatory biomarkers, lipids and early impaired renal function in T2DM with DSPN, as these may be of potential relevance for deteriorating DSPN. Show less
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mech Show more
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis. Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 ( A six-gene prognostic model was established, comprising downregulated genes ( Show less
Gestational exposure to micro- and/or nanoparticles (M/NPs) may be closely associated with adverse maternal and offspring outcomes involving multiple organ dysfunctions. Organ functional change is ach Show more
Gestational exposure to micro- and/or nanoparticles (M/NPs) may be closely associated with adverse maternal and offspring outcomes involving multiple organ dysfunctions. Organ functional change is achieved through metabolic adaptation in response to changes in the external environment; yet, intricacies of these organ dysfunctions and underlying metabolic changes remain poorly understood, particularly at spatial suborgan level. Using a pregnant mouse model exposed to polystyrene (PS)-M/NPs (sizes: 100 nm, 5 ΞΌm, 10 mg/L in drinking water) from gestation day 1 to 18, we construct a comprehensive multisub-organ lipid metabolic landscape. This analysis integrates MALDI-mass spectrometry imaging with histological assessment to monitor changes in maternal suborgans-placenta-fetus unit. Our findings reveal distinct metabolic responses between maternal and fetal organs to gestational PS-M/NPs exposure. We identify potential targeted suborgans and spatial biomarkers associated with PS-M/NPs exposure according to histological damage and metabolic remodeling, including placental junctional and labyrinth zone (e.g., phosphatidylserine, phosphatidylethanolamine [PE]), renal cortex of maternal kidney (e.g., ceramide [Cer], PE, sphingomyelin [SM], phosphatidylglycerol [PG], phosphatidylserine), ventricular muscular layer and interventricular septum of maternal heart (e.g., PE, lysophosphatidylethanolamine [LPE], lysophosphatidic acid [LPA]), fetal brain and spinal cord (e.g., Cer), and fetal liver (e.g., Cer). Furthermore, phosphatidylserine synthesis and glycolipid metabolism pathways are found to be exclusively enriched following PS-NP and PS-MP exposure in the multiorgan network, respectively. We propose an M/NPs scale-exposed suborgan effect framework, which provides a molecular foundation and potential spatial biomarkers for elucidating intersub-organ interactions in response to M/NPs exposure and their role in mediating pregnancy state. Show less
Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain uncl Show more
Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain unclear. This study integrated bioinformatics and experimental validation to identify key genes in OA synovium and their association with immune infiltration. Analysis of the GSE82107 dataset (10 OA, 7 controls) revealed 909 differentially expressed genes (525 upregulated, 384 downregulated). WGCNA identified the "midnightblue" module, and its intersection with DEGs yielded 122 genes enriched in cytokine-cytokine receptor interaction, JAK-STAT signaling, and autophagy pathways. Protein-protein interaction analysis highlighted FLT3LG, MC4R, CXCL10, CARTPT, and LHX2 as core genes (AUC 0.743-0.871). Immune infiltration analysis showed elevated M0 macrophages in OA, with CXCL10 showing a strong positive correlation with M1 macrophage infiltration (rβ=β0.74), and MC4R correlating with the presence of follicular helper T cells (rβ=β0.85). In vitro, OA-derived fibroblast-like synoviocytes exhibited CXCL10 upregulation, MC4R downregulation, and increased IL-6, IL-8, and TNF-Ξ± secretion, which were markedly reduced by CXCL10 knockdown or MC4R overexpression. Synovial tissue assays confirmed these expression patterns. CXCL10 and MC4R may represent promising diagnostic markers and therapeutic targets, offering new insights into OA immunopathogenesis and precision intervention. Show less
Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, Show more
Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies. Show less
Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; howev Show more
Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; however, its specific regulatory mechanisms in PD remain unclear. This study utilized single-cell and bulk RNA sequencing data to identify core genes and investigate their potential roles. We utilized single-cell RNA sequencing data and applied 4 algorithms - area under the curve cell level enrichment, U-statistics-based single-cell signature scoring, single-sample gene set scoring, and AddModuleScore - to assess mitophagy activity and identify candidate genes. Subsequently, based on bulk RNA-seq data, 5 machine learning algorithms, including Least Absolute Shrinkage and Selection Operator Regression, random forest, Boruta, gradient boosting machine, and eXtreme Gradient Boosting, were employed to further screen core genes from the candidate gene set. Finally, immune infiltration analysis, cell communication analysis, and gene interaction network construction were integrated to systematically elucidate the regulatory mechanisms of core genes in the progression of PD. Single-cell RNA sequencing combined with multiple algorithms revealed significantly elevated mitophagy activity in PD tissues, particularly in monocytes/macrophages and endothelial cells. Additionally, we identified 4 core genes: BNIP3L, VPS13C, CTTN, and MAP1LC3B. BNIP3L and CTTN were downregulated in periodontitis, correlating negatively with disease prevalence, immune infiltration, and inflammatory pathways, whereas VPS13C and MAP1LC3B were upregulated, showing positive correlations. CellChat analysis highlighted monocytes/macrophages and endothelial cells with high core gene expression as key mediators of intercellular communication. This study identified BNIP3L, VPS13C, CTTN, and MAP1LC3B as core mitophagy-related genes associated with PD, and highlighted the pivotal roles of monocytes/macrophages and endothelial cells in disease progression. These findings provide new insights into the pathogenesis of PD and offer a theoretical foundation for mitophagy-targeted diagnosis, biomarker identification, and precision therapy. Show less
Little is known about the association between physical activity and the risk of pre-sarcopenic obesity (pre-SO) among adolescents. Hence, this study aimed to examine the association between physical a Show more
Little is known about the association between physical activity and the risk of pre-sarcopenic obesity (pre-SO) among adolescents. Hence, this study aimed to examine the association between physical activity and pre-SO in a sample of 2143 adolescents aged 12 to 18 years from Yinchuan, China. The pre-SO was defined by three criteria: low skeletal muscle mass adjusted by weight (SMM/W) combined with body mass index (BMI), fat mass percentage (FMP), and waist circumference (WC). After adjusting for age, smoking, drinking, sleep time, and high-fat food consumption, participants with high physical activity (HPA) had a lower risk of pre-SO compared to those with low physical activity (LPA) according to the obesity criteria of FMP (ORβ β0.63, 95% CI, 0.48-0.83, Pβ<β0.05), and WC (OR 0.71, 95% CI, 0.52-0.96, Pβ<β0.05). Additionally, restricted cubic spline models showed a linear dose-response association between total physical activity (TPA) and pre-SO no matter what obesity criteria were adopted (all P overall trendβ<β0.05, all P non-linearβ>β0.50). Subgroup analyses revealed that individuals with higher TPA levels exhibited a decreased risk of pre-SO in boys according to the obesity criteria of FMP, and WC. In conclusion, HPA is associated with a reduced risk of pre-SO in adolescents, especially among boys. Show less
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensiv Show more
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensively studied. This study aimed to explore clinical characteristics and the usage of electrolytes and AAs in children with PCMs. Children diagnosed with PCMs who had genetic test reports were included. Relevant information was collected and processed, and clinical characteristics and mutated genes were clarified. Gene databases were searched to explore related electrolytes and AAs in the treatment of PCMs. The effect of calcium was explored in children with DCM. Paired samples T tests and nonparametric Wilcoxon signed-rank tests were performed for comparison between before and after using calcium. In this study, 27 children with gene test results were enrolled to perform gene-related analysis. The median age was 2.5 years old. Mutated genes were collected, including pathogenic, likely pathogenic, uncertain significance, and other mutations. The most frequently mutated genes related to dilated cardiomyopathy (DCM) were For children with DCM, calcium supplements may be beneficial. AAs, including serine, cysteine, and arginine, could be used for supplementary treatment in children with DCM and HCM. Show less
Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease. To investigate whether lipid profile variability in response to diverse sta Show more
Lipid profiles are largely determined by genetic variants, and lipid metabolism plays a crucial role in Alzheimer's disease. To investigate whether lipid profile variability in response to diverse statins could be affected by cholesterol metabolism-related genetic variants in Alzheimer's disease.. This prospective observational pharmacogenetic study was conducted at the Universidade Federal de SΓ£o Paulo (Unifesp), Brazil. Consecutive outpatients were prospectively followed for lipid profile variations over one year, estimated by the associations between statin therapy and the following variants: rs2695121 (NR1H2), rs3846662 (HMGCR), rs11669576 (LDLR8), rs5930 (LDLR10), rs5882 and rs708272 (CETP), rs7412 and rs429358 (APOE), and ACE insertion/deletion polymorphism. All polymorphisms in the 189 patients were in Hardy-Weinberg equilibrium. Statins resulted in lower total cholesterol and LDL cholesterol levels, whereas the effects on HDL cholesterol varied according to the statin used. Atorvastatin resulted in lower triglyceride level variations than simvastatin. APOE-Ξ΅4 carriers showed a better response to atorvastatin in elevating HDL-cholesterol than APOE-Ξ΅4 non-carriers. Carriers of the ACE insertion allele had cumulatively lower total cholesterol and LDL-cholesterol levels, regardless of statin therapy, but lower triglyceride levels when using atorvastatin. Carriers of rs11669576-G had lower total cholesterol and LDL-cholesterol levels when using simvastatin, and lower total cholesterol and triglycerides when using atorvastatin. Concerning CETP haplotypes, carriers of rs5882-A and rs708272-A benefitted the most from statins, which lowered total cholesterol and increased HDL-cholesterol levels, and from atorvastatin lowering triglycerides; however, the effects of atorvastatin lowering total cholesterol and LDL-cholesterol were more pronounced for carriers of rs5882-GG/rs708272-GG. Lipid profile variations may be pharmacogenetically mediated in Alzheimer's disease, thus, confirming their high heritability. Show less
Liver diseases are a major contributor to both morbidity and mortality. Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal. The use of f Show more
Liver diseases are a major contributor to both morbidity and mortality. Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal. The use of floxed rat resource has rapidly increased, but the liver-specific Cre rat lines for studying liver diseases and interested genes are limited, especially in a spatially and temporally restricted manner. RNA sequencing and real-time polymerase chain reaction (PCR) were used to screen and confirm the presence of liver-specific genes. Apoa4-Cre rats and Cyp2c11-Cre rats were produced by CRISPR/Cas9 knockin. Rosa26-imCherry rats were employed to hybridize with the Cre rats to obtain the Apoa4-Cre/Rosa26-imCherry and Cyp2c11-Cre/Rosa26-imCherry rats. The temporal and spatial patterns of Cre expression were determined by the observation of red fluorescence on tissue sections. Hematoxylin-eosin stain was used to evaluate the liver histopathologic changes. The blood biochemical analysis of several liver enzymes and liver lipid profile was performed to evaluate the liver function of Cre rats. Apoa4 and Cyp2c11 were identified as two liver-specific genes. Apoa4-Cre and Cyp2c11-Cre rats were produced and hybridized with Rosa26-imCherry rats. The red fluorescence indicated that the Cre recombinases were specially expressed in the juvenile and adult liver and not in other organs of two hybridized rats. All the blood biochemical parameters except low-density lipoprotein (LDL) did not change significantly in the Cre rats. No histological alterations were detected in the livers of the Cre rats. Liver-specific Apoa4-Cre and Cyp2c11-Cre rats have been established successfully and could be used to study gene knockout, specifically in juvenile and adult liver. Show less
Elevated red blood cell distribution width (RDW) is associated with increased risk of rheumatoid arthritis (RA), but the potential interactions of RDW with genetic risk of incident RA remain unclear. Show more
Elevated red blood cell distribution width (RDW) is associated with increased risk of rheumatoid arthritis (RA), but the potential interactions of RDW with genetic risk of incident RA remain unclear. This study aimed to investigate the associations between RDW, genetics, and the risk of developing RA. We analysed data from 145,025 healthy participants at baseline in the UK Biobank. The endpoint was diagnosed rheumatoid arthritis (ICD-10 codes M05 and M06). Using previously reported results, we constructed a polygenic risk score for RA to evaluate the joint effects of RDW and RA-related genetic risk. Two-sample mendelian randomization and bayesian colocalization were used to infer the causal relation between them. A total of 675 patients with RA were enrolled and had a median followed up of 5.1Β years, with an incidence rate of 0.57/1000 person-years. The hazard ratio of RA was 1.89 (95% CI: 1.45, 2.47) in highest RDW quartile group compared with the lowest RDW quartile group. Individuals within the top quintile of PRS showed a significantly high risk of RA. Moreover, Participants with high genetic risk and those in highest RDW group exhibited a significantly elevated hazard ratio (7.67, 95% CI: 3.98, 14.81), as opposed to participants with low genetic risk and those in lowest RDW group. Interactions between PRS and RDW on the multiplicative and additive scale were observed. Mendelian randomization provided suggestive evidence of a bi-directional causal relationship between RDW and RA. Loci near IL6R, IL1RN, FADS1/FADS2, UBE2L3 and HELZ2 showed colocalization. Increased RDW is associated with elevated risk of incident RA especially in the high genetic risk populations, but only suggestive evidence supports a causal relationship between them. Show less
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) ag Show more
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), accelerated ammonium metabolism of HLCs, which was derived from adipose derived mesenchymal stem cells (ADSCs). Human ADSCs were seed in flat bottom plate, then our differentiation protocol was used for 21 days. OCA treatment had been performed in Step3 for 10days. Then, 1) hepatic maturation, 2) urea cycle genes, 3) urea production, and 4) ammonium metabolism was compared depend on the presence or absence of OCA. HLCs had been successfully produced for 21 days. HLCs with OCA showed significantly higher mRNA expressions of AAT than those without OCA. HLCs with OCA showed significantly higher mRNA expressions of urea cycle genes such as SLC25A13, CPS1, and OTC. Urea production was also tended to be upregulated by OCA addition. HLCs with OCA showed significantly higher clearance of NH4Cl at 6hr and 24 hr after addition of NH4Cl. FXR agonist, OCA, accelerates ammonium metabolism of ADSCs derived HLCs. HLCs could be one of treatment options of hepatic encephalopathy of patients with liver failure or urea cycle disorder in the future. J. Med. Invest. 72 : 54-59, February, 2025. Show less
Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is resp Show more
Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is responsible for a significant number of cancer-related deaths worldwide. Targeted drugs have been used for anti-liver cancer treatment in the advanced stage, while their efficacy is greatly compromised by development of drug resistance. Drug resistance is a complicated process regulated by intrinsic and extrinsic signals and has been associated with poorer prognosis in cancer patients. In the current study, online available dataset analysis uncovered that angiopoietin-like protein 3 (ANGPTL3) manifested lower expression in sorafenib-resistant liver cancer cell lines. Additionally, ANGPTL3 was downregulated in HCC tissues, with its expression positively correlated with good prognosis. Functionally, ectopic expression of ANGPTL3 re-sensitized sorafenib-resistant cells, enhancing the sorafenib-induced reduction in cell viability and migration by suppressing zinc finger protein SNAI1 (SNAI1) expression and the protein stability of carnitine O-palmitoyltransferase 1, liver isoform (CPT1A). Clinical correlation analysis revealed that ANGPTL3 was negatively associated with SNAI1 expression. In conclusion, we identify a novel association between ANGPTL3, SNAI1 and CPT1A on sorafenib therapeutic response. Targeting ANGPTL3/SNAI1/CPT1A axis may serve as a therapeutic approach to improve prognosis of liver cancer patients with sorafenib resistance. Show less
Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with dysregulation of the Show more
Acute respiratory distress syndrome (ARDS) is a lung inflammatory condition associated with the accumulation of fluid edema and cell infiltrates into the alveolar space along with dysregulation of the immune response. Current therapeutics are limited to palliative care, i.e., mechanical ventilators, thus highlighting the need to develop targeted therapeutic for ARDS. Interleukin-27 (IL-27) is a multifunctional cytokine with the capability for immune modulation. Our interest lies in exploring the properties of IL-27, particularly as an anti-inflammatory cytokine that functions as an antagonist of IL-6 signaling, as an inducer of anti-viral genes, as a promoter of tissue repair, and as a regulator of both the innate and adaptive immune responses, possessing promising potential as a therapeutic for ARDS. To overcome the challenge of repeated administration due to the short half-life of cytokines, we utilized a cell-based gene therapy approach. An IL-27-expressing plasmid was transfected into adipose mesenchymal stromal cells (ASC) that serve as the gene therapy carriers. For in vitro studies, we treated mono- and co-culture lung lipopolysaccharide (LPS)-induced lung epithelial and monocytes/macrophages cell line with IL-27-expressing ASC (IL-27 ASC) conditioned media (CM) to determine the effects on pro-inflammatory gene expression. For in vivo studies, male C57BL/6 mice were intratracheally injected with LPS (5Β mg/kg) and treated either PBS, ASC, or IL-27 ASC (5βΓβ10 IL-27 ASC CM reduced pro-inflammatory gene expression of lung epithelial and macrophages cultured in both mono- and co-culture systems. Additionally, IL-27 ASC were able to reduce pro-inflammatory markers, decrease cell infiltration into the lungs, promote genes and immune cells involved in tissue repair, and rebalance innate and adaptive immunity in an LPS-induced in vivo model. Collectively, our in vitro and in vivo results show promising potential for IL-27 cell-based gene therapy as a treatment for ARDS. Show less
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in inn Show more
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1βs regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1βs promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-Ξ³) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less
Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause Show more
Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause of their life expectancy being 15-20 years shorter than that of the general population. Identifying comorbidity patterns and uncovering differences in immune and metabolic function are crucial steps toward improving prevention and management strategies. A retrospective cross-sectional study was conducted using electronic medical records of inpatients discharged between 2015 and 2024 from a municipal psychiatric hospital in China. The study included patients diagnosed with Schizophrenia, Schizotypal, and Delusional Disorders (SSDs) (ICD-10: F20-F29). Comorbidity patterns were identified through latent class analysis (LCA) based on the 20 most common comorbid conditions among SSD patients. To investigate differences in peripheral blood metabolic and immune function, linear regression or generalized linear models were applied to 44 laboratory test indicators collected during the acute episode. The Benjamini-Hochberg method was used for p-value correction, and the false discovery rate (FDR) was calculated, with statistical significance set at FDRβ<β0.05. Among 3,697 inpatients with SSDs, four distinct comorbidity clusters were identified: SSDs only (Class 1), High-Risk Metabolic Multisystem Disorders (Class 2, nβ=β39), Low-Risk Metabolic Multisystem Disorders (Class 3, nβ=β573), and Sleep Disorders (Class 4, nβ=β205). Compared to Class 1, Class 2 exhibited significantly elevated levels of apolipoprotein A (ApoA; Ξ²β=β90.62), apolipoprotein B (ApoB; Ξ²β=β0.181), mean platelet volume (MPV; Ξ²β=β0.994), red cell distribution width-coefficient of variation (RDW-CV; Ξ²β=β1.182), antistreptolysin O (ASO; Ξ²β=β276.80), and absolute lymphocyte count (ALC; Ξ²β=β0.306), along with reduced apolipoprotein AI (ApoAI; Ξ²β=β-0.173) and hematocrit (HCT; Ξ²β=β-35.13). Class 3 showed moderate increases in low-density lipoprotein cholesterol (LDL-C; Ξ²β=β0.113), MPV (Ξ²β=β0.267), white blood cell count (WBC; Ξ²β=β0.476), and absolute neutrophil count (ANC; Ξ²β=β0.272), with decreased HCT (Ξ²β=β-9.81). Class 4 was characterized by elevated aggregate index of systemic inflammation (AISI; Ξ²β=β81.07), neutrophil-to-lymphocyte ratio (NLR; Ξ²β=β0.465), and systemic inflammation response index (SIRI; Ξ²β=β0.346), indicating a heightened inflammatory state. The comorbidity patterns of patients with SCZ can be distinctly classified. During the acute episode, those with comorbid metabolic disorders exhibit a higher risk of cardiovascular diseases and immune system abnormalities, while patients with comorbid sleep disorders present a pronounced systemic inflammatory state and immune dysfunction. This study provides a basis for the chronic disease management and anti-inflammatory treatment, while also offering objective biomarker insights for transdiagnostic research. Show less
Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known f Show more
Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known for minimally invasive biomarkers are scarce. Here, we analyzed 1,345 human plasma proteins using proteome-wide association studies, identifying 78 proteins significantly associated with PC risk. Of these, four proteins (ROR1, FN1, APOA5, and ABO) showed the most substantial causal link to PC, confirmed through Mendelian randomization and colocalization analyses. Data from two clinical cohorts further demonstrated that FN1 and ABO were notably overexpressed in both blood and tumor samples from PC patients, compared to healthy controls or para-tumor tissues. Additionally, elevated FN1 and ABO levels correlated with shorter median survival in patients. Multiple drugs targeting FN1 or ROR1 are available or in clinical trials. These findings suggest that plasma protein FN1 associated with PC holds potential as both prognostic biomarkers and therapeutic targets. Show less
Lipid metabolism may be linked to chronic gastritis, but its causal role remains unclear. While current research emphasizes inflammation, mucosal changes, immune regulation, genetics, and the gut micr Show more
Lipid metabolism may be linked to chronic gastritis, but its causal role remains unclear. While current research emphasizes inflammation, mucosal changes, immune regulation, genetics, and the gut microbiota, the contribution of lipid metabolism is understudied. This study aims to evaluate the impact of serum lipids and the mechanistic roles of lipid-lowering drug targets in chronic gastritis. We conducted a cross-sectional study using data from real world. Multivariable logistic regression was performed to assess the association between serum lipid profiles and gastritis. Mendelian randomization (MR) analyses based on genome-wide association study (GWAS) datasets were performed to detect the causal relationship of serum lipids, plasma lipid species, and lipid-lowering drug targets. Experimental validation was conducted using high-fat diet (HFD)-fed mice and chemically induced CAG rat models. Four thousand sixty one person, including 1,023 patients with chronic atrophic gastritis (CAG), 1,742 with non-atrophic gastritis (NAG), and 1,296 as healthy population were included in the analysis. Through covariates adjustment, TC, ApoA1, and HDL-C showed to be associated with an increased risk of chronic gastritis, whereas TG exhibited a protective effect. MR analysis confirmed a significant inverse causal relationship between TG and gastritis (ORβ=β0.889, 95% CI: 0.825-0.958). Ten plasma lipid species and lipid-lowering gene targets, including LPL and APOC3, were identified as causally associated with disease risk. Mediation analysis revealed six plasma lipid species as potential intermediaries linking genetic variation to gastritis. In vivo experiments demonstrated progressive hepatic steatosis and mild gastric mucosal changes in HFD-fed mice. Immunohistochemical analysis further revealed a significant reduction in LPL and APOC3 expression in gastric tissue (Pβ<β0.05). In the CAG rat model, histological analysis revealed hepatocyte disarray, edema, and gastric mucosal atrophy. Elevated levels of TNF-Ξ±, IL-6, IL-1Ξ² and decreased levels of GAS-17 and PG I/II were also observed (Pβ<β0.05). Western blot analyses further confirmed the downregulation of LPL and APOC3 expression in gastric tissue (Pβ<β0.05). This study provides genetic and experimental evidence, supporting a causal role of lipid metabolism in chronic gastritis. LPL and APOC3 are implicated in its pathogenesis, highlighting potential lipid-targeted strategies for prevention and treatment. Show less
Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insuffi Show more
Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insufficiently understood. We developed a single-cell transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from 11 newly-diagnosed pMN patients and 5 healthy donors. Through correlation analysis, we identified potential biomarkers for disease stratification and poor prognosis. Expression levels of several proinflammatory factors were significantly increased in patients compared to healthy donors, such as interleukins ( Our study provides insight into the immunological mechanism of pMN and identifies numerous biomarkers and signaling pathways as potential therapeutic targets for managing the progression of high-risk pMN. Show less
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People wit Show more
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. Show less
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL Show more
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1). Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study. ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality. Show less
Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (AΞ²) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amy Show more
Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (AΞ²) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) plays a critical role in the production of AΞ², making it a key therapeutic target. In the current work, a CNS library of ChemDiv database containing 44085 compounds was screened against the BACE1 protein. Initially, a structure-based pharmacophore hypothesis was constructed, followed by virtual screening, with the screened hits docked to the BACE1 protein to determine the optimal binding modes. The docking results were examined using the glide gscore and chemical interactions of the docked molecules. The cutoff value of -5 kcal/mol was used to select hits with high binding affinities. A total of seven hits were chosen based on the glide g score. Furthermore, the possible binding mechanisms of the docked ligands were investigated, and it was discovered that all seven selected ligands occupied the same site in the predicted binding pocket of protein. The bioactivity scores of the compounds demonstrated that the chosen compounds possess the features of lead compounds. The toxicity risks and ADMET features of the selected hits were anticipated, and four compounds, J032-0080, SC13-0774, V030-0915, and V006-5608 were chosen for stability analysis. The selected hits were extremely stable and strongly bound to the BACE1 pocket, and conformational changes caused by RMSD, RMSF, and protein-ligand interactions were assessed using MD modeling. Similarly, principal component analysis revealed a large static number of hydrogen bonds. The MM/GBSA binding free energies maps revealed a significant energy contribution in the binding of selected hits to BACE1. The binding free energy landscapes indicated that the hits were bound with a high binding affinity. Thus, the hits could serve as lead compounds in biophysical investigations to limit the biological activity of the BACE1 protein. Show less