👤 Chao Jiang

Overactivation of hepatic de novo lipogenesis (DNL) contributes to fatty liver disease. Although glucose and fructose strongly promote DNL, diary-rich galactose is only weakly lipogenic. However, whether and how it regulates hepatic DNL remains unclear. In this study, we investigated whether low-dose galactose supplementation attenuates glucose- or fructose-induced DNL activation and protects against fatty liver diseases driven by DNL overactivation, such as alcohol-associated liver disease (ALD). In this study, we used integrated hepatocyte and mouse models to assess hepatic DNL and related signaling under high-glucose or high-fructose conditions, with or without low-dose galactose. Pharmacological and genetic interventions targeting the Leloir and hexosamine biosynthetic pathways (HBP) defined underlying mechanisms. For in vivo validation, male C57BL/6 mice were fed an isocaloric control or ethanol-containing diet for 4 wk. We found that glucose engages the HBP-mTORC1-SREBP-1c axis to stimulate hepatic DNL, whereas fructose acts predominantly through carbohydrate-responsive element-binding protein (ChREBP). Low-dose galactose selectively suppressed glucose-induced hepatic fat accumulation, concomitant with the inhibition of the HBP-mTORC1-SERBP-1c pathway. These effects required an intact Leloir pathway for galactose metabolism and were not observed with fructose. In alcohol-fed mice, hepatic HBP-mTORC1-SREBP-1c signaling was markedly upregulated, contributing to steatosis and liver injury. Replacing even a small fraction of dietary glucose with galactose normalized these alterations, attenuating hepatic lipid accumulation and injury without altering systemic glucose levels. In conclusion, glucose-induced hepatic lipogenesis involves the HBP-mTORC1-SREBP-1c pathway, which is also activated during chronic alcohol exposure. Low-dose galactose, obtainable from dairy sources, attenuates this pathway, thereby limiting excessive lipogenesis and protecting against early-stage ALD. Show less

Coronary artery anomalies are rare both in coronary angiogram and computed tomography angiography. Hypertrophic cardiomyopathy (HCM) is the most frequent inherited cardiac disease. The phenotype of HCM associated with anomalous coronary origin is not commonly seen especially in children. We describe a case series of two children with HCM combined right coronary artery (RCA) originated from left coronary sinus. Case 1 was a 9-month-old female with HCM coexisted with anomalous origin of RCA has different clinical presentation, and it maybe due to different gene mutation. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent disease, yet its genetic architecture remains incompletely characterized. We integrated genome-wide association study data from multiple cohorts totaling nearly 3 million individuals of European ancestry and applied cross-trait genomic modeling of hepatic fat and seven cardiometabolic traits to construct an MASLD-specific polygenic architecture. We identified 128 risk variants across 100 loci and prioritized 55 effector genes, including established (e.g., Show less

Langya chickens, a Chinese indigenous breed, exhibit rich genetic resources but relatively low egg production performance. To investigate the genetic basis of egg production traits, we performed low-depth genome resequencing of 1,183 Langya hens and evaluated six phenotypic traits, including age at first egg (AFE), egg number at different laying stages-EN1 (from first egg to 26 weeks), EN2 (27-36 weeks), EN3 (37-43 weeks), total egg number at 43 weeks (E43), and maximal clutch length (MCL). Genetic parameter analysis revealed that MCL exhibited high heritability (0.42) and strong genetic correlations with both egg production and AFE, suggesting its potential as a more effective selection indicator for egg production traits. Genome-wide association studies identified a total of 245 SNPs associated with these traits. Notably, a 6.58 Mb region on chromosome 5 (GGA5, 40.03-46.61 Mb) was enriched for multiple traits and in strong linkage disequilibrium. Candidate genes in this core region, including TSHR, GTF2A1, DIO2, STON2, NRXN3, KCNK10, EML5, and FOXN3, were implicated in transcriptional regulation, thyroid hormone signaling, neuroendocrine modulation, and ovarian function. Additional trait-specific candidate genes, such as ATG2B for EN2, FMNL1 for EN1/EN2, TDP1 for E43, and TPMT for MCL, were also identified. Functional enrichment analyses highlighted pathways related to cellular processes, lipid metabolism, and signal transduction. These findings provide genomic insights into the molecular mechanisms underlying egg production traits and offer valuable candidate genes for marker-assisted breeding in Langya chickens. Show less

Intrahepatic cholangiocarcinoma (ICC) remains one of the most lethal malignancies with an increasing incidence worldwide. Gemcitabine has been considered the standard first-line chemotherapeutic agent for ICC but the therapeutic response is unsatisfactory due to the development of chemoresistance. Caspase-3-mediated pyroptosis has been reported to play significant roles in chemotherapeutic response but the relevant therapeutic strategy remains unstated due to the unclear molecular mechanisms under pyroptosis in ICC. This study was designed to comprehensively explore the crucial role and underlying mechanisms of NRXN3 in pyroptosis and chemosensitivity of ICC. We performed genome-scale CRISPR-Cas9 screen integrated with transcriptomic analysis to identify key regulators of pyroptosis and gemcitabine sensitivity in ICC. In vitro and in vivo experiments were employed to investigate the effects of NRXN3 on gemcitabine-induced pyroptosis. RNA-seq and IP-MS were conducted to explore the mechanisms of NRXN3-regulated pyroptosis and chemosensitivity. NRXN3 was identified to be a critical contributor to pyroptosis and chemosensitivity in ICC. Low NRXN3 expression correlates with poor prognosis and worse therapeutic response. Mechanistically, NRXN3 competitively blocks caspase-3 binding to the RSK1 serine/threonine-protein kinase, thereby inhibiting RSK1-dependent phosphorylation of caspase-3 at T152. Inhibition of caspase-3 phosphorylation impairs its interaction with the ubiquitin ligase component FBXO1 and enhances its stability, thus facilitating caspase-3/GSDME-dependent pyroptotic cell death and chemosensitivity. Furthermore, administration of an RSK1 inhibitor or caspase-3 activator boosts the efficacy of gemcitabine in murine models of ICC. NRXN3 plays a crucial role in maintaining chemotherapy-induced pyroptosis in ICC. Targeting the NRXN3/RSK1/FBXO1/caspase-3 axis emerges as a promising strategy for ICC treatment, with the potential to improve chemosensitivity and survival. Show less

Retinal ischemia-reperfusion (I/R) injury is a key pathological feature of acute glaucoma that induces oxidative stress, inflammation, and retinal glial activation, ultimately leading to retinal degeneration and neuronal dysfunction. This study evaluated the therapeutic potential of 3,4-dihydroxybenzalacetone (DBA) in protecting against I/R-induced retinal damage. DBA was tested in LPS-stimulated BV-2 microglia, in TNFα- or tBHP-treated rMC-1 Müller glial cells, and in a rat model of retinal I/R injury. In vitro assays demonstrated that DBA suppressed oxidative and inflammatory responses in microglia by reducing ROS, NO, IL-6, iNOS, and COX-2 levels. In Müller cells, DBA activated the NRF2/HO-1 pathway under oxidative stress and attenuated TNFα-induced upregulation of MMP-9 and MCP-1. Signaling analysis revealed that DBA inhibited the phosphorylation of p65 and STAT3 in both glial cell types, with additional ERK inhibition observed specifically in Müller cells. In vivo, DBA preserved retinal electrophysiological activity, as evidenced by maintained a- and b-wave responses, and reduced the expression of MMP-9, GFAP, and CD68 in the retina. These findings indicate that DBA confers partial retinal protection by modulating multiple glial-related signaling pathways and suggest its potential as a multi-target therapeutic agent for retinal neurodegenerative diseases. Show less

Mutations in the vacuolar protein sorting 13 homolog C (VPS13C) gene have been associated with Parkinson disease (PD). However, the mutation of VPS13C in Parkinsonism is uncommon and the clinical characteristics are highly heterogeneous. This study identifies 2 novel pathogenic variants in VPS13C, with particular emphasis on follow-up brain magnetic resonance imaging (MRI) images. The patient first exhibited resting tremor in the right limb at the age of 26. As the disease progressed, he developed bradykinesia, rigidity, gait instability, cognitive decline, dysarthria, myoclonus, depressed mood, irritability, and aggression. He was treated with levodopa/benserazide, pramipexole, and rasagiline, but the benefit was only temporary. By the age of 32, his gait instability was further aggravated, manifested as frequent falls, requiring bed rest or wheelchair use. Follow-up brain MRI showed progressive cortical atrophy. Whole-exome sequencing of the patient revealed compound heterozygous pathogenic variants (c.1699C > T, chr15: 62156504-62352664) in VPS13C. VPS13C-related early onset PD. The patient was treated with levodopa/benserazide 125 mg 4 times daily, rasagiline 1 mg once daily, donepezil 5 mg once nightly, and quetiapine 50 mg once nightly. After 6 months of follow-up, his symptoms were further aggravated. This study identifies 2 novel pathogenic variants in VPS13C, expanding the known mutational spectrum of the gene. Additionally, brain MRI may serve as a potential imaging marker for disease progression. A review of the literature indicates that VPS13C-related Parkinsonism appears as a heterogeneous disorder, including PD and dementia with Lewy bodies. VPS13C mutations are highly diverse, with point mutations being the most common, followed by splice-site variants. Genetic screening is essential for an accurate diagnosis and distinction between different forms of early onset PD. This increases clinicians' understanding of the clinical and genetic characteristics of VPS13C-related Parkinsonism. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide and is closely associated with obesity, diabetes, and other metabolic disorders. Because MASLD progression poses serious health risks, elucidating the underlying mechanisms is essential to guide early intervention and therapeutic strategies. Proteomic analysis was used to identity high-fat diet (HFD)-induced proteins in mouse liver. Galectin-1 (GAL1) expression was assessed via immunohistochemistry in human liver tissues. Liver-specific GAL1-deficient mice were generated using adeno-associated virus. Mice were fed either a chow diet or an HFD. Functional studies were performed in cell lines using western blotting, RT-qPCR, immunofluorescence, co-immunoprecipitation, mass spectrometry, and molecular docking analysis. GAL1 expression was elevated in liver tissues from patients with MASLD and in mouse models. Liver-specific GAL1 knockdown alleviated hepatic steatosis and enhanced fatty acid oxidation (FAO). Mechanistically, GAL1 competitively bound to the BRCT domain of poly (ADP-ribose) polymerase 1 (PARP1), thereby interfering with its interaction with the WW domain -containing E3 ubiquitin protein ligase 2 (WWP2). Hepatic GAL1 knockdown promoted the PARP1 -WWP2 interaction and subsequently facilitated ubiquitin-dependent degradation of PARP1. This degradation led to increased NAD Hepatic deficiency of GAL1 alleviates hepatic steatosis by enhancing FAO through promotion of ubiquitin-dependent PARP1 degradation, thereby restoring NAD Show less

To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism. Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA) were established to evaluate the impact of GIP on androgen synthesis Administration of GIP significantly reduced testosterone secretion in a DHEA-induced PCOS mouse model. Consistent with these findings, GIP treatment decreased testosterone release and downregulated the expression of GIP receptor (GIPR), steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and cytochrome P450 family 17 subfamily A member 1 (CYP17A1) in NCI-H295R cells. Notably, RNA-seq revealed that Our study demonstrated that the administration of GIP reduces androgen synthesis in PCOS mouse models and at the cellular level, suggesting its potential as a novel therapeutic target for managing PCOS. Show less

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less

The increasing global aging population presents significant challenges related to cognitive decline, mental health disorders, and social isolation. Martial arts exercise emerges as a multifaceted intervention promoting mental health and cognitive vitality among older adults by integrating physical activity, cognitive engagement, and social interaction. This review synthesizes evidence on the neural mechanisms underlying the benefits of martial arts, highlighting their role in enhancing brain-derived neurotrophic factor (BDNF) expression, neuroplasticity, and neural connectivity, which support improved executive functions, memory, and emotional regulation. Both hard martial arts and soft practices, such as Tai Chi, offer distinct advantages in addressing age-related cognitive and psychosocial challenges. Additionally, martial arts foster strong social support systems, reducing loneliness and enhancing emotional resilience through community engagement and shared achievement. Physical and functional benefits, including improved strength, balance, and cardiovascular health, further contribute to overall well-being. Despite promising results, current studies are limited by heterogeneity in martial arts styles, short intervention durations, and variable methodologies. Future research should focus on long-term, standardized interventions employing advanced neuroimaging and biomarker assessments to better elucidate mechanisms and optimize training protocols. Integrating martial arts into health promotion strategies holds substantial potential for enhancing mental health, cognitive resilience, and quality of life in aging populations. Show less

Retinal degenerative diseases (RDDs) cause irreversible vision loss with limited treatment options. Traditional Chinese medicine (TCM) formulas have demonstrated neuroprotective effects, yet their overall efficacy lacks comprehensive meta-evidence. The aim of this study was to exploratively evaluate the neuroprotective effects of TCM formulas in animal RDD models. A comprehensive literature search was conducted across eight electronic databases to identify animal studies that evaluated the neuroprotective effects of TCM formulas on RDDs. Pairwise meta-analysis and Bayesian network meta-analysis (NMA) were performed to synthesize evidence on key outcomes: neural growth, glial activation, oxidative stress, apoptosis factors, and ophthalmological parameters. Treatment rankings were assessed using the surface under the cumulative ranking curve (SUCRA). Twenty-four studies were included. The compositions and bioactive compounds of the TCM formulas have been defined and identified. Pairwise meta-analysis demonstrated that specific TCM formulas might exert neuroprotective effects on RDDs by regulating key biomarkers. Specifically, Zhen-Bao-Wan, Bu-Shen-Yi-Jing-Fang, and Qi-Shen-Yi-Qi pills modulated neural growth and glial activation by upregulating BDNF, CNTF, and reducing GFAP, respectively. Furthermore, Yi-Qi-Wen-Yang-Tong-Luo decoction, Zi-Yin-Ming-Mu decoction, and Yishi-Tablet suppressed oxidative stress and apoptosis by reducing SOD, retinal apoptotic cells and caspase-3, respectively. Additionally, Bu-Yang-Huan-Wu decoction improved retinal function by elevating ERG-a and ERG-b wave amplitudes. Subgroup analyses indicated that Bu-Yang-Huan-Wu decoction and Qu-Yu-Tong-Luo prescription exhibited superior efficacy in restoring retinal ganglion cell (RGC) counts and retinal thickness in specific RDD models. The NMA results indicated that the included TCM formulas exhibited target-specific and dose‒response trends, with different formulas showing preferential efficacy for distinct biomarkers. Given the limitations identified in this study, these findings should be interpreted as preliminary evidence to guide future research rather than as conclusive results. Future studies with rigorous experimental designs are needed to address these limitations and enhance translational relevance. This study provides preclinical and exploratory evidence that the included TCM formulas might exert neuroprotective effects on animal models of RDDs by modulating glial activation, promoting neuronal growth, and inhibiting oxidative stress and apoptosis. Additional high-quality preclinical studies are essential to validate these effects and inform future clinical translation. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251002491 identifier CRD420251002491. Show less

To investigate the protective effects of secoisolarciresinol digucoside (SDG) on trans fatty acid (TFA)-induced brain inflammatory response and oxidative stress in offspring mice, and to explore the roles of brain-derived neurotrophic factor (BDNF) 28 and tropomyosin receptor kinase B (TrkB) in this process. Female C57BL/6 mice were used in the study. First, pregnant C57BL/6 mice were divided into 5 groups, receiving a normal diet, TFA, low-dose SDG, medium-dose SDG, and high-dose SDG, respectively. After birth, the offspring of the normal diet and TFA groups were subdivided into 2 groups, the normal diet during pregnancy group and the TFA during pregnancy group. The offspring of the low, medium, and high-dose SDG during pregnancy groups were subdivided into 3 groups of low, medium, and high-dose SDG. As a result, the offspring were divided into 13 groups during the lactation period. Only the mother mice were exposed to TFA or SDG intervention. The growth status of the offspring was monitored. After 21 days of lactation, the offspring were sacrificed and the relevant indicators, including pathological changes in the hippocampal region of the brain, levels of tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), antioxidant levels, and BDNF and TrkB mRNA and protein expression levels, were measured. Maternal TFA exposure and SDG intervention did not result in significant differences in the weight, brain weight, and brain weight coefficient of offspring ( Maternal exposure to a TFA-enriched environment during pregnancy and lactation can induce varying degrees of structural and functional impairment in the brains of offspring and alter the expression levels of BDNF and TrkB proteins in the offspring brain. SDG intervention during TFA exposure exerts protective effects against brain injury in offspring mice, potentially by regulating BDNF and TrkB protein expression to appropriate levels, reactivating BDNF-TrkB downstream signaling pathways, and alleviating inflammatory and oxidative damage. Show less

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents have become a standard strategy for advanced hepatocellular carcinoma (HCC). There remains an urgent need for effective biomarkers to guide treatment, with C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) scores and cytokine levels representing promising candidates. We aimed to assess the efficacy, safety, and potential biomarkers of anlotinib plus TQB2450 in patients with advanced HCC. This study was a single-arm, phase Ib trial. Twenty-five patients with advanced HCC were enrolled. Patients received an intravenous infusion of TQB2450 (1200 mg, on Day 1) and oral administration of anlotinib (initiated at 10 mg, once a day, from Day 1 to Day 14), which was repeated every 3 weeks. Blood was collected at baseline for serum cytokine analysis. After a median follow-up of 41.80 months, the median progression-free survival (mPFS) was 5.49 months, and the median overall survival (mOS) was 8.94 months. Treatment-related adverse events (TRAEs) occurred in 22 patients, with grade ⩾3 TRAEs observed in 12 patients. Patients who achieved clinical benefit (CB) had higher baseline serum brain-derived neurotrophic factor (BDNF) levels than non-CB patients (median, 227.97 vs 129.26 pg/ml, Anlotinib plus TQB2450 demonstrated promising efficacy with manageable safety in advanced HCC. Elevated serum BDNF levels might serve as a potential positive prognostic marker and, together with ECOG score, may help complement the CRAFITY score in identifying subgroups that could benefit from ICIs and antiangiogenic therapy. Show less

Triple activation of the glucagon-like peptide 1 receptor (GLP-1R), the GIP receptor (GIPR), and the glucagon receptor (GCGR) is an innovative strategy for treating obesity and diabetes. We report the rational design of triple GLP-1R/GCGR/GIPR agonists, featuring potent GLP-1R and GCGR activity with weaker GIPR activation. Using sequence analysis, molecular dynamics simulations, docking, and amino acid optimization, we developed xGLP-1-based triagonists, with xGLP/GCG/GIP-32 exhibiting a unique activation profile. It shows superior weight loss effects compared to tirzepatide and similar metabolic efficacy to retatrutide, despite significantly less potent GIPR activity. Preliminary mechanistic studies revealed that xGLP/GCG/GIP-32 exhibits biased agonism toward the GIPR and GCGR. These activity data suggest it may not be imperative to focus solely on potent activation of all three receptors. Especially for triple agonists with receptor-biased agonism, there may be room to explore optimal receptor activation ratios. Show less

Dual agonists targeting glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are breakthrough treatments for patients with type 2 diabetes and obesity. Compared to GLP1R agonists, dual agonists show superior efficacy for glucose lowering and weight reduction. However, delineation of dual agonist cell targets remains challenging. Here, we develop and test daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes, and use them to visualize cellular targets. daLUXendins are potent GLP1R/GIPR dual agonists that advantageously show less functional selectivity for mouse GLP1R over mouse GIPR. daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of β cells > α cells = δ cells. Systemic administration of daLUXendin strongly labels GLP1R Show less

The sea cucumber collagen contains a high content of hydrophobic amino acids, which play essential roles in various bioactivities. A total of 2647 unknown active peptide fragments (2-20 amino acids) were obtained via virtual enzymolysis from 16 known collagen sequences in Apostichopus japonicus. Then, the novel bifunctional hexapeptide (DCDPRL, 717.788 Da) with hypoglycemic and antioxidant activities was identified via molecular docking and pharmacokinetics. DCDPRL revealed strong radical scavenging capacity in vitro with IC Show less

This study established a polymerase chain reaction-lateral flow dipstick (PCR-LFD) method for the visual detection of SNP genotypes. Targeting the MC4R gene SNP g.732 C > G, highly specific primers were designed for the mutation site, incorporating a Locked Nucleic Acid (LNA) modification at the 3' terminal nucleotide of the SNP, a BIOTIN modification at the 5' end of the upstream primer, and a fluorescein isothiocyanate (FITC) modification at the 5' end of the downstream primer. The detection primers were used for PCR amplification with the sample, and the reaction system was optimized. The amplification products were subsequently detected using LFD. The results demonstrated that the optimized reaction system and modified primers effectively distinguished among CC, CG, and GG genotypes at the g.732 C > G. Blood samples from 24 Hu sheep were analyzed using the PCR-LFD assay specific to this SNP. The genotyping results from PCR-LFD were completely consistent with those obtained from the mutation analysis of the same blood samples. The PCR-LFD method established in this study did not require genomic DNA extraction; whole blood could be directly used as a template for PCR amplification combined with LFD, enabling on-site visual detection. This positions PCR-LFD as a rapid, simple, and visually interpretable tool for on-site SNP genotyping. Show less

Tryptophan (Trp) is an essential amino acid acting as a key nutrition factor regulating animal growth and development. But how Trp modulates food intake in pigs is still not well known. Here, we investigated the effect of dietary supplementation of Trp with different levels on food intake of growing pigs. The data showed that dietary Trp supplementation with the standardised ileal digestibility (SID) Trp to lysine (Lys) ratio at both 0·18 and 0·20 significantly increased the food intake by activating the expression of orexigenic gene agouti-related peptide (AgRP) and inhibiting the expression of anorexigenic gene pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART) and melanocortin receptor 4 (MC4R) in the hypothalamus. Meanwhile, the level of anorexigenic hormones appetite-regulating peptide YY (PYY) in the duodenum and serum and leptin receptor in the duodenum were also significantly decreased. Importantly, both the kynurenine and serotonin metabolic pathways were activated upon dietary Trp supplementation to downregulate MC4R expression in the hypothalamus. Further mechanistic studies revealed that the reduced MC4R expression activated the hypothalamic AMP-activated protein kinase (AMPK) pathway, which in turn inhibited the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) activity to stimulate food intake. Together, our study unravels the orexigenic effect of dietary Trp supplementation in pigs and expands its potential application in developing nutrition intervention strategy in pig production. Show less

The heterogeneity of the tumor immune microenvironment (TIME) and therapeutic resistance in Colorectal cancer (CRC) present substantial clinical challenges. In this study, 1136 CRC samples from TCGA and GEO were utilized for the overall research design, and tumor subtype classification (Immunity_High and Immunity_Low) was specifically performed on the TCGA cohort (n = 568) using single-sample gene set enrichment analysis (ssGSEA) and t-SNE dimensionality reduction; t-SNE was selected because the study focused on distinguishing local clustering features of immune subtypes-it excels in enhancing sample aggregation within subtypes and highlighting local differences, which aligns with classification needs, so UMAP (prioritizing global structure preservation) was not used. The GEO cohort (n = 568) was used for subsequent validation of the prognostic model and results. A 12-gene prognostic model, comprising ANGPTL4, FABP4, RBP7, and 9 additional non-core genes (CCL22, NOS2, TGFB3, APOD, CHGB, CX3CL1, APOBEC3F, LCN12, BST2), was developed using Least Absolute Shrinkage and Selection Operator-Cox regression (LASSO-Cox regression) regression.The functions of the core genes and potential therapeutic candidates were investigated via single-cell sequencing, molecular docking, dynamics simulations, drug sensitivity analysis, Human Protein Atlas (HPA) and quantitative Real - time Polymerase Chain Reaction (qPCR). The Immunity_High subtype, characterized by the presence of CD8 This multi-omics study integrates multi-omics data to elucidate the immune-metabolic heterogeneity in CRC, establishing a precise prognostic model and providing bioinformatic evidence for key roles of ANGPTL4, FABP4, and RBP7 in the tumor microenvironment, thereby suggesting novel strategies to overcome immunotherapy resistance. Show less

Angiopoietin-like 4 (Angptl4) is a secreted protein that participates in multiple biological processes. Our previous study on the effect of Angptl4 in minimal change disease (MCD) unexpectedly indicated a close correlation between Angptl4 and kidney function, especially in MCD patients combined with AKI, implying a possible function of Angptl4 in AKI. However, the role and molecular mechanism of Angptl4 in AKI are undetermined. Biopsy tissue and serum of patients with AKI were analyzed by ELISA and immunohistochemistry to evaluate ANGPTL4 expression and its correlation with kidney function. For in vitro study, ANGPTL4 overexpressed and knocked down HK-2 cells were used to determine the effect of ANGPTL4 on cell pyroptosis. For in vivo study, Angptl4 global and conditional knockout mice were generated to study AKI using cisplatin- or ischemia/reperfusion-induced AKI mouse models. Additionally, we used various experimental approaches to investigate how ANGPTL4 induces tubular cell injury via interaction with integrin β. Angptl4 was up regulated in kidney tubular epithelial cells of multiple AKI models and correlated with kidney function. ANGPTL4 aggravated tumor suppressor GSDME-dependent cell pyroptosis in vitro. In genetic mice, overexpression of Angptl4 worsened kidney function, inflammation, and cell pyroptosis, whereas ablation of Angptl4 attenuated kidney injury in AKI. Mechanistically, ANGPTL4 interacted with integrin β5 and activated focal adhesion kinase (FAK), promoting kidney tubular pyroptosis through the caspase 3/GSDME signaling pathway. Inhibition of integrin β5 or FAK alleviated kidney tubular pyroptosis and kidney dysfunction. Moreover, ANGPTL4 promoted the secretion of cytokines MCP-1 and RANTES by kidney tubular epithelial cells, enhancing macrophage recruitment. Our results reveal that Angptl4 triggers pyroptosis and worsened kidney injury in AKI and offers a potential target for the diagnosis and treatment of AKI. Show less

Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfunction in endothelial cells (ECs). Endothelial cell-specific molecule 1 (ESM1), has been identified as a marker for activated ECs. Nevertheless, the mechanisms underlying ESM1-induced endothelial cell proliferation remain elusive. The expression of ESM1, ANGPTL4 and autophagy related protein were confirmed by western blot. Proliferation ability was tested by MTT and EdU. Lipids level was confirmed by Oil red staining. Autophagic flux was confirmed by Monodansylcadaverine (MDC) staining and pCMV-mCherry-GFP-LC3B fluorescence staining assay. The mouse model of AS was used to observe the effect of PA on the ESM1-ANGPTL4-autophagy signaling axis. This study elucidates ESM1-ANGPTL4 axis in maintaining proliferation of ECs and lipid reprogramming. Furthermore, it has been observed that PA has the ability to stimulate EC to autonomously increase the expression of ESM1, which in turn can counteract the detrimental effects of PA on ECs. Conversely, when ESM1 is suppressed, the damaging effects of PA on ECs are exacerbated. Mechanistically, our findings indicate that ESM1 facilitates EC proliferation and lipids homeostasis by up-regulating autophagy through ANGPTL4. This effect of ESM1 on ECs can be attenuated by ATG7 inhibiting. Additionally, the serum levels of ESM1 were found to be elevated in AS mice. ESM1 was found to enhance ECs proliferation and mitigate endothelial cell injury induced by PA through the upregulation of autophagy. This mechanism potentially serves as a protective factor against atherosclerosis progression. Show less

Abdominal aortic aneurysm (AAA) is a severe aortic disease for which no pharmacological interventions have yet been developed. This investigation focused on identifying protein-based therapeutic targets and assessing how proteins mediate the interplay between modifiable risk factors and AAA development. Causal inferences between plasma proteins and AAA were drawn using 2-sample Mendelian randomization, followed by comprehensive sensitivity testing, colocalization, and replication efforts. Further analyses included database interrogation, single-cell RNA data analysis, enrichment analysis, protein-protein interaction networks, and immunohistochemistry to map the tissue-specific expression of these proteins, their expression within AAA tissues, and their biological roles. Mediation Mendelian randomization was employed to evaluate the mediating effects of AAA-related proteins on the associations between AAA and 3 risk factors: hypertension, smoking, and obesity. A total of 43 proteins were identified as having causal links to AAA. Colocalization analysis pinpointed 13 proteins with strong evidence of colocalization with AAA. Of these, the causal involvement of 10 proteins was substantiated by external validation data. Consistent evidence for PCSK9 (proprotein convertase subtilisin/kexin type 9), IL6R (interleukin-6R), ECM1 (extracellular matrix protein 1), and ANGPTL4 (angiopoietin-related protein 4) was further validated through tissue immunohistochemistry and blood data. Moreover, Mendelian randomization analysis identified 10 proteins as mediators of the influence of hypertension, smoking, and obesity on AAA development. This analysis identifies 4 proteins (PCSK9, IL6R, ECM1, and ANGPTL4) as high-priority therapeutic targets for AAA and emphasizes the intermediary role of plasma proteins in linking hypertension, smoking, obesity, and AAA. Further investigations are needed to clarify the specific roles of these proteins in AAA pathology. Show less

Acute rejection (AR) is a significant complication in liver transplantation, impacting graft function and patient survival. Kupffer cells (KCs), liver-specific macrophages, can polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, both of which critically influence AR outcomes. Angiopoietin-like 4 (ANGPTL4), a secretory protein, is recognized for its function in regulating inflammation and macrophage polarization. This study investigates the effects of ANGPTL4 on KC polarization through cellular interactions between hepatocytes (HCs) and KCs. Using a rat orthotopic liver transplantation model, we observed reduced ANGPTL4 expression during AR, whereas increased ANGPTL4 levels were linked to immune tolerance. Administration of ANGPTL4 recombinant protein improved liver function, suppressed inflammation, and promoted M2 polarization of KCs. Co-culture experiments demonstrated that hepatocyte-derived ANGPTL4 significantly modulates KC polarization and inflammatory responses, mainly by inhibiting the NF-κB signaling pathway. The results emphasize the promise of ANGPTL4 as a therapeutic target to reduce AR and improve liver transplant outcomes by influencing hepatocyte-KC interactions. Show less

Cardiovascular diseases from abnormal lipid metabolism significantly increase mortality in systemic lupus erythematosus (SLE). The causal link between dyslipidemia and SLE is unclear. Lipid metabolism in patients with SLE was evaluated based on clinical data from 511 patients with SLE and 706 healthy individuals. Bidirectional Mendelian randomization (MR) was employed to assess causal links between 179 plasma lipid metabolites, lipid-lowering drug targets, and SLE risk. Genetic instruments from GWAS and eQTL data were used to evaluate CETP and APOA4 effects. Peripheral blood CETP and apolipoprotein levels in SLE patients were validated via ELISA. SLE patients exhibited reduced HDL-C (P < 0.0001), APOA1 (P < 0.0001), and APOA4 (P < 0.0001), alongside elevated triglycerides (TG, P < 0.0001), APOC3, APOD, and APOF. MR identified three lipid metabolites-PC(18:2₂₀:4), TG(56:6), and TG(58:7)-as causal factors for SLE (P < 2.79E-5). CETP inhibition significantly reduced SLE risk via HDL-C modulation (OR = 0.72, P = 3.38E-08) and influenced LDL-C, TG, and apolipoproteins. Clinical validation confirmed elevated CETP and reduced APOA4 in SLE, correlating with disease activity. APOA4 activation showed protective effects, while PCSK9 inhibition lacked relevance. Bidirectional Mendelian randomization analyses confirmed dyslipidemia as a causal antecedent to SLE, with no evidence of reverse causation. A variety of MR analyses and clinical validation indicated that targeting HDL-C regulation offers significant advantages for managing dyslipidemia in patients with SLE, with CETP identified as the optimal pharmacological target. Show less

ApoA-IV amyloidosis is a rare disease that involves the deposition of ApoA-IV protein aggregates in tissues. It commonly presents as cardiac or renal disease, but can, in rare cases, cause small bowel perforation. This study describes a case of ApoA-IV type amyloidosis causing small bowel perforation after conversion of a sleeve gastrectomy (SG) into a RYGB in a Crohn's disease (CD) and rheumatoid arthritis (RA) patient. It also considers the indications for bariatric and anti-reflux surgery in the setting of co-morbid inflammatory bowel disease (IBD), gastro-oesophageal reflux disease (GORD), and obesity. Obesity can reduce the efficacy of IBD medications and drives a pro-inflammatory state that may worsen IBD, however IBD patients present an operative challenge due to risk of more intestinal adhesions, potential intolerance to intestinal bypass, and risk of affecting options for future bowel resections if required. SG is often chosen over RYGB for CD patients due to limited short-term complications. However, when considering co-morbid GORD, the long-term risk of medication resistant GORD, erosive oesophagitis, and Barrett's oesophagus with SG is significant, especially given that SG is an irreversible procedure. There is growing evidence that bariatric surgery in IBD patients is both safe and effective, however the decision to perform bariatric surgery in an IBD patient involves consideration of the intricate interplay between obesity and IBD. Show less