👤 Youzhi Cai

Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy. However, the molecular characteristics and pathogenesis of CRC peritoneal metastasis are poorly understood. Here, we aimed to elucidate the action and mechanism of adipose-derived stem cells (ADSCs), a prominent component of the peritoneal microenvironment, in CRC peritoneal metastasis formation. Database analysis indicated that ADSCs infiltration was increased in CRC peritoneal metastases, and high expression levels of ADSCs marker genes predicted a poor prognosis. Then we investigated the effect of ADSCs on CRC cells in vitro and in vivo. The results revealed that CRC cells co-cultured with ADSCs exhibited stronger metastatic property and anoikis resistance, and ADSCs boosted the intraperitoneal seeding of CRC cells. Furthermore, RNA sequencing was carried out to identify the key target gene, angiopoietin like 4 (ANGPTL4), which was upregulated in CRC specimens, especially in peritoneal metastases. Mechanistically, TGF-β1 secreted by ADSCs activated SMAD3 in CRC cells, and chromatin immunoprecipitation assay showed that SMAD3 facilitated ANGPTL4 transcription by directly binding to ANGPTL4 promoter. The ANGPTL4 upregulation was essential for ADSCs to promote glycolysis and anoikis resistance in CRC. Importantly, simultaneously targeting TGF-β signaling and ANGPTL4 efficiently reduced intraperitoneal seeding in vivo. In conclusion, this study indicates that tumor-infiltrating ADSCs promote glycolysis and anoikis resistance in CRC cells and ultimately facilitate peritoneal metastasis via the TGF-β1/SMAD3/ANGPTL4 axis. The dual-targeting of TGF-β signaling and ANGPTL4 may be a feasible therapeutic strategy for CRC peritoneal metastasis. Show less

Previous studies have shown an association between lipid-lowering drugs, circulating inflammatory factors, and atrial fibrillation (AF), but the specific effects of lipid-lowering drugs on AF and whether they can be mediated by circulating inflammatory factors remain unclear. We collected 10 genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, PCSK9, NPC1L1, APOB, APOB, ABCG5, ABCG8, LPL, APOC3, and PPARA) and AF based on genome-wide association study (GWAS) summary statistics. Drug target Mendelian randomization (MR) was used to explore the causal relationship between lipid-lowering drugs and AF. In addition, we performed a mediation analysis of 91 circulating inflammatory factors to explore potential mediators. Sensitivity analyses were performed to verify the reliability of the MR Results by MR-Egger intercept test, Cochran's Q test and leave-one-out test. The results of IVW method showed that LPL agonist had a protective effect on AF(OR = 0. 854, 95%CI: 0.816-0.894, Our study provides new insights into the complex interactions among lipid-lowering agents, circulating inflammatory factors and AF, and also identified a potential mediating role of FGF5 in the pathogenesis of AF. Our findings highlight the potential of LPL agonists and targeting specific inflammatory factors for therapeutic intervention in AF, providing promising avenues for future research and clinical strategies for the management and prevention of AF. Show less

Type 2 diabetes (T2DM) is a significant risk factor for coronary heart disease (CHD). This study aimed to assess the variations in biomarkers associated with CHD in T2DM patients across different age groups in the Han Chinese population. A strict selection process was employed, involving three groups: a control group (n = 300) with no medical history, a new-onset T2DM group (n = 300), and a new-onset T2DM + CHD group (n = 300). Participants in each group were further categorized based on age: Group 1 (<60 years), Group 2 (60-75 years), and Group 3 (>75 years). Fasting glucose, hemoglobin A1c (HbA1c), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), ApoB/ApoA1 ratio, lipoprotein(a) [Lp(a)], high-sensitivity C-reactive protein (hsCRP), and homocysteine (HCY) levels were analyzed in all groups. Both T2DM and T2DM + CHD groups exhibited elevated levels of TG, TC, LDL-C, ApoB, ApoB/ApoA1, Lp(a), hsCRP, and HCY, alongside decreased levels of HDL-C and ApoA1 in comparison to the control group. Notably, when comparing the T2DM to the T2DM + CHD groups, significant increases were noted in ApoB, Lp(a), and hsCRP levels in the T2DM + CHD group, whereas other biomarkers did not show significant differences. Across all age groups, the patterns remained consistent, with the T2DM and T2DM + CHD groups showing elevated levels of TG, TC, LDL-C, ApoB, ApoB/ApoA1, Lp(a), hsCRP, and HCY, and decreased levels of HDL-C and ApoA1 compared to their respective age-matched control groups. Furthermore, within each age category, significant increases in ApoB, Lp(a), and hsCRP were specifically observed with advancing age in the T2DM + CHD group, with Lp(a) and hsCRP levels showing particularly notable elevations, underscoring their potential as significant indicators of CHD risk in the T2DM population. Lp(a) and hsCRP may serve as valuable risk biomarkers for the development of CHD in T2DM patients. Understanding the variations in these biomarkers across different age groups can assist in risk assessment and the development of personalized management strategies for CHD in T2DM patients. Show less

Coronary artery disease (CAD) remains the primary cause of death worldwide, and familial hypercholesterolemia (FH) is a common disease that leads to CAD. This study aimed to explore the difference in CAD risk between FH and non-FH patients with high low-density lipoprotein cholesterol (LDL-C) levels. Individuals (≥18 years) who underwent coronary angiography (CAG) from June 2016 to September 2020 were consecutively enrolled. Participants with LDL-C levels ≥4.0 mmol/L were ultimately included in this study. For all participants, next-generation sequencing was performed with expanded gene panels including 11 genes (LDLR, APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, LIPA, LPA, APOBR, LRPAP1, and STAP1). A total of 223 individuals were included in this study. According to the CAG findings, 199 CAD patients and 24 non-CAD patients were included. The proportions of FH genes, regardless of whether 3 major genes or all 11 genes were sequenced, were not significantly different between the CAD and non-CAD groups ( FH mutation did not increase the rate of CAD in individuals with an MLDL-C level ≥4.0 mmol/L. However, among CAD patients (MLDL-C level ≥4.0 mmol/L) with almost normal renal function (≥87.4 ml/min/1.73 m Show less

Triglycerides (TGs) associate with apolipoprotein B100 (apoB100) to form very low density lipoproteins (VLDLs) in the liver. The repertoire of factors that facilitate this association is incompletely understood. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytosolic lipid droplet (LD) biogenesis in tissues that do not form VLDL. We hypothesized that in the liver, in addition to promoting cytosolic LD formation, FITM2 would also transfer TG from its site of synthesis in the ER membrane to nascent VLDL particles within the ER lumen. Experiments were conducted using a rat hepatic cell line (McArdle-RH7777, or McA cells), an established model of mammalian lipoprotein metabolism, and mice. FITM2 expression was reduced using siRNA in cells and by liver specific cre-recombinase mediated deletion of the Fitm2 gene in mice. Effects of FITM2 deficiency on VLDL assembly and secretion in vitro and in vivo were measured by multiple methods, including density gradient ultracentrifugation, chromatography, mass spectrometry, stimulated Raman scattering (SRS) microscopy, sub-cellular fractionation, immunoprecipitation, immunofluorescence, and electron microscopy. 1) FITM2-deficient hepatic cells in vitro and in vivo secrete TG-depleted VLDL particles, but the number of particles is unchanged compared to controls; 2) FITM2 deficiency in mice on a high fat diet (HFD) results in decreased plasma TG levels. The number of apoB100-containing lipoproteins remains similar, but shift from VLDL to low density lipoprotein (LDL) density; 3) Both in vitro and in vivo, when TG synthesis is stimulated and FITM2 is deficient, TG accumulates in the ER, and despite its availability this pool is unable to fully lipidate apoB100 particles; 4) FITM2 deficiency disrupts ER morphology and results in ER stress. The results suggest that FITM2 contributes to VLDL lipidation, especially when newly synthesized hepatic TG is in abundance. In addition to its fundamental importance in VLDL assembly, the results also suggest that under dysmetabolic conditions, FITM2 may be an important factor in the partitioning of TG between cytosolic LDs and VLDL particles. Show less

Apolipoproteins and cortical morphology are closely associated with memory complaints, and both may contribute to the development of Alzheimer's disease. To examine whether apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA1), and their ratio (ApoB/ApoA1) are associated with cortical morphology in patients with memory complaints. Ninety-seven patients underwent neuropsychological testing, measurements of ApoB, ApoA1, ApoB/ApoA1, plasma Alzheimer's biomarker, apolipoprotein E (ApoE) genotyping, and 3T structural magnetic resonance imaging (sMRI) scans. Based on sMRI scanning locations, patients were categorized into the University of Electronic Science and Technology (UESTC) and the Fourth People's Hospital of Chengdu (FPHC). The Computational Anatomy Toolbox within Statistical Parametric Mapping was used to calculate each patient's cortical morphology index based on sMRI data. The cortical morphology index and apolipoproteins were also analyzed. Significant positive correlations were found between ApoB and sulcal depth in the lateral occipital cortex among the UESTC, the FPHC, and the total sample groups, and negative correlations were observed between sulcal depth in the lateral occipital cortex and the scores of the Shape Trails Test Part A and B. In the FPHC group, the scores of the Montreal Cognitive Assessment Basic, delayed recall of the Auditory Verbal Learning Test, Animal Fluency Test and Boston Naming Test were positively correlated with the sulcal depth. ApoB is associated with the sulcal depth in the lateral occipital cortex, potentially relating to speed/executive function in individuals with memory complaints. Show less

The study aimed to explore the correlation between retinal nerve fiber layer thickness (RNFLT) with blood biochemical indicators and cognitive dysfunction in patients with type 2 diabetes mellitus (T2DM) and the possible mechanism, thereby providing more theoretical basis for the occurrence and prevention of diabetes related complications. Eighty T2DM patients treated in our hospital from March 2022 to September 2022 were selected as the study subjects, and the clinical data of the patients were retrospectively analyzed. All patients underwent fundus fluorescein angiography (FFA) to analyze the changes in retinal blood vessels. Patients who met the inclusion criteria were divided as the diabetic retinopathy (DR) group (n=46) and simple diabetes group (n=34). The RNFLT, blood biochemical indexes and changes in cognitive functions of the patients were detected. The correlation between RNFLT with blood biochemical indexes and cognitive dysfunction was analyzed. Compared with the simple diabetes group, patients in the DR group had much lower mean, nasal, inferior and superior thicknesses ( DR patients had significantly reduced RNFLT, elevated levels of blood glucose related indicators, and cognitive dysfunction. There existed a correlation between RNFLT and FBG, HbA1c, HOMA-IR index, TMT-A, TMT-B and MMSE. Show less

Environmental contaminants (ECs) are increasingly recognized as crucial drivers of dyslipidemia and cardiovascular disease (CVD), but the comprehensive impact spectrum and interlinking mechanisms remain uncertain. We aimed to systematically evaluate the association between exposure to 80 ECs across seven divergent categories and markers of dyslipidemia and investigate their underpinning biomolecular mechanisms via an unbiased integrative approach of internal chemical exposome and multi-omics. A longitudinal study involving 76 healthy older adults was conducted in Jinan, China, and participants were followed five times from 10 September 2018 to 19 January 2019 in 1-month intervals. A broad spectrum of seven chemical categories covering the prototypes and metabolites of 102 ECs in serum or urine as well as six serum dyslipidemia markers [total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein (Apo)A1, ApoB, and ApoE4] were measured. Multi-omics, including the blood transcriptome, serum/urine metabolome, and serum lipidome, were profiled concurrently. Exposome-wide association study and the deletion/substitution/addition algorithms were applied to explore the associations between 80 EC exposures detection frequency Eight main ECs [1-naphthalene, 1-pyrene, 2-fluorene, dibutyl phosphate, tri-phenyl phosphate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, chromium, and vanadium] were significantly associated with most dyslipidemia markers. Multi-omics indicated that the associations were mediated by endogenous biomolecules and pathways, primarily pertinent to CVD, inflammation, and metabolism. Clinical measures of cytokines and electrocardiograms further cross-validated the association of these exogenous ECs with systemic inflammation and cardiac function, demonstrating their potential mechanisms in driving dyslipidemia pathogenesis. It is imperative to prioritize mitigating exposure to these ECs in the primary prevention and control of the dyslipidemia epidemic. https://doi.org/10.1289/EHP13864. Show less

Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF. Summary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study's focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods. There was no significant effect of blood lipid traits on IPF risk (all P＞0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05-7.12, P = 0.039), 1.36 (1.02-1.82, P = 0.037), 1.66 (1.12-2.45, P = 0.011), 1.68 (1.14-2.48, P = 0.009), and 1.42 (1.20-1.67, P = 3.17×10 Serum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation. Show less

Diabetes mellitus is generally accompanied by dyslipidaemia, but inconsistent relationships between lipid profiles and diabetes are noted. Moreover, genetic variations in insertion/deletion (I/D) polymorphisms at angiotensin-converting enzyme gene (ACE) and T/C polymorphisms in the angiotensin type 1 receptor gene (AGTR1) are related to diabetes and lipid levels, but the associations are controversial. Thus, the current research aimed to explore the effects of ACE I/D, AGTR1 rs5182 and diabetes mellitus on serum lipid profiles in 385 Chinese participants with an average age of 75.01 years. The ACE I/D variant was identified using the polymerase chain reaction (PCR) method, whereas the AGTR1 rs5182 polymorphism was identified using the PCR-based restriction fragment length polymorphism (PCR-RFLP) method and verified with DNA sequencing. Total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured using routine methods, and the lipid ratios were calculated. ACE I/D, but not AGTR1 rs5182, was a predictor of TG/HDL-C for the whole study population. Both ACE I/D and AGTR1 rs5182 were predictors of HDL-C and LDL-C levels in females but not in males. Moreover, in females, diabetes mellitus and ACE I/D were identified as predictors of TG and TG/HDL-C, whereas AGTR1 rs5182 and diabetes mellitus were predictors of TG/HDL-C. Moreover, diabetes mellitus and the combination of ACE I/D and AGTR1 rs5182 variations were predictors of TG and TG/HDL-C exclusively in females. The results demonstrated the potential for gender-dependent interactions of ACE I/D, AGTR1 rs5182, and diabetes on lipid profiles. These findings may serve as an additional explanation for the inconsistent changes of blood lipids in individuals with diabetes mellitus, thereby offering a novel perspective for the clinical management of blood lipid levels in diabetic patients. Show less

Tanshinone I (Tan I) has been proven to exert an anti-inflammatory effect, but the complete mechanism remains unclear. In this study, Tan I was described to have no effect on Syk expression in resting or LPS-stimulated macrophages ex vivo, but dramatically suppressed Syk phosphorylation and CD80, CD86, and IL-1β expression of macrophages. The inflammatory activity of macrophages in ApoC3-transgenic (ApoC3 Show less

Lung adenocarcinoma (LUAD), a type of non-small cell lung cancer (NSCLC), originates from not only bronchial epithelial cells but also alveolar type 2 (AT2) cells, which could differentiate into AT2-like cells. AT2-like cells function as cancer stem cells (CSCs) of LUAD tumorigenesis to give rise to adenocarcinoma. However, the mechanism underlying AT2 cell differentiation into AT2-like cells in LUAD remains unknown. We analyze genes differentially expressed and genes with significantly different survival curves in LUAD, and the combination of these two analyses yields 147 differential genes, in which 14 differentially expressed genes were enriched in cell cycle pathway. We next analyze the protein levels of these genes in LUAD and find that Cyclin-A2 (CCNA2) is closely associated with LUAD tumorigenesis. Unexpectedly, high CCNA2 expression in LUAD is restrictedly associated with smoking and independent of other driver mutations. Single-cell sequencing analyses reveal that CCNA2 is predominantly involved in AT2-like cell differentiation, while inhibition of CCNA2 significantly reverses smoking-induced AT2-like cell differentiation. Mechanistically, CCNA2 binding to CDK2 phosphorylates the AXIN1 complex, which in turn induces ubiquitination-dependent degradation of β-catenin and inhibits the WNT signaling pathway, thereby failing AT2 cell maintenance. These results uncover smoking-induced CCNA2 overexpression and subsequent WNT/β-catenin signaling inactivation as a hitherto uncharacterized mechanism controlling AT2 cell differentiation and LUAD tumorigenesis. Show less

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aβ-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aβ toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aβ deposition in Aβ Show less

The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood-brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aβ and its nerve repair function. In addition, siRNA reduces the production of Aβ plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aβ, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD. Show less

The hippocampus is a heterogeneous structure, comprising histologically and functionally distinguishable hippocampal subfields. The volume reductions in hippocampal subfields have been demonstrated to be linked with Alzheimer's disease (AD). The aim of our study is to investigate the hippocampal subfields' genetic architecture based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. After preprocessing the downloaded genetic variants and imaging data from the ADNI database, a co-sparse reduced rank regression model was applied to analyze the genetic architecture of hippocampal subfields volumes. Homology modeling, docking, molecular dynamics simulations, and Co-IP experiments for protein-protein interactions were used to verify the function of target protein on hippocampal subfields successively. After that, the association analysis between the candidated genes on the hippocampal subfields volume and clinical scales were performed. The results of the association analysis revealed five unique genetic variants (e.g., ubiquitin-specific protease 10 [USP10]) changed in nine hippocampal subfields (e.g., the granule cell and molecular layer of the dentate gyrus [GC-ML-DG]). Among five genetic variants, USP10 had the strongest interaction effect with BACE1, which affected hippocampal subfields verified by MD and Co-IP experiments. The results of association analysis between the candidated genes on the hippocampal subfields volume and clinical scales showed that candidated genes influenced the volume and function of hippocampal subfields. Current evidence suggests that hippocampal subfields have partly distinct genetic architecture and may improve the sensitivity of the detection of AD. Show less

Alzheimer's disease (AD) is a highly heritable disease. The morphological changes of cortical cortex (such as, cortical thickness and surface area) in AD always accompany by the change of the functional connectivity to other brain regions and influence the short- and long-range brain network connections, causing functional deficits of AD. In this study, the first hypothesis is that genetic variations might affect morphology-based brain networks, leading to functional deficits; the second hypothesis is that protein-protein interaction (PPI) between the candidate proteins and known interacting proteins to AD might exist and influence AD. 600 470 variants and structural magnetic resonance imaging scans from 175 AD patients and 214 healthy controls were obtained from the Alzheimer's Disease Neuroimaging Initiative-1 database. A co-sparse reduced-rank regression model was fit to study the relationship between non-synonymous mutations and morphology-based brain networks. After that, PPIs between selected genes and BACE1, an enzyme that was known to be related to AD, are explored by using molecular dynamics (MD) simulation and co-immunoprecipitation (Co-IP) experiments. Eight genes affecting morphology-based brain networks were identified. The results of MD simulation showed that the PPI between TGM4 and BACE1 was the strongest among them and its interaction was verified by Co-IP. Hence, gene variations influence morphology-based brain networks in AD, leading to functional deficits. This finding, validated by MD simulation and Co-IP, suggests that the effect is robust. Show less

We investigated the correlation between serum C1q/TNF-related protein 4 (CTRP4) level and flow-mediated dilation (FMD) in patients with type 2 diabetes mellitus (T2DM), and evaluated the biological effects of CTRP4 on human umbilical vein endothelial cells (HUVECs). A group of 165 patients diagnosed with T2DM were included in this study. Endothelial function was measured with the examination of brachial artery FMD. ELISA kit was used to measure the levels of CTRP4 in serum. HUVECs were stimulated with recombinant CTRP4 protein to assess its biological functions. The levels of CTRP4 showed a significant variation among three groups based on FMD tertiles (p = 0.001). What's more, FMD had a significant difference among three CTRP4 tertile groups (p < 0.05) and was negatively related to serum CTRP4 levels (r = -0.270, p < 0.001). In T2DM patients, logistic regression analysis demonstrated that CTRP4 was the primary influence factor of low FMD (p < 0.01). In receiver operating characteristic curve analysis, the area under the curve of CTRP4 for predicting low FMD was 0.66 (95%CI 0.58-0.75). When stimulated HUVECs with recombinant CTRP4 protein, we found that CTRP4 could concentration-dependently ameliorate proliferation and migration of HUVECs in wounding healing and transwell assay. This protein could also decrease the expression of IL-6 and TNF-α and promote the release of NO in HUVEC supernatants, with suppression of NF-κB and STAT3 phosphorylation. Serum CTRP4 concentrations were negatively associated with FMD. CTRP4 alleviated proliferation, migration and inflammation in HUVECs through the suppression of NF-κB and STAT3 signaling pathways. Show less

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors. Although several treatments have been proposed, the long-term prognosis of this cancer is poor. Lipid droplets and mitochondria are important organelles that regulate energy metabolism in cells and are postulated to promote the occurrence and progression of tumors. However, few risk prediction models have been constructed based on lipid drop-mitochondria-related genes (LMRGs). In this study, we constructed a lipid drop-mitochondrial (LD-M) risk score model based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Biological functions and clinical benefits associated with the various risk scores were analyzed using R software, GraphPad Prism 9, and the online database system. An LD-M risk score model comprising ABLIM3, AK4, CAV2, CPS1, CYP24A1, DLGAP5, FGR, and SH3BP5, was developed and its predictive power was validated. The risk score was closely associated with the cell cycle. Immunophenoscore (IPS) and Tumor immune dysfunction and exclusion (TIDE) results demonstrated that the low-risk group was more sensitive to immunotherapy. Drug sensitivity analysis indicated that BMS-754807, ZM447439, SB216763, and other drugs had lower IC50 values in the low-risk group. Our results suggest that the LD-M risk score is an effective prognostic indicator for individualized treatment of LUAD. Show less

Hyperammonemia refers to elevated levels of ammonia in the blood, which is an important pathological feature of liver cirrhosis and hepatic failure. Preclinical studies suggest tropifexor (TXR), a novel non-bile acid agonist of Farnesoid X Receptor (FXR), has shown promising effects on reducing hepatic steatosis, inflammation, and fibrosis. This study evaluates the impact of TXR on hyperammonemia in a piglet model of cholestasis. We here observed blood ammonia significantly elevated in patients with biliary atresia (BA) and was positively correlated with liver injury. Targeted metabolomics and immunblotting showed glutamine metabolism and urea cycles were impaired in BA patients. Next, we observed that TXR potently suppresses bile duct ligation (BDL)-induced injuries in liver and brain with improving the glutamine metabolism and urea cycles. Within the liver, TXR enhances glutamine metabolism and urea cycles by up-regulation of key regulatory enzymes, including glutamine synthetase (GS), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1). In primary mice hepatocytes, TXR detoxified ammonia via increasing ureagenesis. Mechanically, TXR activating FXR to increase express enzymes that regulating ureagenesis and glutamine synthesis through a transcriptional approach. Together, these results suggest that TXR may have therapeutic implications for hyperammonemic conditions in cholestatic livers. Show less

Polyunsaturated fatty acids (PUFAs) including omega-3 and omega-6 are obtained from diet and can be measured objectively in plasma or red blood cells (RBCs) membrane biomarkers, representing different dietary exposure windows. Show less

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC. Show less

Inflammatory bowel disease (IBD) is a growing global health problem. IBD is commonly prevalent in Europe and America and the incidence rate in Asia is on the rise due to altered dietary structure. Diosgenin is a natural steroidal saponin derived from Dioscorea plants. Diosgenin is the main active ingredient of some Chinese medicines which are mainly used to treat coronary heart disease, angina and hyperlipidemia. Recently, growing evidence has exhibited a crucial role of diosgenin and dioscin in alleviating IBD in multiple ways. However, the precise mechanism of diosgenin against IBD needs further exploration. In this study, network pharmacological and systematic bioinformatic analyses were performed to investigate the diosgenin's targets against IBD. 71 targets such as SRC, TNF and STAT3 were identified as overlapped genes between diosgenin and IBD. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis exhibited their involvement in the tyrosine kinase signaling pathway and its membrane receptors. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and its downstream Ras-MAPK pathway and PI3K-Akt pathway might become the mechanism of diosgenin against IBD. In addition, molecular docking analysis showed that diosgenin has the massive potential of direct binding to tyrosine kinase and its receptors such as SRC, EGFR, FGFR1 and VEGFR. The results above collectively provided evidence that diosgenin is a promising nutraceutical food against IBD. Show less

Fibroblast growth factors (FGFs) are required for the specification and formation of the epibranchial placodes, which give rise to the distal part of the cranial sensory ganglia. However, it remains unclear whether FGFs play a role in regulating the neurite outgrowth of the epibranchial placode-derived ganglia during further development. Previous studies have shown that Fibroblast growth factor 8 (FGF8) promotes neurite outgrowth from the statoacoustic ganglion in vitro. However, these studies did not distinguish between the neural crest- and placode-derived components of the sensory ganglia. In this study, we focused on the petrosal and nodose ganglia as representatives of the epibranchial ganglia and investigated their axonal outgrowth under the influence of FGF8 signaling protein in vitro. To precisely isolate the placode-derived ganglion part, we labeled the placode and its derivatives with enhanced green fluorescent protein (EGFP) through electroporation. The isolated ganglia were then collected for qRT-PCR assay and cultured in a collagen gel with and without FGF8 protein. Our findings revealed that both placode-derived petrosal and nodose ganglia expressed FGFR1 and FGFR2. In culture, FGF8 exerted a neural trophic effect on the axon outgrowth of both ganglia. While the expression levels of FGFR1/2 were similar between the two ganglia, the petrosal ganglion exhibited greater sensitivity to FGF8 compared to the nodose ganglion. This indicates that the placode-derived ganglia have differential responsiveness to FGF8 signaling during axonal extension. Thus, FGF8 is not only required for the early development of the epibranchial placode, as shown in previous studies, but also promotes neurite outgrowth of placode-derived ganglia. Show less

Receptor-binding peptides are promising candidates for tumor target therapy. However, the inability to occupy "hot spots" on the PPI interface and rapid metabolic instability are significant limitations to their clinical application. We investigated a new strategy in which an FGFR1-binding peptide (Pep1) was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus. The resulting Pep1-DNP conjugates retained FGFR1 binding affinity and exhibited a similar potency in inhibiting FGF2-dependent cell proliferation, comparable to that of native Pep1 in vitro. In addition, three conjugates could recruit anti-DNP antibodies onto the surface of cancer cells, thereby mediating the CDC efficacy. In vivo pharmacokinetic studies and antitumor studies demonstrated that optimal conjugate Show less

Gene fusions and MET alterations are rare and difficult to detect in plasma samples. The clinical detection efficacy of molecular residual disease (MRD) based on circulating tumor DNA (ctDNA) in patients with non-small cell lung cancer (NSCLC) with these mutations remains unknown. This prospective, non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions (ALK, ROS1, RET, and FGFR1), MET exon 14 skipping or de novo MET amplification. We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021- and 338-gene panels, respectively. Detectable MRD correlated with a significantly higher recurrence rate (P < 0.001), yielding positive predictive values of 100% and 90.9%, and negative predictive values of 82.4% and 86.4% at landmark and longitudinal time points, respectively. Patients with detectable MRD showed reduced disease-free survival (DFS) compared to those with undetectable MRD (P < 0.001). Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not (P = 0.05). To our knowledge, this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations. Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes. Show less

The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor β-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis. Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes. KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism. KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis. Show less

Recently, FGFR4 has become a hot target for the treatment of cancer owing to its important role in cellular physiological processes. FGFR4 has been validated to be closely related to the occurrence of cancers, such as hepatocellular carcinoma, rhabdomyosarcoma, breast cancer and colorectal cancer. Hence, the development of FGFR4 small-molecule inhibitors is essential to further understanding the functions of FGFR4 in cancer and the treatment of FGFR4-dependent diseases. Given the particular structures of FGFR1-4, the development of FGFR4 selective inhibitors presents significant challenges. The non-conserved Cys552 in the hinge region of the FGFR4 complex becomes the key to the selectivity of FGFR4 and FGFR1/2/3 inhibitors. In this review, we systematically introduce the close relationship between FGFR4 and cancer, and conduct an in-depth analysis of the developing methodology, binding mechanism, kinase selectivity, pharmacokinetic characteristics of FGFR4 selectivity inhibitors, and their application in clinical research. Show less

Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs. Significance: Given the broad prevalence, comorbidities, and risk of malignant transformation associated with CH, there is an unmet need to identify therapeutic targets. We develop an ex vivo platform to perform CRISPR/Cas9 screens in primary HSPCs. We identify KDM3B and downstream signaling components as genotype-specific dependencies in CH and myeloid malignancies. See related commentary by Khabusheva and Goodell, p. 1768. Show less

The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus's high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential. We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits. Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10 These findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages. Show less

Adenosine-to-inosine (A-to-I) editing is the most common type of RNA editing in humans and the role of A-to-I RNA editing remains unclear in Parkinson's disease (PD). We aimed to explore the potential causal association between A-to-I editing and PD, and to assess whether changes in A-to-I editing were associated with cognitive progression in PD. The RNA-seq data from 380 PD patients and 178 healthy controls in the Parkinson's Progression Marker Initiative cohort was used to quantify A-to-I editing sites. We performed cis-RNA editing quantitative trait loci analysis and a two-sample Mendelian Randomization (MR) study by integrating genome-wide association studies to infer the potential causality between A-to-I editing and PD pathogenesis. The potential causal A-to-I editing sites were further confirmed by Summary-data-based MR analysis. Spearman's correlation analysis was performed to characterize the association between longitudinal A-to-I editing and cognitive progression in patients with PD. We identified 17 potential causal A-to-I editing sites for PD and indicated that genetic risk variants may contribute to the risk of PD through A-to-I editing. These A-to-I editing sites were located in genes NCOR1, KANSL1 and BST1. Moreover, we observed 57 sites whose longitudinal A-to-I editing levels correlated with cognitive progression in PD. We found potential causal A-to-I editing sites for PD onset and longitudinal changes of A-to-I editing were associated with cognitive progression in PD. We anticipate this study will provide new biological insights and drive the discovery of the epitranscriptomic role underlying Parkinson's disease. Show less