Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, which affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mende Show more
Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, which affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (P-value < 5×10 Show less
Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal cell carcinoma, originating from renal tubular epithelial cells in the kidney. Hypoxia proves to be a feat Show more
Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal cell carcinoma, originating from renal tubular epithelial cells in the kidney. Hypoxia proves to be a feature commonly observed in solid tumors, leading to increased resistance to treatment and tumor progression. scRNA-seq data were procured from GSE159115 data set. We utilized UMAP and NMF algorithm for clustering and dimensionality reduction. The FindAllMarkers function was used to compare various groups and identify potential hypoxia marker genes. A series of in vitro experiments, including CFA, flow cytometry targeting cell cycle, CCK-8, and EDU, was applied to investigate how ANGPTL4 regulated the ccRCC progression. Two cell lines of ccRCC cells, 786-O and Caki, were used for si-ANGPTL4 transfection. We annotated a total of a total of 6 cell clusters, namely ccRCC malignant cells, T cells, endothelial cells, myeloid cells, smooth muscle cells, and B cells. We observed higher levels of hypoxia-score in the ccRCC malignant cells, while lowest hypoxia-score in T and B cells. We detected multiple hypoxia-related subclusters of TME cells in ccRCC, among which S100A4 CD8+ T cells and nonhypoxia CD8+ T cells were found with a marked elevation of T cell inhibitory gene score. We identified that ANGPTL4+ endothelial cells might function as an integrative role in tumor angiogenesis. Multiple TME subclusters showed high potency in stratification of the prognosis of ccRCC patients. Moreover, by a series of in vitro experiment, we found ANGPTL4 regulated the ccRCC cell proliferation, probably through ERK/P38 pathway. We discerned multiple hypoxia-related subclusters of TME cells in ccRCC, which displayed distinct functional features and great potency in predicting prognosis of ccRCC patients. We identified the role of ANGPTL4 in regulating ccRCC proliferation via ERK/p38 pathway. Show less
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function. Renal ischemia-reperfusion injury (RIRI) is one of the main causes of AKI with the underlying mecha Show more
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function. Renal ischemia-reperfusion injury (RIRI) is one of the main causes of AKI with the underlying mechanism incompletely clarified. The liver X receptors (LXRs), including LXRα and LXRβ, are members of the nuclear receptor superfamily. It has been shown that LXRs play an important role in regulating glucose and lipid metabolism, cholesterol efflux, and inflammation. The purpose of this study was to explore the role and mechanism of LXRs in RIRI. We determined the effects of LXR activation on renal function and histological changes in a mouse RIRI model and a cellular model of hypoxia/reoxygenation (H/R). Show less
Obesity has emerged as a prominent global health concern, with heat stress posing a significant challenge to both human health and animal well-being. Despite a growing interest in environmental determ Show more
Obesity has emerged as a prominent global health concern, with heat stress posing a significant challenge to both human health and animal well-being. Despite a growing interest in environmental determinants of obesity, very few studies have examined the associations between heat stress-related environmental factors and adiposity. Consequently, there exists a clear need to understand the molecular mechanisms underlying the obesogenic effects of heat stress and to formulate preventive strategies. This study focused on culturing porcine subcutaneous preadipocytes at 41.5 ℃ to induce heat stress, revealing that this stressor triggered apoptosis and fat deposition. Analysis demonstrated an upregulation in the expression of HSP70, BAX, adipogenesis-related genes (PPARγ, AP2, CEBPα and FAS), the p-AMPK/AMPK ratio and SIRT1, PGC-1α in the heat stress group compared to the control group (P < 0.05). Conversely, the expression of lipid lysis-related genes (ATGL, HSL and LPL) and Bcl-2 decreased in the heat stress group compared to the control group (P < 0.05). Furthermore, subsequent activator and/or inhibitor experiments validated that heat stress modulated HSP70 and AMPK signalling pathways to enhance lipogenesis and inhibit lipolysis in porcine subcutaneous preadipocytes. Importantly, this study reveals, for the first time, that EGCG mitigates heat-stress-induced fat deposition by targeting HSP70 through the activation of AMPK-SIRT1-PGC-1α in porcine subcutaneous preadipocytes. These findings elucidate the molecular mechanisms contributing to heat stress-induced obesity and provide a foundation for the potential clinical utilisation of EGCG as a preventive measure against both heat stress and obesity. Show less
Persistent exposure to low-dose of cadmium is strongly linked to both the development and prognosis of non-small cell lung cancer (NSCLC), yet the precise molecular mechanism behind this relationship Show more
Persistent exposure to low-dose of cadmium is strongly linked to both the development and prognosis of non-small cell lung cancer (NSCLC), yet the precise molecular mechanism behind this relationship remains uncertain. In this study, cadmium-related pathogenic genes (CRPGs) in NSCLC were identified via differential expression analysis. NSCLC patient clusters related to CRPGs were constructed through univariate Cox and K-means clustering algorithms. Multivariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were employed to determine the prognosis. Sixteen CRPGs showed a significant association with NSCLC. We found biological and prognostic differences between patients in clusters A and B. A predictive prognostic risk model for NSCLC revealed that FAM83H, MSMO1, and SNAI1 are central. Hence, the 3 hub genes were named. To further elucidate the role of CRPGs in NSCLC, A549 cells were exposed to CdCl Show less
Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma Show more
Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice. We engineered After being fed a Western diet for 12 weeks, Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed Show less
Type 2 Diabetes Mellitus (T2D) and Osteoarthritis (OA) are both prevalent diseases that significantly impact the health of patients. Increasing evidence suggests that there is a big correlation betwee Show more
Type 2 Diabetes Mellitus (T2D) and Osteoarthritis (OA) are both prevalent diseases that significantly impact the health of patients. Increasing evidence suggests that there is a big correlation between T2D and OA, but the molecular mechanisms remain elusive. The aims of this study are to investigate the shared biomarkers and potential molecular mechanisms in T2D combined with OA. T2D and OA-related differentially expressed genes (DEGs) were identified via bioinformatic analysis on Gene Expression Omnibus (GEO) datasets GSE26168 and GSE114007 respectively. Subsequently, extensive target prediction and network analysis were finished with Gene Ontology (GO), protein-protein interaction (PPI), and pathway enrichment with DEGs. The transcription factors (TFs) and miRNAs coupled in co-expressed DEGs involved in T2D and OA were predicted as well. The key genes expressed both in the clinical tissues of T2D and OA were detected with western blot and qRT-PCR assay. Finally, the most promising candidate compounds were predicted with the Drug-Gene Interaction Database (DGIdb) and molecular docking. In this study, 209 shared DEGs between T2D and OA were identified. Functional analysis disclosed that these DEGs are predominantly related to ossification, regulation of leukocyte migration, extracellular matrix (ECM) structural constituents, PI3K/AKT, and Wnt signaling pathways. Further analysis via Protein-Protein Interaction (PPI) analysis and validation with external datasets emphasized MMP9 and ANGPTL4 as crucial genes in both T2D and OA. Our findings were validated through qRT-PCR and Western blot analyses, which indicated high expression levels of these pivotal genes in T2D, OA, and T2D combined with OA cases. Additionally, the analysis of Transcription Factors (TFs)-miRNA interactions identified 7 TFs and one miRNA that jointly regulate these important genes. The Receiver Operating characteristic (ROC) analysis demonstrated the significant diagnostic potential of MMP9 and ANGPTL4.Moreover, we identified raloxifene, ezetimibe, and S-3304 as promising agents for patients with both T2D and OA. This study uncovers the shared signaling pathways, biomarkers, potential therapeutics, and diagnostic models for individuals suffering from both T2D and OA. These findings not only present novel perspectives on the complex interplay between T2D and OA but also hold significant promise for improving the clinical management and prognosis of patients with this concurrent condition. Show less
The human extravillous trophoblast (EVT) cell invasion is an important process during placentation. Although the placenta is normal tissue, the EVT cells exhibit some features common to cancer cells, Show more
The human extravillous trophoblast (EVT) cell invasion is an important process during placentation. Although the placenta is normal tissue, the EVT cells exhibit some features common to cancer cells, including high migratory and invasive properties. Snail and Slug are transcription factors that mediate the epithelial-mesenchymal transition (EMT), a crucial event for cancer cell migration and invasion. It has been shown that GDF-11-induced matrix metalloproteinase 2 (MMP2) expression is required for EVT cell invasion. Whether GDF-11 can regulate Snail and Slug expression in human EVT cells remains unknown. If it does, the involvement of Snail and Slug in GDF-11-induced MMP2 expression and EVT cell invasion must also be defined. In the present study, using the immortalized human EVT cell line, HTR-8/SVneo, and primary cultures of human EVT cells as experimental models, our results show that GDF-11 upregulates Snail and Slug expression. ALK4 and ALK5 mediate the stimulatory effects of GDF-11 on Snail and Slug expression. In addition, we demonstrate that SMAD2 and SMAD3 are required for the GDF-11-upregulated Snail expression, while only SMAD3 is involved in GDF-11-induced Slug expression. Moreover, our results reveal that Snail mediates GDF-11-induced MMP2 expression and cell invasion but not Slug. This study increases our understanding of the biological function of GDF-11 in human EVT cells and provides a novel mechanism for regulating MMP2 and EVT cell invasion. Show less
Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. Hi-C and RNA-seq were appli Show more
Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. Hi-C and RNA-seq were applied to study the 3D chromatin landscapes and gene expression of HCC and ANHT. Hi-C Pro was used to generate genome-wide raw interaction matrices, which were normalized via iterative correction (ICE). Moreover, the chromosomes were divided into different compartments according to the first principal component (E1). Furthermore, topologically associated domains (TADs) were visualized via WashU Epigenome Browser. Furthermore, differential expression analysis of ANHT and HCC was performed using the DESeq2 R package. Additionally, dysregulated genes associated with 3D genome architecture altered were confirmed using TCGA, qRT-PCR, immunohistochemistry (IHC), etc. RESULTS: First, the intrachromosomal interactions of chr1, chr2, chr5, and chr11 were significantly different, and the interchromosomal interactions of chr4-chr10, chr13-chr21, chr15-chr22, and chr16-chr19 are remarkably different between ANHT and HCC, which resulted in the up-regulation of TP53I3 and ZNF738 and the down-regulation of APOC3 and APOA5 in HCC. Second, 49 compartment regions on 18 chromosomes have significantly switched (A-B or B-A) during HCC tumorigenesis, contributing to up-regulation of RAP2A. Finally, a tumor-specific TAD boundary located on chr5: 6271000-6478000 and enhancer hijacking were identified in HCC tissues, potentially associated with the elevated expression of MED10, whose expression were associated with poor prognosis of HCC patients. This study demonstrates the crucial role of chromosomal structure variation in HCC oncogenesis and potential novel biomarkers of HCC, laying a foundation for cancer precision medicine development. Show less
Psoriasis and inflammatory bowel disease (IBD) are chronic immune-mediated diseases that adversely affect patients' quality of life. Interleukin (IL)-27 plays an important role in a variety of infecti Show more
Psoriasis and inflammatory bowel disease (IBD) are chronic immune-mediated diseases that adversely affect patients' quality of life. Interleukin (IL)-27 plays an important role in a variety of infectious diseases, autoimmune disorders, and cancers. However, its therapeutic effects in psoriasis and colitis remain underexplored. In this study, we evaluated the therapeutic potential of recombinant Lactococcus lactis (L. lactis) expressing IL-27 (pIL-27) in imiquimod-induced psoriasis and dextran sodium sulfate-induced colitis mouse models. In the psoriasis mouse model, oral administration of pIL-27 significantly reduced skin scaling, mitigated weight loss, lowered psoriasis area and severity index scores, diminished epidermal hyperplasia and inflammatory cell infiltration, and decreased inflammatory cytokine levels. In the colitis mouse model, oral administration of pIL-27 alleviated weight loss, improved disease activity index scores, prevented colon shortening, ameliorated histopathological changes, and decreased inflammatory cytokine levels. Furthermore, recombinant L. lactis expressing IL-27 could modulate the gut microbiota, increasing the amount of beneficial bacteria and reducing harmful bacteria in the intestine, thereby alleviating the progression of psoriasis and colitis. These results suggest the potential of IL-27 as a therapeutic option for treating psoriasis and IBD. Show less
Although abnormal lipid metabolism is one of the major risk factors for diabetes, the correlation between lipids and glucose is rarely discussed in the general population. The differences in lipid-glu Show more
Although abnormal lipid metabolism is one of the major risk factors for diabetes, the correlation between lipids and glucose is rarely discussed in the general population. The differences in lipid-glucose correlations across gender and ethnicity have been even more rarely studied. We examined the association between fasting blood glucose (FBG) and lipids, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB), using 6,093 participants aged 20 years or older from the National Health and Nutrition Examination Survey (NHANES). Analyses were performed using multiple logistic regression and generalised additive models. When other confounders were considered, we found that fasting glucose was positively correlated with triglycerides and negatively correlated with HDL-C, whereas total cholesterol, LDL-C cholesterol, and fasting glucose were related to each other in a U-curve fashion, with inflection points of 5.17 mmol/L and 2.3 mmol/L, respectively.This relationship persisted in subgroups of different sexes and races. A positive correlation was found between fasting glucose and ApoB, but subgroup analyses revealed that this relationship was not correlated across gender and race. In the general population, fasting blood glucose levels were positively correlated with TG, negatively correlated with HDL-C, and U-shaped with total cholesterol and LDL-C. The likelihood of developing diabetes was 40% higher when LDL-C was greater than 2.3 mmol/L than in patients with LDL-C less than 2.3 mmol/L. Show less
Clinical studies have shown that asthma is a risk factor for dementia or Alzheimer's disease (AD). To investigate whether asthma aggravates AD in APP/PS1 mice and explore the potential mechanisms, an Show more
Clinical studies have shown that asthma is a risk factor for dementia or Alzheimer's disease (AD). To investigate whether asthma aggravates AD in APP/PS1 mice and explore the potential mechanisms, an asthma model was established using six-month-old APP/PS1 mice, and montelukast was used as a therapeutic agent in APP/PS1 mice with asthma. The Morris water maze test showed that asthma aggravates spatial learning and memory abilities. Asthma also upregulates the NF-κB inflammatory pathway in APP/PS1 mice and promotes the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid-β (Aβ) deposition, neuronal damage, synaptic plasticity deficiency, activation of microglia and astrocytes. The level of LTD4 and its receptor CysLT1R in the hippocampus of APP/PS1 mice after the asthma modeling was established was higher than that in APP/PS1 mice, suggesting that asthma may affect the pathology of AD through LTD4 and its receptor Cys-LT1R. Montelukast ameliorates these pathological changes and cognitive impairment. These results suggest that asthma aggravates AD pathology and cognitive impairment of APP/PS1 mice via upregulation of the NF-κB inflammatory pathway, and montelukast ameliorates these pathological changes. Show less
Inorganic phosphorus (Pi) deficiency significantly impacts plant growth, development, and photosynthetic efficiency. This study evaluated 206 rice accessions from a MiniCore population under both Pi-s Show more
Inorganic phosphorus (Pi) deficiency significantly impacts plant growth, development, and photosynthetic efficiency. This study evaluated 206 rice accessions from a MiniCore population under both Pi-sufficient (Pi Show less
Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe Show more
Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe and effective application. However, there is little known regarding the molecular mechanism of reducing toxicity after EL processing. This research aimed to screen the differential markers for EL and PEL, explore the differential mechanisms of inflammatory injury induced by EL and processed EL (PEL) to expound the mechanism of alleviating toxicity after EL processing. The results showed that 15 potential biomarkers, mainly belonging to diterpenoids, were screened to distinguish EL from PEL. EL promoted the expressions of TLR4, NLRP3, NF-κB p65, IL-1β and TNF-α, increased lipid rafts abundance and promoted TLR4 positioning to lipid rafts. Meanwhile, EL decreased LXRα and ABCA1 expression, and reduced cholesterol efflux. In contrast to EL, the effects of PEL on these indicators were markedly weakened. In addition, Euphorbia factors L Show less
The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous c Show more
The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous cell carcinoma (LUSC). Several higher frequency of gene alterations are identified as potentially actionable in LUSC. Our work aimed to explore the complex interplay of multiple genetic alterations and pathways contributing to the pathogenesis of LUSC, with a very low frequency of a single driver molecular alterations to develop more effective therapeutic strategies in the future. We retrospectively analyzed the targeted next-generation sequencing (NGS) data (approximately 600 genes) of 335 patients initially diagnosed with non-small cell lung cancer (NSCLC) at our institution between January 2019 and March 2023 and explored the somatic genome alteration difference between LUSC and LUAD. We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D ( Our results prompted that somatic LoF mutations of Show less
Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which may be involved in depression, A Show more
Neuropsychiatric disorders shorten human life spans through multiple ways and become major threats to human health. Exercise can regulate the estrogen signaling, which may be involved in depression, Alzheimer's disease (AD) and Parkinson's disease (PD), and other neuropsychiatric disorders as well in their sex differences. In nervous system, estrogen is an important regulator of cell development, synaptic development, and brain connectivity. Therefore, this review aimed to investigate the potential of estrogen system in the exercise intervention of neuropsychiatric disorders to better understand the exercise in neuropsychiatric disorders and its sex specific. Exercise can exert a protective effect in neuropsychiatric disorders through regulating the expression of estrogen and estrogen receptors, which are involved in neuroprotection, neurodevelopment, and neuronal glucose homeostasis. These processes are mediated by the downstream factors of estrogen signaling, including N-myc downstream regulatory gene 2 (Ndrg2), serotonin (5-HT), delta like canonical Notch ligand 1 (DLL1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), etc. In addition, exercise can act on the estrogen response element (ERE) fragment in the genes of estrogenic downstream factors like β-amyloid precursor protein cleavase 1 (BACE1). However, there are few studies on the relationship between exercise, the estrogen signaling pathway, and neuropsychiatric disorders. Hence, we review how the estrogen signaling mediates the mechanism of exercise intervention in neuropsychiatric disorders. We aim to provide a theoretical perspective for neuropsychiatric disorders affecting female health and provide theoretical support for the design of exercise prescriptions. Show less
Psoriasis is an inflammatory skin disease, there is no radical cure. Traditional Chinese medicine has accumulated a lot of clinical experience in the treatment of psoriasis and developed a variety of Show more
Psoriasis is an inflammatory skin disease, there is no radical cure. Traditional Chinese medicine has accumulated a lot of clinical experience in the treatment of psoriasis and developed a variety of treatment methods, among which Yinxieling optimization formula (PSORI-CM01) have a definite clinical effect in the treatment of psoriasis, but their mechanism of action is still unclear. To investigate the molecular mechanism of the PSORI-CM01 in the treatment of psoriasis. Firstly, potential active compounds and key signaling pathways of PSORI-CM01 were explored by the systems pharmacology method. Then MTT assay was used to screen the potentially active compounds of PSORI-CM01, and explore the combined effects of potentially active compounds. The regulation of potentially active compounds on inflammatory factors were evaluated by a Human Th17 Magnetic Bead Panel. The regulation of PSORI-CM01 on key targets in the key signaling pathways were explored by qRT-PCR method. Finally, the molecular mechanism of PSORI-CM01 in the treatment of psoriasis was explained by the systems pharmacology method. The potentially active compounds of PSORI-CM01 included gallic acid, liquiritigenin, rosmarinic acid, syringic acid, isoliquiritin apioside, caffeic acid, naringenin, cryptochlorogenic acid, (+)-taxifolin, p-coumaric acid, chlorogenic acid, fraxin, 5-hydroxymethylfurfural, lithospermic acid, isoliquiritigenin, salviandic acid B, octahydrocurcumin, catechin, syringaldehyde, methyl rosmarinate, paeonol, protocatechuic acid, astilbin, isoastilbin, isofraxidin and zederone. Both antagonistic and synergistic effects were determined in the combinations of active compounds. Most of the active compounds up-regulated IL-2, IL-6, IL-9 and TNF-α, and down-regulated IFN-γ, IL-1β, IL-2, IL-9, IL-10, IL-13, IL-15, IL-17F, IL-21, IL-22 and IL-27. The PI3K-Akt signaling pathway would be the key signaling pathway of PSORI-CM01. The qRT-PCR results showed that its compounds can effectively regulate the expression of key targets in this pathway. The molecular mechanism of PSORI-CM01 for treating psoriasis would be mediated by regulating the network of inflammatory factors through the PI3K-Akt signaling pathway. Show less
Chemoenzymatic dynamic kinetic resolution (DKR), combining a metal racemization catalyst with an enzyme, has emerged as an elegant solution to transform racemic substrates into enantiopure products, w Show more
Chemoenzymatic dynamic kinetic resolution (DKR), combining a metal racemization catalyst with an enzyme, has emerged as an elegant solution to transform racemic substrates into enantiopure products, while compatibility of dual catalysis is the key issue. Conventional solutions have utilized presynthesized metal complexes with a fixed and bulky ligand to protect the metal from the enzyme system; however, this has been generally limited to anionic ligands. Herein, we report our strategy to solve the compatibility issue by employing a reliable ligand that firmly coordinates Show less
The main objective of this study was to investigate the antitumor effect of a mouse anti-human glypican-1 (GPC1) monoclonal antibody (mAb) on non-small cell lung carcinoma (NSCLC) and associated molec Show more
The main objective of this study was to investigate the antitumor effect of a mouse anti-human glypican-1 (GPC1) monoclonal antibody (mAb) on non-small cell lung carcinoma (NSCLC) and associated molecular mechanisms. The anti-proliferative and anti-migratory activities of anti-GPC1 mAb were examined in A549 and H460 NSCLC cells and LL97A lung fibroblasts. The inhibitory effect of anti-GPC1 mAb on tumor growth was evaluated in an orthotopic lung tumor model. The in vitro study showed that anti-GPC1 mAb profoundly inhibited the anchorage-independent growth of A549 and H460 NSCLC cells and exhibited relatively high cytotoxic activities towards LL97A lung fibroblasts, A549/LL97A and H460/LL97A coculture spheroids. Moreover, anti-GPC1 mAb significantly decreased the expression of phospho-Src (p-Src; Tyr416), p-Akt (Ser473) and β-catenin in the co-cultured LL97A lung fibroblasts, and the expression of phospho-mitogen-activated protein kinase kinase (p-MEK; Ser217/221) and phospho-90 kDa ribosomal s6 kinase (p-p90RSK; Ser380) in co-cultured A549 cells. When anti-GPC1 mAb was administered to tumor-bearing mice, the inhibitory effect of anti-GPC1 mAb on the orthotopic lung tumor growth was not statistically significant. Nonetheless, results of Western blot analysis showed significant decrease in the phosphorylation of fibroblast growth factor receptor 1 (FGFR1) at Tyr766, Src at Tyr416, extracellular signal-regulated kinase (ERK) at Thr202/Tyr204, 90 kDa ribosomal S6 kinase (RSK) at Ser380, glycogen synthase kinases 3α (GSK3α) at Ser21 and GSK3β at Ser9 in tumor tissues. These data implicate that anti-GPC1 mAb treatment impairs the interaction between tumor cells and tumor associated fibroblasts by attenuating the paracrine FGFR signal transduction. The relatively potent cytotoxicity of anti-GPC1 mAb in lung fibroblasts and its potential inhibitory effect on the paracrine FGFR signal transduction warrant further studies on the combined use of this mAb with targeted therapeutics to improve therapeutic outcomes in lung cancer. 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 a Show more
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
Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasi Show more
Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism. Show less
Di-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various dail Show more
Di-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various daily plastic products through wear and leaching into the surrounding environment and decompose into the more toxic metabolite mono-2-ethylhexyl phthalic acid (MEHP) after entering the human body. However, the impacts and mechanisms of MEHP on neuroblastoma are unclear. We exposed MYCN-amplified neuroblastoma SK-N-BE(2)C cells to an environmentally related concentration of MEHP and found that MEHP increased the proliferation and migration ability of tumor cells. The peroxisome proliferator-activated receptor (PPAR) β/δ pathway was identified as a pivotal signaling pathway in neuroblastoma, mediating the effects of MEHP through transcriptional sequencing analysis. Because MEHP can bind to the PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPARβ/δ and ANGPTL4 in the metabolic process, a non-targeted metabolomics analysis revealed that MEHP altered multiple metabolic pathways, particularly lipid metabolites involving fatty acyls, glycerophospholipids, and sterol lipids, which may also be potential factors promoting tumor progression. We have demonstrated for the first time that MEHP can target binding to PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma. Show less
This study aims to investigate the association between nine tag single nucleotide polymorphisms (SNPs) in the A case-control study was conducted to investigate the association between CAD and Results Show more
This study aims to investigate the association between nine tag single nucleotide polymorphisms (SNPs) in the A case-control study was conducted to investigate the association between CAD and Results of the polymorphism study indicated that the The Show less
Alzheimer's disease (AD) is a degenerative disease of the central nervous system. The pathogenesis is still not fully clear. One of the main histopathological manifestations is senile plaques formed b Show more
Alzheimer's disease (AD) is a degenerative disease of the central nervous system. The pathogenesis is still not fully clear. One of the main histopathological manifestations is senile plaques formed by β-amyloid (Aβ) accumulation. Aβ is generated from the sequential proteolysis of amyloid precursor protein (APP) by β-secretase [i.e. β-site APP cleaving enzyme 1 (BACE1)] and γ-secretase, with a rate-limiting step controlled by BACE1 activity. Therefore, inhibiting BACE1 activity has become a potential therapeutic strategy for AD. The development of reliable detection methods for BACE1 activity plays an important role in early diagnosis of AD and evaluation of the therapeutic effect of new drugs for AD. This article has reviewed the recent advances in BACE1 activity detection techniques. The challenges of applying these analysis techniques to early clinical diagnosis of AD and development trends of the detection techniques have been prospected. Show less
To explore the diagnostic value of serum apolipoprotein B100 (Apo B100) combined with hippocampal volume in Alzheimer's disease (AD). A total of 59 AD patients and 59 healthy subjects were selected. T Show more
To explore the diagnostic value of serum apolipoprotein B100 (Apo B100) combined with hippocampal volume in Alzheimer's disease (AD). A total of 59 AD patients and 59 healthy subjects were selected. The Mini-Mental State Examination (MMSE) was used for neuropsychological assessment. Blood glucose and serum lipid levels were detected by biochemical analyzer. Polymerase chain reaction (PCR) was used to detect apolipoprotein E (Apo E) ε3/ε4 genotypes in the plasma. Hippocampal volume was calculated using Slicer software. Independent-sample t test or Mann-Whitney U test were used to compare the levels of various indicators between the two groups. Spearman's correlation analysis was used to analyze the correlation between each level. The receiver operating characteristic curve (ROC) was plotted, and the area under the curve (AUC) was calculated to compare the diagnostic efficacy of individual and combined detection of serum Apo B100 levels and hippocampal volume in AD. Compared with the healthy control group, the levels of serum total cholesterol (TC), low-density lipoprotein (LDL), Apo B100, and plasma Apo E ε3/ε4 were higher in the AD group, and serum high-density lipoprotein (HDL) level was lower in the AD group (both p < 0.05). The hippocampal volume in the AD group was lower than in the control group (p < 0.01). The serum Apo B100 level was negatively correlated with MMSE score (r = -0.646), whereas hippocampal volume was positively correlated with MMSE score (r = 0.630). ROC curve analysis showed that the AUC of the combined serum Apo B100 level and hippocampal volume for AD was higher than that of either alone (AUC = 0.821, p < 0.01). Serum Apo B100 level is elevated, and the hippocampal volume is reduced in AD patients. The combined detection of the two has a higher diagnostic efficiency for AD than other alone and has the potential to become an important indicator for the diagnosis of AD in the future. Show less
Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interva Show more
Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms. Show less
Breast cancer (BC) is the most common and fatal cancer among women, yet the causal relationship between circulating lipids, lipid-lowering drugs, and BC remains unclear. Mendelian randomization (MR) a Show more
Breast cancer (BC) is the most common and fatal cancer among women, yet the causal relationship between circulating lipids, lipid-lowering drugs, and BC remains unclear. Mendelian randomization (MR) and summary data-based MR (SMR) analysis are used to explore the causal relationship between plasma lipids, lipid-lowering drug targets, and BC. The result of MR suggested that per mg/dL higher levels of LDL-C (OR = 1.045, FDR = 0.023), HDL-C (OR = 1.079, FDR = 0.003), TC (OR = 1.043, FDR = 0.026), and APOA-I (OR = 1.085, FDR = 2.64E-04) were associated with increased BC risk, while TG was associated with reduced BC risk (OR = 0.926, FDR = 0.003). Per mg/dL higher levels of HDL-C (OR = 1.080, FDR = 0.011) and APOA-I (OR = 1.083, FDR = 0.002) were associated with increased ER+BC risk, while TG was associated with reduced ER+BC risk (OR = 0.909, FDR = 0.002). For every per 1 mg/dL decrease in LDL, HMGCR (OR: 0.839; FDR = 0.016), NPC1L1 (OR: 0.702; FDR = 0.004), and PCSK9 (OR: 0.916; FDR = 0.026) inhibition were associated with reduced BC risk, whereas CETP inhibition (OR: 1.194; FDR = 0.026) was associated with increased BC risk. For every per 1 mg/dL decrease in LDL, HMGCR (OR: 0.822; FDR = 0.023), NPC1L1 (OR: 0.633; FDR = 2.37E-03), and APOB inhibition (OR: 0.816; FDR = 1.98E-03) were associated with decreased ER-BC risk, while CETP inhibition (OR: 1.465; FDR = 0.011) was associated with increased ER-BC risk. SMR analysis indicated that HMGCR was associated with increased BC risk (OR: 1.112; p = 0.044). Lipids are associated with the BC risk, and lipid-lowering drugs targets HMGCR, NPC1L1, PCSK9, and APOB may be effective strategies for preventing BC. However, lipid-lowering drugs target CETP may potentially increase BC risk. Show less
N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of RNAs and plays a key regulatory role in various biological processes. As a member of the insulin-like growth factor Show more
N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification of RNAs and plays a key regulatory role in various biological processes. As a member of the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) family, IGF2BP1 has recently demonstrated its ability to specifically bind m6A-modified sites within mRNAs and effectively regulate their mRNA stability. However, the precise roles of IGF2BP1 in mammalian skeletal muscle development, along with its downstream mRNA targets during myogenesis, have yet to be fully elucidated. Here, we observed that IGF2BP1 expression significantly decreased during myogenic differentiation. Knockdown of IGF2BP1 significantly inhibited myoblast proliferation while promoted myogenic differentiation. In contrast, IGF2BP1 overexpression robustly stimulated myoblast proliferation but suppressed their differentiation. Combined analysis of high-throughput sequencing and RNA stability assays revealed that IGF2BP1 can enhance fibroblast growth factor receptor 1 (FGFR1) mRNA stability and promote its translation in an m6A-dependent manner, thereby regulating its expression level and the Extracellular Signal-Regulated Kinase (ERK) pathway. Additionally, knockdown of FGFR1 rescued the phenotypic changes (namely increased cell proliferation and suppressed differentiation) induced by IGF2BP1 overexpression via attenuating ERK signaling. Taken together, our findings suggest that IGF2BP1 maintains the stability and translation of FGFR1 mRNA in an m6A-dependent manner, thereby inhibiting skeletal myogenesis through activation of the ERK signaling pathway. This study further enriches the understanding of the molecular mechanisms by which RNA methylation regulates myogenesis, providing valuable insights into the role of IGF2BP1-mediated post-transcriptional regulation in muscle development. Show less
Fish physiological health is often negatively impacted by high-temperature environments and there are few studies on how dietary lipids affect fish growth and physiology when exposed to heat stress. T Show more
Fish physiological health is often negatively impacted by high-temperature environments and there are few studies on how dietary lipids affect fish growth and physiology when exposed to heat stress. The main objective of this research was to examine the impact of dietary lipid levels on growth and physiological status of juvenile turbot (Scophthalmus maximus L.) and determine if dietary lipid concentration could alleviate the possible adverse effects of heat stress. Five diets containing 6.81%, 9.35%, 12.03%, 14.74%, and 17.08% lipid, respectively, were formulated and fed to turbot (initial weight 5.13 ± 0.02 g) under high-temperature conditions (24.0-25.0 °C). Meanwhile, the diet with 12.03% lipid (considered by prior work to be an optimal dietary lipid level) was fed to turbot of the same size at normal temperature. Results suggested that, among the different dietary lipid levels under high-temperature conditions, fish fed the optimal lipid (12.03%) exhibited better growth compared to non-optimal lipid groups, as evidenced by higher weight gain and specific growth rate. Simultaneously, the optimal lipid diet may better maintain lipid homeostasis, as attested by lower liver and serum lipid, along with higher liver mRNA levels of lipolysis-related genes (pgc1α, lipin1, pparα, lpl and hl) and lower levels of synthesis-related genes (lxr, fas, scd1, pparγ, dgat1 and dgat2). Also, the optimal lipid diet might mitigate oxidative damage by improving antioxidant enzyme activity, decreasing malondialdehyde levels, and up-regulating oxidation-related genes (sod1, sod2, cat, gpx and ho-1). Furthermore, the optimal lipid may enhance fish immunity, as suggested by the decrease in serum glutamic-oxalacetic/pyruvic transaminase activities, down-regulation of pro-inflammatory genes and up-regulation of anti-inflammation genes. Correspondingly, the optimal lipid level suppressed MAPK signaling pathway via decreased phosphorylation levels of p38, JNK and ERK proteins in liver. In summary, the optimal dietary lipid level facilitated better growth and physiological status in turbot under thermal stress. Show less