Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying ef Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)-a bioactive glycoside from Show less
Calcific aortic valve stenosis (CAVS) can lead to cardiac adverse outcomes; however, currently, no effective pharmacological interventions are available to prevent or delay disease progression. Emergi Show more
Calcific aortic valve stenosis (CAVS) can lead to cardiac adverse outcomes; however, currently, no effective pharmacological interventions are available to prevent or delay disease progression. Emerging evidence has identified significant associations between CAVS and key biomarkers, including Lp(a) (lipoprotein [a]), low-density lipoprotein cholesterol, and PCSK9 (proprotein convertase subtilisin/kexin type 9). However, robust evidence from randomized controlled trials is still lacking to substantiate these associations. The EPISODE (Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis) trial is a prospective, evaluator-blinded, randomized controlled trial designed to assess the therapeutic efficacy of PCSK9 inhibitors in patients with CAVS. A total of 160 patients with mild-to-moderate or asymptomatic severe CAVS will be randomly assigned to receive either statin monotherapy or a combination of statins and PCSK9 inhibitors. Participants will undergo follow-up assessments at 3-month intervals for 24 months, including transthoracic ultrasonic cardiogram, computed tomography, and quality-of-life evaluations using the EuroQol-5 Dimension-3 Level questionnaire. The primary end point is the annualized change in peak aortic jet velocity, whereas secondary end points encompass changes in aortic valve area, calcification score, incidence of heart valve surgery, and quality of life. Safety end points include all-cause mortality and cardiovascular events. The trial aims to evaluate the efficacy of PCSK9 inhibitors in modulating disease progression, reducing adverse cardiovascular events, and improving clinical outcomes in patients with CAVS. The anticipated findings are expected to provide critical insights for developing novel therapeutic strategies for early intervention in CAVS. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04968509. Show less
Sperm flagellum defects are tightly associated with male infertility. Centriolar satellites are small multiprotein complexes that recruit satellite proteins to the centrosome and play an essential rol Show more
Sperm flagellum defects are tightly associated with male infertility. Centriolar satellites are small multiprotein complexes that recruit satellite proteins to the centrosome and play an essential role in sperm flagellum biogenesis, but the precise mechanisms underlying this role remain unclear. Show less
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases Show more
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less
Osteoglophonic Dysplasia (OGD) is an autosomal dominant skeletal dysplasia characterized by impaired bone growth resulting in short stature, severe craniofacial abnormalities, and in some patients FGF Show more
Osteoglophonic Dysplasia (OGD) is an autosomal dominant skeletal dysplasia characterized by impaired bone growth resulting in short stature, severe craniofacial abnormalities, and in some patients FGF23-mediated hypophosphatemia. It is caused by gain-of-function variants in FGFR1, particularly in or near the transmembrane domain of the receptor. We used CRISPR in mice to knock-in the FGFR1 p.N330I variant, chosen based on its association with FGF23 excess. Skeletal phenotyping of this Show less
People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, a Show more
People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, and the increased risk of MCI and AD is associated with the lack of estrogen during menopause. Previous studies have shown that Tiao Geng Decoction (TGD) may have antioxidant and anti apoptotic properties, which may prevent neurodegenerative diseases. However, whether TGD is effective in improving mild cognitive impairment due to postmenopausal estrogen deficiency and its potential pharmacological mechanisms remain unclear. The aim of this study was to investigate the possible pharmacological mechanisms of TGD in preventing postmenopausal MCI. We utilized RNA-seq technology to screen for differentially expressed genes (DEGs) and enrichment pathways in the hippocampal tissue of different groups of mice. Additionally, we adopted single-cell sequencing technology to study the cell types of Alzheimer's disease (AD) group and Normal Control (NC) group, the differential marker genes of each cell subgroup, and the GO enrichment analysis of each cell type. Both RNA sequencing and single-cell sequencing results showed a significant correlation between TGD and NF-κb pathway in improving mild cognitive impairment in postmenopausal women. The experimental verification results showed that the spatial learning and memory abilities of APP/PS1 model mice were weakened after ovariectomy, and the reproductive cycle on vaginal smears was in the interphase of diestrus. The levels of serum E2, and P-tau181 in mice were significantly down regulated, while the levels of brain tissue homogenate A β 42, IL-1 β, and IL-18 were significantly up-regulated, indicating successful modeling. Combining Western blotting, RT-qPCR, and transmission electron microscopy analyses, it was found that the low estrogen environment induced by oophorectomy can activate the NF-κb signaling pathway, activate the expression of NLRP3 inflammasome and A β secretase BACE1, and induce neuroinflammatory damage in hippocampal astrocytes. These results conform to the modeling characteristics of MCI. After TGD intervention, the spatial learning and memory abilities of MCI mice were significantly improved. The pharmacological validation results indicated that high concentration doses of TGD had a more significant effect on MCI. Subsequently, we used high concentration TGD (0.32 g/ml) as the traditional Chinese medicine group for further validation, protein blotting and RT-qPCR results indicated that TGD can effectively stimulate the secretion of ER α and ER β, inhibit the NF-κb pathway, downregulate BACE1, and inhibit the expression of NLRP3 inflammasome related proteins. In addition, the immunofluorescence results of hippocampal astrocytes showed that TGD can effectively facilitate the expression of AQP1 and significantly lower the sedimentation of A β compared with the model group. Our research suggests that there is a high correlation between a low estrogen environment and the occurrence and development of MCI. TGD may regulate the ERs/NF - κ b/AQP1 signaling pathway, promote estrogen secretion, activate AQP1, reduce A β deposition, reverse MCI neuroinflammatory injury, improve mild cognitive impairment, and prevent the occurrence of AD. This study revealed for the first time that TGD may be a potential new alternative drug for preventing and improving menopausal MCI. Show less
Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, bu Show more
Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders. Show less
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatme Show more
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatments such as statin drugs and stent implantation are associated with significant side effects or limited efficacy, highlighting the urgent need for new therapeutic strategies. Pulsed electromagnetic fields (PEMFs), due to their noninvasive nature and anti-inflammatory properties, show potential in the treatment of atherosclerosis. This study utilized ApoE-/- mice, ApoE-/-NLRP3-/- knockout mice, human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human plasma samples for experiments, revealing significant endothelial cell (EC) inflammation and pyroptosis during the progression of atherosclerosis. PEMFs were found to effectively inhibit the activation of the NLRP3 inflammasome, reduce plaque formation, and delay the progression of atherosclerosis. Proteomic analysis of plasma from atherosclerosis patients further indicated elevated expression levels of proteins related to inflammation and pyroptosis, with particularly notable changes in membrane proteins. Mechanistic studies demonstrated that PEMFs improve mitochondrial dysfunction in ECs by regulating membrane tension and the mechanosensitive tension-mediated transient receptor potential vanilloid 4 (TRPV4) channels, thereby reducing pyroptosis. This discovery not only reveals a novel mechanobiological pathway but also provides a solid theoretical foundation for the development of PEMF-based therapies for atherosclerosis. Schematic diagram of the mechanism by which PEMFs treat atherosclerosis (created in BioRender). Wei, B. (2025) https://BioRender.com/undefined ). Show less
Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential Show more
Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs. Show less
This study aimed to collaboratively investigate the mechanism of variations in intramuscular fat (IMF) content in Wandong cattle using transcriptomics and metabolomics techniques. Longissimus dorsi (L Show more
This study aimed to collaboratively investigate the mechanism of variations in intramuscular fat (IMF) content in Wandong cattle using transcriptomics and metabolomics techniques. Longissimus dorsi (LD) muscle samples were collected from thirteen free-range Wandong cattle in Fengyang County, Anhui Province, China. From this initial cohort, eight animals closely matched in age and body weight were selected. Based on IMF content measured by Soxhlet extraction, these eight cattle were divided into two groups: the high-IMF (HF, n = 4) and low-IMF (LF, n = 4) groups. Subsequent analyses were performed on integrated datasets comprising the transcriptome, metabolome, and fatty acid profile. The results revealed a significant increase in IMF in the HF group compared to the LF group ( Show less
The Kruppel-like factor 15(KLF15) gene functions as a crucial transcriptional modulator involved in numerous cellular processes such as differentiation, proliferation, growth, and programmed cell deat Show more
The Kruppel-like factor 15(KLF15) gene functions as a crucial transcriptional modulator involved in numerous cellular processes such as differentiation, proliferation, growth, and programmed cell death. The epithelial-to-mesenchymal transition (EMT) provides malignant cells with the adaptability and movement necessary for tumor advancement and spread, with zinc finger E-box binding homeobox 1(ZEB1) playing a pivotal role as a transcriptional factor in EMT. This investigation initially examined the association between the KLF15 protein and EMT associated transcription factors such as ZEB1, Slug, and Snail, along with marker proteins like E-cadherin and β-catenin in bladder cancer. Furthermore, we explored their connections with clinicopathological attributes and conducted prognostic analyses. Immunohistochemical techniques were utilized to ascertain the presence of KLF15 protein and EMT-associated transcription factor proteins, along with their marker proteins in 110 specimens of bladder cancer tissues. Concurrently, clinicopathological data and postoperative survival statistics were amassed. The rates of KLF15 and Slug protein expression were linked with pathological differentiation, lymphatic involvement, and pTNM staging. The protein expression rates of ZEB1, Slug, Snail, E-cadherin, and β-catenin also showed associations with lymphatic metastasis and pTNM stages. Notably, the expression of KLF15, the coexpression of KLF15 and ZEB1, and lymphatic metastasis emerged as independent prognostic indicators for the overall survival rates in bladder cancer cases. EMT enhances the risk of tumor recurrence and reduces overall survival durations in bladder cancer cases. Furthermore, KLF15 is a significant contributor to the EMT pathway in bladder cancer, primarily through its interaction with the transcription factor ZEB1. KLF15 and ZEB1 might serve as key biomarkers for metastasis and prognosis, offering potential new targets for therapeutic intervention in bladder cancer. Show less
This study aims to comprehensively analyze the genetic characteristics and prognostic value of stemness- and epithelial-mesenchymal transformation (EMT)-related gene signatures in lung adenocarcinoma Show more
This study aims to comprehensively analyze the genetic characteristics and prognostic value of stemness- and epithelial-mesenchymal transformation (EMT)-related gene signatures in lung adenocarcinoma (LUAD). The RNA-sequencing transcriptome profiling data and corresponding clinical information of LUAD were procured from TCGA-LUAD and GEO datasets. After screening, we first obtained 1488 stemness- and EMT-related genes. Then 304 hub genes were obtained via WGCNA, of which 52 genes were established to be prognosis-related hub genes. Thereafter, a prognostic model containing 11 genes (ANGPTL4, CCL20, ENO1, FGF2, LGR4, PIM2, S100P, SATB2, SHOX2, ZNF322, and CFTR) was constructed. We demonstrated that a higher risk score was an independent negative prognostic factor in LUAD patients. A nomogram was further constructed to better predict the survival of LUAD patients. More importantly, we found that the low-risk group has a more favorable anti-tumor immune microenvironment and may benefit more from immunotherapy. We finally noticed that the high-risk group was more sensitive to most drugs including drugs commonly used to treat LUAD patients. In conclusion, this study has summarized the alterations and prognostic role of stemness- and EMT-related gene signatures in LUAD and constructed a prognostic model to accurately and stably predict survival and guide individualized treatment decisions. Show less
Gallstone disease (GD) is a common gastrointestinal disorder with a significant genetic component. Despite known risk factors, the genetic basis of GD remains incompletely understood. We aimed to iden Show more
Gallstone disease (GD) is a common gastrointestinal disorder with a significant genetic component. Despite known risk factors, the genetic basis of GD remains incompletely understood. We aimed to identify novel genetic loci associated with GD, explore their clinical implications and investigate their therapeutic potential. We conducted a genome-wide association study from the UK Biobank followed by a meta-analysis, integrating summary statistics from the FinnGen R11, with further replication from Biobank Japan. Using systematic bioinformatic approaches, we performed gene prioritisation, colocalisation analysis, transcriptome-wide association study, Mendelian randomisations, cross-trait genetic correlations, phenome-wide association study, clinical investigations and gene-environment interactions by leveraging data from the FinnGen, Genotype-Tissue Expression project and Liver Cell Atlas single-cell transcriptomics data set. Our study highlighted novel susceptibility loci near candidate genes (ie, This study provides new insights into the genetic basis of GD and highlights the role of hepatocytes in GD pathogenesis. These findings have implications for the personalised prevention strategies and new therapeutic interventions in individuals predisposed to GD. Show less
Lanthanides-doped luminescent materials have gathered considerable attention due to their application potential in stress sensing, lighting and display, anti-counterfeiting technology and so forth. Ho Show more
Lanthanides-doped luminescent materials have gathered considerable attention due to their application potential in stress sensing, lighting and display, anti-counterfeiting technology and so forth. However, existing materials mainly cover the 380-1540 nm range, with slight extension to the UV region, impeding their applications in solar-blind imaging, background-free tracking, concealed communication, etc. To address this challenge, here we propose guidelines for far-UVC (200-230 nm) optical design. Accordingly, we achieve multi-stimulated far-UVC luminescence at ~222 nm in Pr Show less
Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcin Show more
Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain unclear. PDCD5-overexpressing cell and xenograft tumor models were developed. Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, wound healing, Transwell, flow cytometry, immunohistochemistry, and hematoxylin-eosin staining were employed to explore the effects of PDCD5 on HCC cell behaviors and tumor growth. The enzyme-linked immunosorbent assay and western blot were used to detect pyroptosis-related marker levels. The molecular mechanisms underlying PDCD5's role in HCC were investigated through transcriptome sequencing and coimmunoprecipitation. SRI-011381, a TGF-β signaling activator, was applied to evaluate the impact of PDCD5 in modulating the TGF-β/Smad2/3/Snail pathway. PDCD5 expression was reduced in HCC cells. Overexpression of PDCD5 inhibited HCC cell proliferation, migration, invasion, and xenograft tumor growth. Additionally, PDCD5 overexpression promoted apoptosis and pyroptosis, with corresponding increases in inflammatory factors and Caspase-1, GSDMD, and NLRP3 protein levels. Mechanistically, PDCD5 bound to receptor-regulated Smads (Smad2/3), inhibiting the TGF-β pathway. Treatment with the TGF-β pathway activator SRI-011381 significantly counteracted the inhibitory effects of PDCD5 overexpression on HCC progression. Our findings suggest that PDCD5 impedes the progression of HCC by promoting pyroptosis via regulation of TGF-β/Smad2/3/Snail pathway, which could be a possible therapeutic target for HCC. Show less
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known Show more
Colorectal cancer (CRC) metastasis remains a major cause of mortality, driven by epithelial-to-mesenchymal transition (EMT) and invasion. Programmed cell death 4 (Pdcd4), a tumor suppressor, is known to inhibit translation via interaction with eukaryotic initiation factor 4A (eIF4A). Previous studies have established that Pdcd4 suppresses stress-activated protein kinase 1-interacting protein 1 (Sin1) translation through the mTORC2-Akt axis, thereby downregulating Snail expression and EMT in CRC cells. However, whether Pdcd4 directly regulates Slug, another critical EMT transcription factor, remains unexplored. PDCD4 shRNA and SLUG siRNA were used to knock down Pdcd4 and Slug in colorectal cancer cells, respectively. The sucrose gradient fractionation was performed to determine SLUG translation. A luciferase reporter assay was used to determine the role of the SLUG 5' untranslated region (5'UTR) on Pdcd4 inhibition. The effect of Slug on promoting invasion was determined by Matrigel invasion assays. Knockdown of Pdcd4 in colorectal cancer cells increased Slug protein levels without altering SLUG mRNA abundance. Sucrose gradient fractionation revealed that Pdcd4 knockdown elevated the proportion of SLUG mRNA in polysome fractions, demonstrating Pdcd4-mediated suppression of SLUG translation. To validate the mechanism, the SLUG 5'UTR was cloned and fused to a luciferase reporter and named SLUG-5'UTR-Luc. Pdcd4 knockdown markedly enhanced SLUG-5'UTR-Luc activity; whereas, ectopic Pdcd4 expression suppressed it, indicating that the SLUG 5'UTR is critical for Pdcd4-mediated translational repression. Treatment with the eIF4A inhibitor silvestrol substantially reduced Slug protein levels and SLUG-5'UTR-Luc activity. In addition, Pdcd4 overexpression decreased Slug protein abundance and restored E-cadherin expression. Notably, Slug knockdown in Pdcd4-deficient cells rescued E-cadherin expression and abrogated the invasive phenotype. These findings suggest that up-regulation of Slug translation by Pdcd4 knockdown contributes to enhanced invasion. Pdcd4 suppresses colorectal cancer invasion by translationally downregulating Slug expression. Show less
Liver and lung are the most common metastatic sites in colorectal cancer (CRC), where the tumor microenvironment (TME) plays a crucial role in the progression and metastasis of CRC. Understanding the Show more
Liver and lung are the most common metastatic sites in colorectal cancer (CRC), where the tumor microenvironment (TME) plays a crucial role in the progression and metastasis of CRC. Understanding the interactions between various types of cells in the TME can suggest innovative therapeutic strategies. Using single-cell RNA sequencing (scRNA-Seq) and clinical samples, fibroblast growth factor-19 (FGF19, rodent FGF15) is found to mediate a significant interaction between CRC cells and cancer-associated fibroblasts (CAFs), activating the hepatic stellate cells (HSCs)-to-CAFs differentiation. In various CRC metastatic mouse models, it is shown that FGF15 has a more pronounced effect on liver metastasis compared to pulmonary metastasis. More importantly, the differentially expressed genes (DEGs) are also identified from the RNA-Seq dataset upon the activation of HSCs by FGF19 and compared the DEGs in matched primary and metastatic mRNA samples from patients with CRC liver metastasis (CRCLM), it is found that the ANGPTL4 gene is significantly associated with HSCs activation. Different mouse models also demonstrated the impact of the FGF19/ANGPTL4 axis on the severity of CRCLM. Importantly, disruption of this axis significantly inhibits CRCLM in vivo. This study is among the first to demonstrate the impact of the FGF19/ANGPTL4 axis on CRCLM, offering a novel therapeutic strategy. Show less
The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies Show more
The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate. Using genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness. The genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs. Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995-0.999], P = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996-0.999], P = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively. Our study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue. Show less
Tumor angiogenesis is required for the progression of non-small cell lung cancer (NSCLC), and anti-vascular endothelial growth factor (anti-VEGF) antibody bevacizumab and multitarget tyrosine kinase i Show more
Tumor angiogenesis is required for the progression of non-small cell lung cancer (NSCLC), and anti-vascular endothelial growth factor (anti-VEGF) antibody bevacizumab and multitarget tyrosine kinase inhibitor anlotinib are anti-cancer treatment options, the combined effect of which in NSCLC remains unclear. A vascularized microfluidic chip was applied to model angiogenesis, together with Bevacizumab plus anlotinib (B+A) inhibited angiogenesis, reducing vessel density to 10% of control values and also reducing diameter and green fluorescent protein (GFP) area ratio. B+A inhibited cell viability by 78%, colony formation by 90%, and invasion by 75% in NSCLC cell lines A549 and H1299; downregulated N-cadherin 5.34-fold, vimentin 6.46-fold, and α-SMA 4.35-fold; and upregulated E-cadherin 3.75-fold. The rates of apoptosis of A549 and H1299 cells were increased 3.85-fold. The phosphorylation of VEGFR2, PDGFRβ, and FGFR1 was also reduced. B+A reduced tumor volume 7.23-fold and weight 7.08-fold, decreased tumor cell density, and lowered Ki-67 expression in an HIF-1α inhibitor PX478 did not enhance the anti-tumor effects of B+A, but HIF-1α activator DMOG reversed them. In addition, the combination therapy enhanced CD4 Show less
Prostate cancer is epithelial malignant prostate hyperplasia caused by a tumor. We found prostate cancer GSE141551 and GSE200879 profiles from gene expression omnibus database, followed by differentia Show more
Prostate cancer is epithelial malignant prostate hyperplasia caused by a tumor. We found prostate cancer GSE141551 and GSE200879 profiles from gene expression omnibus database, followed by differentially expressed genes (DEGs) analysis, weighted gene co-expression network analysis, protein-protein interaction analysis, gene function enrichment analysis, and comparative toxicology database analysis. Finally, the gene expression heat map was drawn, and miRNA information regulating core DEGs was retrieved. A total of 1151 DEGs were found, most of them focusing on systematic development, cell development, cell differentiation, regulation of multicellular biological processes, anatomical morphogenesis, MAPK signaling pathway, proteoglycans in cancer, fluid shear stress, and atherosclerosis. The core genes (MYL9, TAGLN, SMTN, CNN1, MYH11, MYLK, MYOCD, ACTC1, LMOD1, and TPM2) obtained in end are all lowly expressed in prostate cancer samples and are associated with hypertension, tumor metastasis, prostate tumors, and tumor aggressiveness. LMOD1 and SMTN are lowly expressed in prostate cancer and may be used as markers in prostate cancer nursing. Show less
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-se Show more
Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC Show less
G-patch domain-containing protein 2 (GPATCH2), a member of the G-patch domain-containing family, has been implicated in tumor cell growth, but the link between GPATCH2 and hepatocellular carcinoma (HC Show more
G-patch domain-containing protein 2 (GPATCH2), a member of the G-patch domain-containing family, has been implicated in tumor cell growth, but the link between GPATCH2 and hepatocellular carcinoma (HCC) remains uncertain. In the current study, comprehensive bioinformatics analysis revealed that GPATCH2 was markedly upregulated in HCC and positively correlated with aggressive clinicopathological features, including histologic grade, AFP, albumin level, and adjacent hepatic tissue inflammation, as well as miserable outcomes in HCC. GPATCH2 also has certain diagnostic value for HCC, histologic grade, and 1-, 3-, and 5-year survival outcomes. Functionally, loss-of-function experiments disclosed that silencing GPATCH2 suppressed HCC cell proliferation, migration, invasion, and xenograft tumor growth in the subcutaneous mouse model. Silencing GPATCH2 also resulted in an increase in the expression level of CDH1, while causing a decrease in the expression levels of FN1, TWIST1, SNAI1, and SNAI2. Rescue experiments further confirmed SNAI2 as a critical downstream effector mediating GPATCH2-driven oncogenic activity in HCC. Mechanistically, GPATCH2 was uncovered to be transcriptionally activated by the transcription factor Yin Yang 1 (YY1), and can mediate the role of YY1 in promoting HCC progression and elevating SNAI2 expression. Taken together, GPATCH2 is a YY1-regulated oncogenic driver that promotes HCC advancement through SNAI2, highlighting its potential as a diagnostic, prognostic, and therapeutic target for HCC. Show less
"Penumbra freezing" aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers a Show more
"Penumbra freezing" aims to extend vascular recanalization treatment to acute ischemic stroke (AIS) patients beyond the standard time window by preserving the ischemic penumbra. Efficient biomarkers are crucial for identifying patients eligible for AIS treatment. This study enrolled 141 AIS patients who exceeded the conventional treatment window. Using CT perfusion imaging, patients were categorized into "penumbra freezing" and "non-penumbra freezing" groups based on the EXTEND criteria. Multiple regression analysis assessed the association of nine baseline factors and five blood lipid indicators with "penumbra freezing." Diagnostic accuracy was evaluated using ROC curves. Mendelian randomization (MR) analysis validated these findings using blood lipid indicators as exposures and penumbra biomarkers as outcomes. Among AIS patients beyond the treatment window, males exhibited better penumbra preservation (OR=0.243, 95% CI=0.072-0.813, p=0.022), while those with hyperlipidemia showed poorer preservation (OR=2.429, 95% CI=1.027-7.747, p=0.043). In the "penumbra freezing" group, ApoA1 levels were significantly lower (1.29 ± 0.03 g/L) compared to the "non-penumbra freezing" group (1.42 ± 0.06 g/L, p=0.034). Conversely, Lp(a) levels were significantly higher in the "penumbra freezing" group (304.63 ± 52.44 mg/L) than in the "non-penumbra freezing" group (110.26 ± 40.71 mg/L, p=0.034). Higher ApoA1 levels increased the likelihood of "non-penumbra freezing" beyond the time window (OR=3.206, 95% CI=1.034-9.938, p=0.044), while elevated Lp(a) levels reduced this likelihood (OR=0.075, 95% CI=0.007-0.848, p=0.036). MR analysis confirmed genetic associations of ApoA1 and Lp(a) with penumbra biomarkers. ApoA1 and Lp(a) may be linked to ischemic penumbra status, but further validation is needed due to limitations in sample size and study methodology. ApoA1 and Lp(a) are promising biomarkers for identifying AIS patients eligible for "penumbra freezing," suggesting the potential to extend the treatment window. Show less
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a li Show more
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a lipoprotein lipase (LPL) activity inhibitor, can inhibit triglycerides (TGs) decomposition, and fibroblast growth factor 21 (FGF21) enhances fatty acids' β-oxidation in liver. We constructed a novel fusion protein combining the anti-ANGPTL3 nanobody FD03 and FGF21 (FD03-FGF21), which exerted appropriate binding affinities to ANGPTL3 and β-Klotho respectively. Our results showed FD03-FGF21 restored bioactivity of LPL which inhibited by ANGPTL3 and activated downstream pathway of FGF21 in iLite FGF21 assay-ready cells. Next, FD03-FGF21 showed a significant therapeutic effect in MAFLD mice, including attenuation of metabolic dyslipidemia, hepatic lipid accumulation, and impaired glucose tolerance. Compared to other treatments, FD03-FGF21 achieved the most significant therapeutic effect with a 79.78 % attenuation of low-density lipoprotein cholesterol (LDL-C) and a 95.8 % reduction of hepatic lipid accumulation. Mechanistically, transcriptomic analysis revealed that differential expression genes (DEGs) were principally clustered into lipid metabolism and oxidative stress pathways after the fusion protein treatment, especially the key lipid metabolism genes of LDLR and CD36 were significantly upregulated and downregulated respectively, as confirmed by WB. Furthermore, lipidomic and metabolomic analysis indicated the fusion protein ameliorated disorders in lipid and protein metabolism mainly through the downregulation of DG and upregulation of PC. Hepatic oxidative stress and inflammation were significantly reduced after administration of the fusion protein in MAFLD mice. Collectively, FD03-FGF21 represents an effective therapeutic strategy for MAFLD therapy through ameliorating lipid metabolism and oxidative stress. Show less
To investigate longitudinal changes in pelvic floor support in primiparous women with pelvic organ prolapse (POP) after vaginal delivery, focusing on single- and multiple-compartment involvement. Two Show more
To investigate longitudinal changes in pelvic floor support in primiparous women with pelvic organ prolapse (POP) after vaginal delivery, focusing on single- and multiple-compartment involvement. Two hundred primiparas after vaginal delivery were prospectively enrolled and underwent pelvic floor MRI at six weeks postpartum. POP was diagnosed and classified into subgroups (single or multiple compartments involved) based on MRI findings. Primiparas with POP underwent repeat MRI at four months postpartum. Pelvic floor measurements, including injury score and functional parameters of the levator ani muscle (puborectal hiatus line, H line; muscular pelvic floor relaxation line, M line; levator hiatus area, LHA; iliococcygeus angle, ICA; levator plate angle, LPA), were assessed on MRI. Measurements were compared among POP subgroups and a normal control group (without POP) at six weeks postpartum. Additionally, changes between six weeks and four months postpartum were analyzed within POP subgroups. Based on MRI criteria, approximately 41.5% of primiparas were diagnosed with POP, predominantly cystoceles commonly associated with uterine prolapse. Functional parameters of the levator ani, except for LPA at rest, were significantly increased in POP subgroups compared to controls. At four months postpartum, M line, H line, and LPA significantly decreased, and prolapsed organs were elevated in cases with multiple compartments involved, compared to six weeks postpartum. No significant changes were observed in cases with single-compartment involvement during follow-up. A substantial proportion of primiparas experienced postpartum POP. Impaired levator ani function contributed to POP. Pelvic floor support improved during early postpartum in cases with multiple-compartment involvement. Show less
COL4A1, a key component of the basement membrane, has been increasingly implicated in tumor progression, yet its role in colon cancer remains incompletely understood. In this study, we conducted a com Show more
COL4A1, a key component of the basement membrane, has been increasingly implicated in tumor progression, yet its role in colon cancer remains incompletely understood. In this study, we conducted a comprehensive integrative analysis using transcriptomic data from the TCGA-COAD cohort, combined with functional validation in colon cancer cell lines. Gene set enrichment analysis (GSEA) revealed that high COL4A1 expression was associated with oncogenic pathways including epithelial-mesenchymal transition (EMT), KRAS signaling, and inflammatory responses. Immune infiltration analysis indicated that COL4A1 expression negatively correlated with CD8 Show less
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave ada Show more
Understanding the adaptive evolution of brain function in extreme environments remains a central challenge in evolutionary biology. This study investigates the molecular mechanisms underlying cave adaptation by comparing brain transcriptomes of sympatric cave-dwelling ( Show less
The established body of knowledge attests to the pivotal influence of ANGPTL4 on lipid metabolism and vascular biology. Nevertheless, its potential implication in neurodegenerative disease remains to Show more
The established body of knowledge attests to the pivotal influence of ANGPTL4 on lipid metabolism and vascular biology. Nevertheless, its potential implication in neurodegenerative disease remains to be fully characterized. The present investigation delves into the involvement of ANGPTL4 in the pathological progression of PD, both in vitro and in vivo. PD models were induced by intraperitoneal administration of MPTP and LPS in WT and ANGPTL4 The observations unveiled that ANGPTL4 deficiency exacerbated behavioral aberrations, intensified dopaminergic neuron loss, and stimulated microglial activation along with p21-dependent senescence. There was an elevation in the expression of proinflammatory cytokines in the PD model. Furthermore, the administration of rANGPTL4 protein reversed the observed phenotypes in ANGPTL4 Our findings posit a salutary role for ANGPTL4 in counteracting PD, rendering it a prospective therapeutic target for the development of innovative drugs aimed at treating neuroinflammation-associated neurological diseases, including PD. Show less
Symptom burden in primary brain tumor patients varies, emphasizing the need for comprehensive understanding to improve patient care. This study aims to identify distinct symptom clusters among brain t Show more
Symptom burden in primary brain tumor patients varies, emphasizing the need for comprehensive understanding to improve patient care. This study aims to identify distinct symptom clusters among brain tumor patients in Shanghai, China, using Latent Profile Analysis (LPA) to guide personalized diagnosis, treatment, and supportive care. A longitudinal study was conducted among 161 patients with primary brain tumors in Shanghai. Participants completed the MD Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) at three intervals: the day of admission (T1), three days after surgery (T2), and two weeks after surgery (T3). Latent Profile Analysis (LPA) was used to identify subgroups with unique symptom patterns. Six distinct subgroups were identified (entropy = 0.964), ranging from low-burden to persistently severe patterns. Subgroup membership was partially associated with age, tumor grade, and diagnosis. These subgroups were: transient postoperative burden group, stable symptom with cognitive emergence group, distress-predominant, low burden group, elderly-high grade, persistently severe group, nausea-dominant recovery group, and distress-plus-nausea, younger urban group. Our findings reveal substantial heterogeneity in perioperative symptom experiences among brain tumor patients. Identifying subgroups with high and persistent symptom burden may help clinicians target interventions such as enhanced education, proactive monitoring, rehabilitation, psychological support, and antiemetic management. This subgroup-based approach may improve quality of life, reduce morbidity, and guide precision supportive care in neuro-oncology. Show less