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
Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none Show more
Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none have been verified in Chinese patients. This study aimed to evaluate the efficacy and safety of ongericimab, a novel PCSK9 monoclonal antibody, in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. This was a randomized, multicenter, double-blind, placebo-controlled phase 3 study designed to enroll 120 statin-intolerant adult patients. Eligible patients were randomly assigned in a 2:1 ratio to receive ongericimab 150 mg or placebo subcutaneously every 2 weeks for 12 weeks in the double-blind treatment period, followed by 40 weeks of ongericimab treatment during the open-label period. The primary endpoint was a percentage change in LDL-C from baseline to week 12. The key secondary endpoints included percentage change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and lipoprotein(a) [Lp(a)]. From February 6, 2023, to September 23, 2024, a total of 139 patients were enrolled. The least-squares (LS) mean difference between ongericimab and placebo groups in LDL-C from baseline to week 12 was -66.2 % (95 % CI: 74.2 %, -58.2 %; p < 0.0001), with reductions sustained up to week 52. Ongericimab also significantly reduced levels of non-HDL-C, ApoB, TC, and Lp(a). The overall incidence of treatment-emergent adverse events was comparable between the ongericimab and placebo groups. Ongericimab significantly reduced LDL-C as well as other atherogenic lipid levels and was well tolerated in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. http://www. gov; Unique Identifier: NCT05621070. Show less
This study aimed to investigate the effects of perioperative esketamine on postoperative depression and pain in patients undergoing laparoscopic total hysterectomy. 135 patients undegoing laparoscopic Show more
This study aimed to investigate the effects of perioperative esketamine on postoperative depression and pain in patients undergoing laparoscopic total hysterectomy. 135 patients undegoing laparoscopic total hysterectomy were recruited and randomly allocated to three groups. Finally, a total of 127 patients were selected into the statistical analysis, with the final grouping information as follows: sufentanil group (S1, n = 44), sufentanil combined with 0.25 mg/kg esketamine group (SK1, n = 42) and sufentanil combined with 0.5 mg/kg esketamine group (SK2,n = 41) intraoperatively, then postoperative analgesia was maintained with sufentanil (2 µg/kg) via patient-controlled intravenous analgesia (PCIA) in all groups, while a 1 mg/kg dose of esketamine was added to the PCIA regimen for patients in groups SK1 and SK2. The peripheral blood serum brain-derived neurotrophic factor (BDNF) level, 5-hydroxytryptamine (5-HT) level, Hamilton Depression Scale (HAM-D) scores, visual analogue scale(VAS) scores and the number of PCIA button pressed times in perioperative period were collected. Meanwhile, the postoperative adverse effects including nausea, vomiting, dizziness, respiratory depression and hallucinations were collected and compared between the three groups. Relative to preoperative baseline levels, BDNF and 5-HT levels decreased at the 1th day(1d) post surgery in all groups(P < 0.05), and then followed by a gradual increase thereafter. Compared with S1 group, the SK1 and SK2 group showed significantly higher serum BDNF and 5-HT levels at 1d, 2d and 5d after operation (P < 0.05), and revealed even higher at 1d and 2d after operation in SK2 group(P < 0.05). The HAM-D scores at 1d, 2d and 5d post operation were significantly reduced in SK1 and SK2 group (P < 0.05) compared to S1 group, and decreased even lower at 1d and 2d postoperative in SK2 group(P < 0.05), but no significant difference was found among three groups at 1d before and the 7d after operation. Simultaneously, the VAS scores decreased significantly in SK1 and SK2 group at the 1th hour(1 h), 6 h, 12 h, 24 h, and 48 h after surgery (P < 0.05), and the PCIA button pressed times were also significantly reduced in SK1 and SK2 group (P < 0.05) during the postoperative 48 h. Furthermore, the SK1 and SK2 group showed the lower dosage of remifentanil during the surgery(P < 0.05). However, the postoperative adverse effects had no statistical differences among the three groups. The combined intraoperative and postoperative administration of esketamine was effective in alleviating postoperative depression and pain, without increasing adverse effects in patients undergoing laparoscopic total hysterectomy. Moreover, the 0.5 mg/kg dosage intraoperatively may have the better alleviation property of depression-related indicators. The study was registered with the Chinese Clinical Trial Registry at www.chictr.org.cn (registration date: October 31, 2022; registration number: ChiCTR2200065198). Show less
Xiaokun Li, Zhiheng Rao, Wenhao Hu+2 more · 2025 · Obesity reviews : an official journal of the International Association for the Study of Obesity · Blackwell Publishing · added 2026-04-24
Metabolic dysfunction-associated steatohepatitis (MASH) is a condition characterized by hepatosteatosis, inflammation, and tissue damage, with steatosis as the initial stage, which involves chronic, e Show more
Metabolic dysfunction-associated steatohepatitis (MASH) is a condition characterized by hepatosteatosis, inflammation, and tissue damage, with steatosis as the initial stage, which involves chronic, excess deposition of lipids in hepatic lipid droplets. Despite the growing prevalence and serious risks it poses, including liver decompensation, the need for transplantation, and increased patient mortality, MASH currently faces no approved pharmacotherapy. Several promising treatment candidates have emerged from recent clinical trials, including analogs of FGF21 and agonists of the associated FGFR1-KLB complex. These agents were well-tolerated in trials and have demonstrated significant improvements in both histological and biochemical markers of liver fat content, inflammation, injury, and fibrosis in patients with MASH. Endocrine FGF21 plays a vital role in maintaining homeostasis of lipid, glucose, and energy metabolism. It achieves this through pathways that target lipids or lipid droplets in adipocytes and hepatocytes. Mechanistically, pharmacological FGF21 acts as a potent catabolic factor to promote lipid or lipid droplet lipolysis, fatty acid oxidation, mitochondrial catabolic flux, and heat-dissipating energy expenditure, leading to effective clearance of hepatic and systemic gluco-lipotoxicity and inflammatory stress, thereby preventing obesity, diabetes, and MASH pathologies. In this review, we aim to provide an update on the outcomes of clinical trials for several FGF21 mimetics. We compare these outcomes with preclinical studies and offer a lipid-centric perspective on the mechanisms underlying the clinical benefits of these agents for MASH. 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
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
Giuliana Ascone, Rajdeep Kaur, Arwaa Mehran+14 more · 2025 · bioRxiv : the preprint server for biology · Cold Spring Harbor Laboratory · added 2026-04-24
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
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
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
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
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
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
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strat Show more
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. 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
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
This study investigated the effects of dietary carbohydrate levels on growth performance, body composition, and hepatic expression of metabolic genes in Chinese hook snout carp (
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
Traditional approaches to assessing sleep quality in clinical nurses often overlook population heterogeneity and the complex interplay of influencing factors. This study employs Latent Profile Analysi Show more
Traditional approaches to assessing sleep quality in clinical nurses often overlook population heterogeneity and the complex interplay of influencing factors. This study employs Latent Profile Analysis (LPA) and Association Rule Mining (ARM) to identify distinct sleep quality subgroups and uncover key factor combinations, thereby informing targeted intervention strategies. A total of 1,686 nurses from 123 hospitals in Shandong Province were recruited through multistage stratified sampling. LPA was used to classify participants based on seven sleep dimensions from the Pittsburgh Sleep Quality Index (PSQI), while ARM was applied to identify frequent itemsets of sleep disorder triggers. Key influencing factors were further examined using univariate analysis and multivariate logistic regression. Three latent sleep profiles were identified: high (63.11%), moderate (34.10%), and low (2.79%) sleep quality. The low-sleep subgroup was characterized by higher proportions of being unmarried/divorced (42.55%), low monthly income (≤ 3,000 CNY, 42.55%), non-permanent employment (76.60%), and severe psychological distress (44.68%). In contrast, the high-sleep subgroup featured higher rates of being married (85.62%), moderate income (3,001–7,000 CNY, 73.03%), and low psychological distress (51.32%). Key determinants included marital status (OR = 2.153/2.252), income (OR = 9.098), employment type (OR = 1.475), and psychological state (OR = 0.060–0.555). ARM revealed distinct risk combinations: “low income + non-permanent employment” (lift = 3.895) for the low-sleep group; “married + moderate income + non-permanent employment + patient conflict” for the moderate group; and “high income + low psychological distress” buffering night-shift effects in the high-sleep group. By integrating LPA and ARM, this study reveals the multidimensional heterogeneity and interactive mechanisms underlying clinical nurses’ sleep quality. The findings support a stratified intervention framework combining institutional safeguards with precision strategies to enhance sleep health management in nursing populations. Show less
Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) is a neuronal system-specific transmembrane protein that is highly expressed in the brains o Show more
Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) is a neuronal system-specific transmembrane protein that is highly expressed in the brains of patients with Alzheimer's disease (AD), and our previous findings showed that LINGO-1 antagonism can improve cognitive function and protect hippocampal GABAergic interneurons in AD model mice. However, the specific mechanism underlying these effects is not clear. In this study, an adeno-associated virus (AAV) was used to directly interfere with hippocampal LINGO-1 in vivo, and LINGO-1 antagonists, cannabinoid type 1 receptor (CB1R) agonists, and CB1R antagonists were used to treat mouse hippocampal neurons (HT22 neurons) in vitro. We found that overexpressing hippocampal LINGO-1 in normal young mice impaired spatial learning and memory and reduced hippocampal CB1R protein levels, whereas silencing hippocampal LINGO-1 in AD model mice had the opposite effect. Additionally, antagonizing LINGO-1 increased CB1R/tyrosine kinase receptor B (TrkB) signalling and rescued CB1R- rich cholecystokinin-GABAergic (CCK-GABAergic) interneurons in HT22 neurons transduced with an APP/PS1-expressing virus. Competitive inhibition of LINGO-1 and CB1R was observed, and antagonizing LINGO-1 reversed the changes in HT22 neurons caused by the inhibition of CB1R, such as the decreases in the protein levels of doublecortin (DCX), TrkB, and phosphorylated TrkB (p-TrkB). These findings provide an important scientific basis for further exploration of the mechanism by which LINGO-1 regulates cognitive function and hippocampal GABAergic interneurons in AD model mice. 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
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
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether c Show more
Renal clear cell carcinoma (RCC) is the most common type of kidney cancer, and its relationship with kidney fibrosis and inflammatory responses has attracted considerable attention. However, whether causal relationships exist among these associations remains unclear, as traditional observational studies are susceptible to confounding factors. To evaluate causal relationships between kidney cancer, kidney fibrosis, and inflammatory factors using Mendelian randomization, and explore tumor microenvironment heterogeneity through single-cell analysis. Based on large-scale GWAS data, bidirectional Mendelian randomization analysis was performed to assess causal relationships between kidney cancer and kidney fibrosis, using MR Egger, inverse variance weighted (IVW), and weighted mode methods. Causal associations between kidney cancer and inflammatory factors including Axin-1, C-C motif chemokine 28, and interleukin-10 receptor subunit were analyzed. Single-cell RNA sequencing data from the GEO database (GSM4819725) was integrated for tumor microenvironment analysis. Bidirectional Mendelian randomization analysis revealed no significant causal relationship between kidney cancer and kidney fibrosis [kidney cancer→kidney fibrosis: IVW OR=0.992(95%CI: 0.913-1.077, P=0.842); kidney fibrosis→kidney cancer: IVW OR=0.922(95%CI: 0.824-1.030, P=0.151)]. However, significant positive causal associations were identified between kidney cancer and multiple inflammatory factors: Axin-1 levels [OR=1.448(95%CI: 1.107-1.894, P=0.007)], C-C motif chemokine 28 [OR=1.287(95%CI: 1.076-1.540, P=0.006)], and interleukin-10 receptor subunit [OR=1.135(95%CI: 1.032-1.248, P=0.009)]. Sensitivity analyses confirmed the robustness of results. Single-cell analysis revealed cellular heterogeneity in the tumor microenvironment, including various cell types such as immune cells, T cells, and NK cells, with pseudotime analysis demonstrating cell differentiation trajectories and dynamic gene expression changes. Mendelian randomization analysis provides genetic evidence for causal relationships between kidney cancer and inflammatory factors, while excluding direct causal associations between kidney cancer and kidney fibrosis. Show less
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
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
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that are widely found in organisms and play an important regulatory role in various biological processes, especially immune and infla Show more
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that are widely found in organisms and play an important regulatory role in various biological processes, especially immune and inflammatory responses. However, the function of miR-320b in the inflammatory responses of bovine mammary epithelial cells (bMECs) remains to be elucidated. In this study, we examined the miR-320b mimic transduction group (miR-320b_mimic) and negative control mimic transduction group (NC_mimic) of lipopolysaccharide-treated bMECs using data-independent acquisition (DIA) proteomics and untargeted metabolomics. Subsequently, we performed a joint analysis of the sequencing data. Proteomic analysis identified 330 differentially abundant proteins (DAPs) primarily related to PPAR, ferroptosis, arachidonic acid metabolism, IL-17, and complement and coagulation cascades. Metabolome analysis identified 128 and 66 differentially accumulated metabolites (DAMs) in the positive and negative ion mode primarily involved in linoleic acid metabolism, cholesterol metabolism, AMPK, MAPK, and chemokine. Integrated metabolomics and proteomics analysis revealed the co-enrichment of DAPs and DAMs in choline metabolism in cancer, endocrine resistance, glycerophospholipid metabolism, primary bile acid biosynthesis, and the ferroptosis signaling pathways. The results of quantitative real-time PCR (RT-qPCR) showed that compared with the NC_mimic group, mRNA expression levels of COX-2, IL-12 A, iNOS, MAPK1, and MAPK14 genes were significantly down-regulated, and the mRNA expression levels of PPARγ, CEBPα, CEBPβ, FABP4, and LPL genes were significantly up-regulated in the miR-320b_mimic group. These results provide crucial insights into the molecular regulatory functions of miR-320b and offer valuable data for further research on molecular breeding aimed at enhancing mastitis resistance in bovine animals. 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
Intensive aquaculture frequently utilizes high-fat diets (HF) as a cost-effective strategy, yet this practice often induces hepatic steatosis, oxidative stress, and chronic inflammation in carnivorous Show more
Intensive aquaculture frequently utilizes high-fat diets (HF) as a cost-effective strategy, yet this practice often induces hepatic steatosis, oxidative stress, and chronic inflammation in carnivorous fish. Betaine, a natural methyl donor, has shown potential as a functional feed additive, but its comprehensive protective mechanisms under HF stress remain to be fully elucidated. Juvenile largemouth bass (Micropterus salmoides) were fed one of four isonitrogenous diets for 8 weeks: a normal-fat control (Control), a high-fat diet (HF), and two high-fat diets supplemented with 0.5% (HFB0.5) or 1.0% (HFB1) betaine. Growth performance, digestive enzyme activities, serum biochemical parameters, hepatic antioxidant capacity, and the expression of genes related to antioxidant defense, lipid metabolism, and inflammation were analyzed. The HF group exhibited significantly impaired growth, digestive function, and antioxidant capacity, along with elevated lipid peroxidation, dyslipidemia, and pro-inflammatory cytokine expression. Betaine supplementation restored growth performance and feed efficiency to control levels, ameliorated digestive enzyme activities (particularly enhancing lipase), and activated the hepatic Nrf2-Keap1 pathway, upregulating antioxidant genes (nrf2, sod1, cat, gpx, ho-1, gr) and enhancing enzyme activities. Betaine also improved serum lipid profiles, upregulated genes related to fatty acid oxidation (pparα, cpt-1) and lipolysis (lpl, hsl), suppressed lipogenic genes (srebp-1, fas), and rebalanced inflammatory cytokines by reducing tnf-α and il-1β while increasing tgf-β1 and il-10. Dietary betaine effectively counteracts HF-induced metabolic stress in M. salmoides through coordinated multi-pathway regulation. It enhances antioxidant defense, reprograms hepatic lipid metabolism toward catabolism, and restores inflammatory homeostasis. These findings underscore betaine's role as a multi-functional feed additive capable of mitigating HF-related metabolic disorders and promoting overall health in carnivorous fish aquaculture. Show less
Neonatal piglets possess lysosome-rich foetal-type enterocytes that facilitate uptake and intracellular processing of maternally provided nutrients. However, the role of lysosomes in early-life growth Show more
Neonatal piglets possess lysosome-rich foetal-type enterocytes that facilitate uptake and intracellular processing of maternally provided nutrients. However, the role of lysosomes in early-life growth and intestinal maturation remains unclear. Therefore, this study was conducted to determine the role of lysosomes in the development of neonatal intestine in piglets. For 1-day-old neonatal piglets, a total of 12 piglets (Duroc Ă— (Landrace Ă— Large Yorkshire)) were divided into 2 groups using a split-litter design. To initiate malfunction in lysosomes, newborn piglets were subjected to oral gavage with imipramine (25Â mg/kg bodyweight) once daily for 7 days. For 21-day-old piglets, a total of 12 piglets were divided into two groups, and each group received the same treatment as described above. Piglets receiving imipramine demonstrated significantly stunted growth at 7 days of age, but not at 27 days. By postnatal day 7, the foetal-type enterocytes of untreated piglets were restricted in the mid to upper ileal villus and contained several large lysosomal vacuoles. In contrast, marked changes in ileal morphological and histological structure were observed following imipramine treatment, as evidenced by reduced degree of vacuolation, decreased lysosomal count, as well as pronounced mitochondrial swelling; however, no vacuolated enterocytes were found in 27-day-old piglets. Furthermore, signaling pathways associated with lipid transport and metabolism were significantly enriched, and the related hub genes were identified by bioinformatic analysis after imipramine administration. These findings were further confirmed by biochemical analysis demonstrating that serum levels of total cholesterol (TC) and apolipoprotein A1 (ApoA1) were significantly increased while serum ApoB was decreased in 7-day-old piglets receiving imipramine treatment. Additionally, there was an opposite trend in levels of ApoA1and ApoB in ileal mucosa compared to serum. These results demonstrate that lysosome dysfunction induced by imipramine resulted in significant growth retardation, pronounced morphological and ultrastructural alterations in ileal enterocytes, along with disrupted lipid metabolism in early postnatal piglets; however, no such effect was observed in 27-day-old piglets. These findings enhance understanding of lysosomal functions and intestinal maturation in neonatal piglets. Show less