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
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediat Show more
Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE ε4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The People’s Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (ε2, ε3, and ε4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count × neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with ε3 as the reference. The frequencies of APOE alleles ɛ3, ɛ2, and ɛ4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in ɛ2 carriers than in ɛ3 (373.74*10⁹/L vs. 403.53*10⁹/L, APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses. 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
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
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
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
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
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
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder Show more
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts' analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. 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
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
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
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
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
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
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
Coronary heart disease (CHD) has a significant co-morbid association with chronic kidney disease (CKD), but identification tools for the risk of concomitant CKD in patients with CHD are still lacking. Show more
Coronary heart disease (CHD) has a significant co-morbid association with chronic kidney disease (CKD), but identification tools for the risk of concomitant CKD in patients with CHD are still lacking. The purpose of this research was to construct machine learning (ML) models for identifying undetected CKD in CHD patients. 1786 CHD patients undergoing coronary intervention were retrospectively included. Lasso regression and multifactor logistic regression were used to screen feature variables. Five ML models, ie, logistic regression (LR), support vector machine (SVM), random forest (RF), gradient boosting machine (GBM), and extreme gradient boosting (XGBoost), were constructed. Participants were divided into the training set and validation set in a 7:3 ratio. The evaluation metrics included the area under the curve, calibration curve, and decision curve. Totally, 1786 CHD patients were enrolled and split into training (70%) and validation (30%) sets. The prevalence of CKD was 21.8% (390/1786). Multivariate logistic regression analysis showed that men, advanced age, hypertension, diabetes mellitus, history of atrial fibrillation (AF), high Gensini, low hemoglobin, low plateletcrit (PCT), high triglycerides (TG), high lipoprotein(a) (Lp(a)), hyperkalemia, high uric acid to albumin ratio (UAR), high systemic inflammation response index (SIRI), low lymphocyte to monocyte ratio (LMR), and high apolipoprotein B to apolipoprotein A1 (ApoB/ApoA1) ratio were the key clinical and laboratory test indicators of CKD. The XGBoost model performed optimally in the validation set (AUC=0.909, 95% CI 0.881 -0.937). SHapley Additive explanation analysis identified UAR, hypertension, Gensini score, age, and SIRI as the top 5 key features. The XGBoost model constructed on routine clinical data was effective in identifying CKD risk in CHD patients, with UAR as a novel strong predictor. Decision curve analysis confirmed the clinical utility of the model, indicating that it may be used to guide decisions for enhanced monitoring and early intervention over a wide range of risk thresholds. 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 investigated the effects of dietary carbohydrate levels on growth performance, body composition, and hepatic expression of metabolic genes in Chinese hook snout carp (
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
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
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
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
William Stewart, Bin Hu, Fengqiao Li+6 more · 2025 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabete Show more
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (mIL-27) to coactivate PGC-1α, PPARα, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (siDPP-4) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1α, PPARα, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1 % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of siDPP-4 and mIL-27. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction. 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
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
Regulating strategies for long persistent luminescence (LPL) are always in high demand. Herein, a series of coordination polymers (CPs) (SUST-Z1-Z4) are fabricated using 1,10-phenanthroline derivative Show more
Regulating strategies for long persistent luminescence (LPL) are always in high demand. Herein, a series of coordination polymers (CPs) (SUST-Z1-Z4) are fabricated using 1,10-phenanthroline derivatives involving different substituents (─H, ─CH Show less