👤 Chenlin Xiu

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

Diabetes constitutes a risk factor for cognitive impairment, whereas insulin resistance serves as the shared pathogenesis underlying both diabetes and cognitive decline. The use of metformin for treating cognitive impairment remains controversial. The present study found that hesperetin, a flavanone derived from citrus peel, enhanced metformin's efficacy in reducing blood sugar levels, improving insulin sensitivity, and ameliorating cognitive impairment in diabetic rats. Additionally, it reduced the required dosage of metformin to one-third of its conventional dose. Transcriptome analysis and 16S rRNA sequencing revealed that the activation of insulin and cyclic-adenosine monophosphate response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathways benefited from the regulation of gut microbiota and the promotion of short-chain fatty acid (SCFA) producers such as Show less

SANET-ep (NCT02588170) and SANET-p (NCT02589821) demonstrated the efficacy and safety of surufatinib versus placebo in patients with advanced extra-pancreatic and pancreatic neuroendocrine tumours (NETs). Here, we present a pooled analysis of final overall survival (OS) from two randomised phase 3 studies. The SANET studies were randomised, placebo-controlled, double-blind, phase 3 studies in China, comparing the efficacy and safety of oral 300-mg surufatinib (n = 265) versus placebo (n = 133) in patients with unresectable/metastatic, well-differentiated NETs (grade 1/2). After progression of disease or study unblinding, patients receiving placebo crossed over/switched to open-label surufatinib. By pooling the data from the two studies, OS analysis was completed using Kaplan-Meier methodology and a Cox proportional hazards model in the intention-to-treat population. Exploratory analyses were performed using different models to correct the confounding effect introduced by crossover. Long-term safety was assessed. At study termination, 69 % of the placebo group had crossed over/switched to surufatinib. Median OS was 50.1 versus 46.8 months for patients initially on surufatinib versus those initially on placebo (stratified hazard ratio [HR] 0.935, 95 % confidence interval [CI] 0.684-1.278; p = 0.6727). After correcting the confounding effect introduced by crossover/switching, the HR ranged from 0.558 to 0.825. Commonly (≥10 %) reported treatment-related adverse events (grade 3/4) included hypertension and proteinuria. OS of patients initially on surufatinib was not significantly longer versus patients initially on placebo, likely due to the high amount of crossover from placebo to surufatinib. No new safety signals were observed. SANET-ep (NCT02588170) and SANET-p (NCT02589821). Show less

Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10 This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy. Show less

Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect quality of life. Although these conditions frequently co-occur, their heterogeneity remains poorly understood. This study integrates the Health Ecology Model (HEM) and employs Latent Profile Analysis (LPA) to identify distinct psychological profiles of depression and anxiety among patients with acute ischemic stroke (AIS), as well as to investigate their multilevel determinants. Patients with AIS from a tertiary hospital in Guangdong Province, China, from January to November 2024 were included. Within one week of stroke onset, the data of sociodemographic, clinical characteristics, swallowing function, stroke severity, activities of daily living, resilience and social support were collected according to the HEM guidelines. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess the depression and anxiety symptoms of the patients three months after stroke onset. LPA was employed to identify distinct psychological profiles, and variables with a A total of 551 patients with AIS were included in the study, 49 were lost to follow-up or withdrew, resulting in a final analytic sample of 502 participants (91.11%). Three distinct psychological profiles were identified: no depression-anxiety (67.93%), high-risk depression-anxiety (21.12%) and major depression-anxiety (10.95%). In the multivariate analysis, the results indicated that occupation (OR = 0.61, 95% CI [0.40-0.93]), National Institutes of Health Stroke Scale (NIHSS, OR = 1.60, 95% CI [1.06-2.42]), Barthel Index (BI, OR = 1.67, 95% CI [1.27-2.19]) and hypertension (OR = 2.37, 95% CI [1.29-4.35]) were independent predictors of the high-risk depression-anxiety profile, while NIHSS (OR = 2.33, 95% CI [1.42-3.85]), BI (OR = 2.65, 95% CI [1.62-4.35]) and resilience (OR = 0.92, 95% CI [0.87-0.98]) were significantly associated with the major depression-anxiety profile. This study reveals significant heterogeneity in psychological distress among AIS survivors. Key predictors of post-stroke emotional comorbidity include occupation, hypertension, stroke severity, activities of daily living and low resilience. Early identification of high-risk individuals can significantly enhance screening and intervention strategies, particularly by focusing on symptoms such as anhedonia and nervousness. Future research should focus on longitudinal designs and objective biomarkers to better understand the mechanisms behind post-stroke emotional comorbidity. Show less

Methylglyoxal-induced ROS elevation is the primary cause of neuronal damage. Metformin is a traditional hypoglycemic drug that has been reported to be beneficial to the nervous system. In this study, flavonoids were found to enhance the protective effect of metformin when added at a molar concentration of 0.5%. The structure-activity relationship (SAR) analysis indicated that ortho- substitution in the B ring, and the absence of double bonds between the 2 and 3 position combined with the gallate substitution with R configuration at the 3 position in the C ring played crucial roles in the synergistic effects, which could be beneficial for designing a combination of the compounds. Additionally, the mechanism study revealed that a typical flavonoid, EGCG, enhanced ROS scavenging and anti-apoptotic ability via the BCL2/Bax/Cyto C/Caspase-3 pathway, and synergistically inhibited the expression of GSK-3β, BACE-1, and APP in PC-12 cells when used in combination with metformin. The dose of metformin used in the combination was only 1/4 of the conventional dose when used alone. These results suggested that ROS-mediated apoptosis and the pathways related to amyloid plaques (Aβ) formation can be the targets for the synergistic neuroprotective effects of flavonoids and metformin. Show less

The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. This study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size. Show less

Ferroptosis is an important mode of regulated cell death (RCD). Its inhibition is closely related to therapeutic resistance and poor prognosis in hepatocellular carcinoma (HCC). Previous reports have demonstrated ferroptosis as a biological process highly dependent on selective autophagy, such as ferritinophagy, lipophagy, and clockophagy. Our study also revealed a role for ER-phagy-mediated ferroptosis in HCC cells treated with multi-targeted tyrosine kinase inhibitors (TKIs). In the current study, we found that the homologous circular RNA (circRNA) of the family with sequence similarity 134, member B ( Show less

Ovarian cancer (OC) is the most lethal gynaecological tumor. Changes in glycolysis have been proven to play an important role in OC progression. We aimed to identify a novel glycolysis-related gene signature to better predict the prognosis of patients with OC. mRNA and clinical data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Genotype Tissue Expression (GTEx) database. The "limma" R package was used to identify glycolysis-related differentially expressed genes (DEGs). Then, a multivariate Cox proportional regression model and survival analysis were used to develop a glycolysis-related gene signature. Furthermore, the TCGA training set was divided into two internal test sets for validation, while the ICGC dataset was used as an external test set. A nomogram was constructed in the training set, and the relative proportions of 22 types of tumor-infiltrating immune cells were evaluated using the "CIBERSORT" R package. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined by single-sample gene set enrichment analysis (ssGSEA) with the "GSVA" R package. Finally, the expression and function of the unreported signature genes ISG20 and SEH1L were explored using immunohistochemistry, western blotting, qRT-PCR, proliferation, migration, invasion and xenograft tumor assays. A five-gene signature comprising ANGPTL4, PYGB, ISG20, SEH1L and IRS2 was constructed. This signature could predict prognosis independent of clinical factors. A nomogram incorporating the signature and three clinical features was constructed, and the calibration plot suggested that the nomogram could accurately predict the survival rate. According to ssGSEA, the signature was associated with KEGG pathways related to axon guidance, mTOR signalling, tight junctions, etc. The proportions of tumor-infiltrating immune cells differed significantly between the high-risk group and the low-risk group. The expression levels of ISG20 and SEH1L were lower in tumor tissues than in normal tissues. Overexpression of ISG20 or SEH1L suppressed the proliferation, migration and invasion of Caov3 cells in vitro and the growth of xenograft tumors in vivo. Five glycolysis-related genes were identified and incorporated into a novel risk signature that can effectively assess the prognosis and guide the treatment of OC patients. Show less

Gastric cancer is still among the leading causes of cancer deaths worldwide. Despite the improvements in diagnostic methods, the status of early detection has not been achieved so far. Early diagnosis of gastric cancer may significantly improve the cure rate of patients. Therefore, a new diagnostic method is needed. In this study, subtractive SELEX was performed to screen gastric cancer serum-specific DNA aptamers by using gastric cancer serum and normal serum as the target and negative serum, respectively. Four highly specific aptamers generated for gastric cancer serum, Seq-3, Seq-6, Seq-19 and Seq-54, were developed using whole-serum subtractive SELEX technology with Show less

Bactericidal permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) play important roles in host antimicrobial defense. In the present study, we identified one isoform of BPI/LBP gene from turbot (Scophthalmus maximus), designated as SmBPI/LBP1. The full-length cDNA sequence of SmBPI/LBP1 was 1826 bp, which encoding one secreted protein with 480 amino acid residues. Structurally, the SmBPI/LBP1 showed high similarity to its homologs from other vertebrates or invertebrates, which all contained a signal peptide, a BPI/LBP/CETP N-terminal with a LPS-binding domain, and a BPI/LBP/CETP C-terminal domain. The deduced amino acid sequences of SmBPI/LBP1 shared significant similarity to BPI/LBP of Seriola lalandi dorsalis (71%) and Paralichthys olivaceus (69%). Phylogentic analysis further supported that SmBPI/LBP1 act as a new member of vertebrate BPI/LBP family. SmBPI/LBP1 was ubiquitously expressed in all tested tissues, with the highest expression level in spleen tissue. The mRNA expression of SmBPI/LBP1 in spleen and kidney were significantly up-regulated after Vibrio vulnificus challenge. Finally, the recombinant SmBPI/LBP1 showed high affinity to lipopolysaccharide, followed by peptidoglycan and lipoteichoic acid, which is the ubiquitous component of Gram-negative or Gram-positive bacteria. These results indicated that SmBPI/LBP1 probably played important roles in immune response against bacteria infection. Show less

Branched-chain amino acids catabolism plays an important role in human cancers. Colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, and the new global incidence is over 1.2 million cases. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a rate-limiting enzyme in branched-chain amino acids catabolism, which plays an important role in many serious human diseases. Here we investigated that abnormal branched-chain amino acids catabolism in colorectal cancer is a result of the disease process, with no role in disease initiation; BCKDK is widely expressed in colorectal cancer patients, and those patients that express higher levels of BCKDK have shorter survival times than those with lower levels; BCKDK promotes cell transformation or colorectal cancer ex vivo or in vivo. Mechanistically, BCKDK promotes colorectal cancer by enhancing the MAPK signaling pathway through direct MEK phosphorylation, rather than by branched-chain amino acids catabolism. And the process above could be inhibited by a BCKDK inhibitor, phenyl butyrate. Show less