👤 Yue He

Tail fat deposition constitutes a distinctive adaptive phenotype in sheep. The Large-tailed Han (LTH) and Small-tailed Han (STH) breeds display pronounced divergence in tail fat storage, offering an ideal model for elucidating lipid metabolism regulation. Integrated sRNA-Seq and RNA-Seq analysis identified 521 differentially expressed genes and 144 miRNAs, which were significantly enriched in lipid metabolism pathways, including fatty acid metabolism and PPAR signaling. Key candidate genes ( Show less

Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge this gap, yet its immune system has not been comprehensively characterised at single-cell resolution. Here, we present a single-cell transcriptomic atlas of the tree shrew immune system, profiling 39 cell types across 12 tissues. We uncover human-like tonsillar structures and two transcriptionally distinct splenic macrophage subsets: an NR1H3 Show less

Hepatic intercellular communication is the driving force for the progression of chronic Hepatitis B virus (CHB)-associated hepatopathologies, with the dynamic molecular mechanisms largely unknown. Combining scRNA-seq and spatial transcriptomic analysis, the kinetic landscape of the liver microenvironment across time and space in AAV-HBV mice, which develop from inflammation to ultimately hepatocellular carcinoma is generated. Kupffer cells (KCs), originally resided within the peri-portal area, are persistently recruited to the HBV-enriched peri-central region via increased CXCL9 produced by endothelial cells, facilitating the interaction between KCs and HBV Show less

This study was designed to investigate the primary targets and possible mechanisms of ranitidine (Ra) against diabetic retinopathy (DR). Single-cell sequencing technology and the SPIED3 platform were employed to characterize key genes in retinal Müller cells (RMCs) of diabetic mice and identify potential small-molecule compounds separately. The effects of small-molecule compounds on the cell viability and proliferative capacity of mouse retinal Müller cells (rMC-1) cultured in high-glucose (HG) were evaluated using the cell counting kit-8 (cck-8) and 5-ethyl-2-deoxyuridine (Edu) assay. Glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS), and Fe2+ were identified as indicators of ferroptosis. Then, network pharmacology was used to predict specific targets for Ra. Western blotting was used to identify ferroptosis-related proteins, including glutathione peroxidase 4 (GPX4), cystine/glutamate transporter (xCT), serine/threonine-protein kinase AKT1, and glycogen synthase kinase-3β (GSK3β). The predicted results suggested that the potential mechanism of RMCs damage in diabetic mice is associated with ferroptosis. The cck-8 results indicated Ra played a regulatory role in HG-induced rMC-1 by enhancing cell viability. Besides, Edu results showed that Ra promoted the proliferation of rMC-1 cells. Network pharmacological analyses predicted a potential mechanism of Ra effect in HG-induced rMC-1, mainly associated with the AKT1 and GSK3β genes. Phenotypically, Ra elevated intracellular GSH levels, while reducing MDA, Fe²⁺, and ROS concentrations. Mechanistically, Ra increased xCT and GPX4 expression through the promotion of AKT1/GSK3β phosphorylation, thereby alleviating ferroptosis in HG-induced rMC-1 cells. The study highlighted that the mechanism of DR is closely associated with ferroptosis and demonstrated that Ra inhibits HG-induced ferroptosis of rMC-1 cells by regulating the AKT1/GSK3β signaling pathway, thereby providing a theoretical basis for using Ra in managing DR. Show less

Wilms tumor (WT), the most common pediatric malignant renal tumor, shows high recurrence in high-risk subtypes due to chemoresistance. Tumor microenvironment (TME) remodeling, particularly M2-type tumor-associated macrophages (TAMs), contributes to chemoresistance, but underlying mechanisms remain unclear. This study explored TME-related chemoresistance mechanisms in WT and developed targeted therapeutic strategies. Clinical WT samples were analyzed for M2-type TAMs infiltration and SNRPC expression. Bioinformatics analysis of TARGET-WT data identified M2-associated genes. In vitro experiments (cell transfection, qRT-PCR, Western blot, co-culture, ChIP and dual-luciferase reporter assays) explored SNRPC’s role in regulating M2-type TAMs. Animal models (orthotopic tumor and lung metastasis) verified in vivo effects. A hybrid exosome nanosystem (DOX/siSNRPC@hEVs) was constructed and evaluated for efficacy and safety. Statistical analyses included t-test, ANOVA, and survival analysis. M2-type TAMs (CD68⁺CD163⁺) infiltration was higher in chemoresistant WT and associated with poor prognosis. SNRPC was overexpressed in chemoresistant WT, correlated with M2-type TAMs, and promoted tumor malignancy and M2-type TAMs polarization. Mechanistically, SNRPC activated NF-κB signaling, inducing CXCL17 upregulation to recruit M2-type TAMs, with partial CXCL17 release via migrasomes. DOX/siSNRPC@hEVs showed high targeting, reduced toxicity, inhibited tumor growth/metastasis, and reversed chemoresistance by reducing M2-type TAMs. The SNRPC-NF-κB-CXCL17-M2 TAMs axis drives WT chemoresistance. DOX/siSNRPC@hEVs effectively targets this axis, providing a novel strategy for high-risk WT. [Image: see text] The online version contains supplementary material available at 10.1186/s13046-026-03680-z. Show less

Focal damage to articular cartilage incurred during joint injuries frequently progresses to post-traumatic osteoarthritis (PTOA) due to the limited intrinsic repair capacity of cartilage. Chondrogenic progenitor cells (CPCs) residing within the cartilage can contribute to repair if effectively recruited and activated. Early interventions that enhance CPC homing and their subsequent chondrogenesis offer a regenerative strategy to prevent PTOA progression, addressing the current lack of effective early clinical therapies. GDF5 stands out as a key protein involved in cartilage development, yet its potential to mobilize CPC-mediated regeneration remains underexplored. We evaluated the effects of GDF5 on CPC migration, proliferation, chondrogenic differentiation, and anti-catabolic activity using in vitro CPC models. To assess CPC chemotaxis in a clinically relevant biomaterial context, GDF5 was incorporated into a hyaluronic acid/fibrin interpenetrating network (IPN) hydrogel and tested in an ex vivo cartilage defect model. GDF5 acted as a potent chemoattractant for CPCs, promoting their recruitment toward cartilage defects when delivered via a hyaluronic acid/fibrin IPN hydrogel in an ex vivo model. GDF5 also enhanced CPC proliferation, consistent with activation of a glycolysis-associated transcriptional program. In addition, GDF5 significantly upregulated chondrogenic markers, including SOX9, COL2a1, and ACAN, and elevated extracellular matrix components in CPCs, potentially through activation of the PI3K/AKT signaling pathway. Furthermore, GDF5 reduced expression of a key catabolic enzyme ADAMTS5, possibly through the WWP2/miR-140 axis. These findings highlight the versatile role of GDF5 on endogenous CPCs. When combined with a hydrogel platform, GDF5 may serve as an early therapeutic strategy to convert injured cartilage from a passive site of degeneration into one of active regeneration. Show less

This study aimed to investigate the therapeutic effects of minocycline on neuropathic pain by examining its regulatory influence on hippocampal proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels, given the established involvement of neuroinflammation and BDNF dysregulation in the pathogenesis of neuropathic pain and associated neurological dysfunctions. This study used a rat model of neuropathic pain induced by L5 spinal nerve transection (L5-SNT). Forty-eight male Sprague-Dawley rats were divided into four groups: naive, sham-operated, model + saline, and model + minocycline. Minocycline was administered intraperitoneally at 40 mg/kg daily. Mechanical allodynia was assessed using the von Frey test, while real-time reverse transcription and ELISA were employed to quantify hippocampal expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and BDNF at various time points postsurgery. L5-SNT induced significant mechanical allodynia in the model + saline group, which was significantly attenuated by minocycline treatment in the model + minocycline group on days 3, 7, and 11 postsurgery (P < 0.05). Minocycline significantly reduced TNF-α, IL-6, and BDNF levels in the hippocampus, particularly on day 7 post-SNT (P < 0.05); however, minocycline did not significantly affect IL-1β levels. These findings suggest that minocycline's analgesic effects may be mediated through the downregulation of key proinflammatory cytokines and BDNF in the hippocampus. Minocycline administration significantly mitigates mechanical allodynia and modulates hippocampal neuroinflammatory markers in a rat model of neuropathic pain. These results highlight minocycline's potential as a therapeutic option for neuropathic pain, particularly in targeting neuroinflammation within the hippocampus. Show less

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) ameliorate motor deficits in cerebral palsy (CP), but the effect of injection frequency remains unclear. Moreover, most studies have focused on mild CP models (unilateral carotid artery occlusion [UCAO] model). This study explored the effect and mechanism of hUC-MSCs in a rat model of moderate-to-severe CP (bilateral carotid artery occlusion [BCAO] model). On postnatal Day 4 (P4), Wistar rat pups underwent BCAO induction. Subsequently, they received either a single intrathecal injection of hUC-MSCs on P21 or repeated injections on P21, P28, P35, and P42. Motor performance was assessed using the rotarod and front-limb suspension tests, while neuronal regeneration and inflammation were evaluated via biomarkers including neuronal nuclear antigen (NeuN), ionized calcium-binding adapter molecule-1 (Iba-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and brain-derived neurotrophic factor (BDNF). P18 model screening confirmed that the BCAO model resulted in more severe brain damage and motor impairment than the UCAO model. After injection of lentivirally transfected hUC-MSCs, it was found that hUC-MSCs could nest in the damaged area and survive for at least 3 days. Administration of hUC-MSCs following BCAO modeling led to notable improvements in both behavioral performance and histological outcomes. Furthermore, repeated injections offered greater therapeutic benefits compared to single injection. It indicated that the efficacy of repeated injections of hUC-MSCs in the treatment of moderate-to-severe CP was superior to that of single injection. Its mechanism was related to the improvement of damaged myelin structure, reduced immunoinflammatory responses, and increased neurotrophic support. Show less

This study aimed to comprehensively evaluate the clinical effectiveness and safety of acupuncture combined with repetitive transcranial magnetic stimulation (rTMS) in treating post-stroke cognitive impairment (PSCI) through meta-analysis and trial sequential analysis (TSA), moreover to provide an evidence-based basis for the treatment of PSCI in clinical practice. The study conducted a comprehensive search of eight major domestic and international databases, including PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP and China Biology Medicine (CBM). Four English and four Chinese databases of randomized controlled trials of acupuncture combined with rTMS for the treatment of PSCI from inception until July 2025. Systematic reviews and meta-analyses were conducted based on the Cochrane systematic review method by using RevMan5.4 and Stata/MP 18.0, and trial sequential analyses were performed by TSA 0.9. Sixteen RCTs involving 1,058 patients were included, including 532 patients in the experimental group and 526 patients in the control group. Meta-analysis results showed that the experimental group had a higher clinical effectiveness rate in treating patients with PSCI compared to the control group [RR = 1.29, 95% CI (1.08, 1.55), Acupuncture combined with rTMS can improve cognitive function, regulate daily living ability, and regulate neurotransmitter levels in patients with PSCI, which is worthy recommended in the clinic. However, due to limitations in sample size, inclusion quality and incomplete reporting, it is worth noting that more rigorously designed and high-quality studies are needed to further validate these conclusions. Show less

Jiaotaiwan (JTW) is a classic traditional Chinese medicine (TCM) prescription for treating depression, but its potential mechanisms are not fully understood. The aim of this study is to detect the levels of serum Short-chain fatty acids (SCFAs) and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP-response element binding protein (CREB)-brain derived neurotrophic factor (BDNF) signaling pathway, further revealing the scientific connotation of the antidepressant effect of JTW. In this multicenter, randomized, controlled study, 120 patients with depression were divided into the JTW (16.5 g/d) group, JTW (16.5 g/d) + selective serotonin reuptake inhibitors (SSRIs) group, and SSRIs group. Hamilton depression Scale-24 (HAMD-24) and Self-rating depression scale (SDS) were used for efficacy evaluation. Enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to evaluate the expression levels of cAMP-PKA-CREB-BDNF signaling pathway. Serum SCFAs concentrations were analyzed using liquid chromatograph-mass spectrometer (LC-MS) targeted metabolomics. After eight weeks of treatment, HAMD score and SDS score were significantly decreased in the three groups, and HAMD score in JTW + SSRIs group was significantly lower than that in SSRIs group. After treatment, the expression levels of cAMP-PKA-CREB-BDNF signaling pathway were significantly increased in the three group, with the JTW + SSRIs group showing more significant increase. After treatment, the levels of isobutyric, butyric, isovaleric, and valeric acids in the JTW + SSRIs groups were significantly higher than that before treatment, and the levels of isobutyric, and isovaleric acids in the JTW + SSRIs group was significantly higher than that in the JTW group and SSRIs groups. JTW can alleviate symptoms in patients with depression, and its antidepressant mechanism may be related to regulating serum SCFAs and cAMP-PKA-CREB-BDNF signaling pathway. Show less

BackgroundCurrent therapeutic strategies for Alzheimer's disease (AD) demonstrate limited efficacy in decelerating disease progression, underscoring an exigent need for the development of more potent disease-modifying therapeutics.ObjectiveThe primary aim of this research was to identify novel therapeutic targets to improve AD prognosis.MethodsFirst, we conducted a meta-analysis of brain tissue transcriptome datasets from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) associated with AD. Next, Mendelian randomization (MR) and summary-based MR (SMR) analyses were utilized to screen for potential AD drug targets. Colocalization analyses were employed to examine whether DNA methylation, gene expression, and AD risk are driven by shared single nucleotide polymorphisms (SNPs). Finally, single-gene gene set enrichment analysis (GSEA), protein-protein interaction (PPI) networks, drug prediction, and molecular docking were employed to infer potential biological mechanisms.ResultsA meta-analysis of twelve brain tissue datasets revealed 262 druggable AD-related DEGs. According to MR analysis, Show less

GLP-1 has become a prime target for medical treatment due to its significant therapeutic efficacy. However, the activation mechanisms of class B1 GPCRs, including glucagon-like peptides (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), remain poorly understood. This study focuses on understanding the activation mechanisms of the GLP-1 receptor (GLP-1R) by investigating its conformational changes from activated/inactivated to inactivated/activated states. By analyzing the dynamic conformational changes of the receptor during activation, a closure-open transition in the extracellular domain (ECD) and a movement trend of the transmembrane helices are observed, which indicates a similarity to the activation mechanism of class A GPCRs. Furthermore, the binding characteristics of a dual agonist Tirzepatide (LY3298176) is studied in detail and it is revealed that the conserved residues contribute in a similar fashion toward binding to both GLP-1R and GIPR. Mutations in non-conserved residues in Tirzepatide affect the binding affinity, with C-terminal mutations weakening the binding affinity toward GLP-1R, while N-terminal mutations enhancing the affinity to GIPR, resulting in a biased binding mode. These findings enriched our fundamental understanding of GLP-1R/GIPR activation and provided theoretical guidance for the design and development of future peptide-based agonists and offer insights into the optimization of other dual or multi-target agonists. Show less

Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers. A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration. A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity. Show less

This study established a polymerase chain reaction-lateral flow dipstick (PCR-LFD) method for the visual detection of SNP genotypes. Targeting the MC4R gene SNP g.732 C > G, highly specific primers were designed for the mutation site, incorporating a Locked Nucleic Acid (LNA) modification at the 3' terminal nucleotide of the SNP, a BIOTIN modification at the 5' end of the upstream primer, and a fluorescein isothiocyanate (FITC) modification at the 5' end of the downstream primer. The detection primers were used for PCR amplification with the sample, and the reaction system was optimized. The amplification products were subsequently detected using LFD. The results demonstrated that the optimized reaction system and modified primers effectively distinguished among CC, CG, and GG genotypes at the g.732 C > G. Blood samples from 24 Hu sheep were analyzed using the PCR-LFD assay specific to this SNP. The genotyping results from PCR-LFD were completely consistent with those obtained from the mutation analysis of the same blood samples. The PCR-LFD method established in this study did not require genomic DNA extraction; whole blood could be directly used as a template for PCR amplification combined with LFD, enabling on-site visual detection. This positions PCR-LFD as a rapid, simple, and visually interpretable tool for on-site SNP genotyping. Show less

Dynamic interactions between genetic predispositions and environmental exposures significantly shape the escalating prevalence of childhood obesity. This systematic review synthesizes observational and clinical trial evidence on the gene-environment interplays influencing childhood obesity, highlighting the role of genetic variants and environmental moderators such as dietary habits, physical activity, sleep durations, parental behaviors, socioeconomic status, ethnicity, gender, as well as lifestyle interventions. We conducted an exhaustive search across 5 databases (Medline, PubMed, EMBASE, Web of Science, and Cochrane Library), adhering to PRISMA guidelines. We ultimately included 147 studies that investigated these interplays in diverse populations. Specifically, 83 studies focused on gene-diet interplays, 23 on gene-physical activity, 5 on sedentary behavior, 3 on screen time, 7 on sleep duration, 10 on parental behavior, 4 on socioeconomic status, 16 on gender, 8 on age, 7 on ethnicity, and 13 on the effects of lifestyle interventions. Notably, we meta-analyzed energy expenditure and macronutrient consumption, including carbohydrates, proteins, and fats, as well as the proportion of energy supplied by each nutrient between carriers and noncarriers of the FTO effect allele, revealing that carriers consumed a higher proportion of fat calories, with no other significant differences noted. This review demonstrates that genetic risk variants, particularly in FTO (e.g., rs9939609) and MC4R (e.g., rs17782313), amplify the adverse effects of obesogenic behaviors, offering insights into the intricate pathophysiology of childhood obesity and suggesting the potential for personalized interventions based on genetic profiles. Show less

Senescence is significantly associated with cancer promotion. This study aimed to characterize senescent cells at the single-cell level in nasopharyngeal carcinoma (NPC) and elucidate the phenotype of tumorigenic senescent cell clusters. The composition of NPC based on the single-cell sequencing dataset GSE150430 from clinical specimens of 15 treatment-naïve patients and one patient with chronic nasopharyngitis were investigated. Using single-cell transcriptomics, we identified the major types of senescent cells in NPC and determined that senescent epithelial C3 cells and SPP1+ macrophages were associated with tumor progression, and expressed unique arrays of pro-tumor surface proteins and senescence-associated secretory phenotype (SASP) factors. SASP is endowed with inflammatory cytokines and chemokines, which involve in the process of 'inflammatory ageing' and tumor progression. Epithelial cell cluster C3 upregulated epithelial-mesenchymal transition (EMT)-related genes associated with tumor metastasis. SPP1+ macrophages displayed a distinct secretome dominated by pro-inflammatory cytokines such as CCL2, CCL8, and IL-6, and were more enriched in glycolytic pathways compared with other subpopulations of macrophages. In particular, the senescent cell population showed higher and stronger intercellular communication compared with the non-senescent cell population. Furthermore, C3 interacted with SPP1+ macrophages through ANGPTL4-SD2. Our findings reveal the important role of senescent cells in the development of NPC, highlighting potential therapeutic pathways and cancer prevention strategies. Show less

Angiopoietin-like 4 (Angptl4) is a secreted protein that participates in multiple biological processes. Our previous study on the effect of Angptl4 in minimal change disease (MCD) unexpectedly indicated a close correlation between Angptl4 and kidney function, especially in MCD patients combined with AKI, implying a possible function of Angptl4 in AKI. However, the role and molecular mechanism of Angptl4 in AKI are undetermined. Biopsy tissue and serum of patients with AKI were analyzed by ELISA and immunohistochemistry to evaluate ANGPTL4 expression and its correlation with kidney function. For in vitro study, ANGPTL4 overexpressed and knocked down HK-2 cells were used to determine the effect of ANGPTL4 on cell pyroptosis. For in vivo study, Angptl4 global and conditional knockout mice were generated to study AKI using cisplatin- or ischemia/reperfusion-induced AKI mouse models. Additionally, we used various experimental approaches to investigate how ANGPTL4 induces tubular cell injury via interaction with integrin β. Angptl4 was up regulated in kidney tubular epithelial cells of multiple AKI models and correlated with kidney function. ANGPTL4 aggravated tumor suppressor GSDME-dependent cell pyroptosis in vitro. In genetic mice, overexpression of Angptl4 worsened kidney function, inflammation, and cell pyroptosis, whereas ablation of Angptl4 attenuated kidney injury in AKI. Mechanistically, ANGPTL4 interacted with integrin β5 and activated focal adhesion kinase (FAK), promoting kidney tubular pyroptosis through the caspase 3/GSDME signaling pathway. Inhibition of integrin β5 or FAK alleviated kidney tubular pyroptosis and kidney dysfunction. Moreover, ANGPTL4 promoted the secretion of cytokines MCP-1 and RANTES by kidney tubular epithelial cells, enhancing macrophage recruitment. Our results reveal that Angptl4 triggers pyroptosis and worsened kidney injury in AKI and offers a potential target for the diagnosis and treatment of AKI. Show less

Hypoglycemia is a commonly neglected complication in elderly diabetic patients, which can lead to cardiovascular events. Endothelial cell dysfunction is the primary inducer of cardiovascular events, and it is associated with hypoglycemia-triggered cytokine release and inflammatory programmed cell death. A comprehensive understanding of lineage-specific variations in pathological vascular changes is essential to mitigate cardiovascular events and ensure therapeutic efficacy. Herein, unbiased clustering analyses and single-nucleus RNA sequencing are performed on cells of the thoracic aorta in db/db and insulin-induced hypoglycemic db/db mice. Comparative analyses show changes in lineage-specific genes, subpopulation composition, intercellular communication, and molecular biology in hypoglycemic diabetic mice. The analyses also revealed the changes of different cells, particularly endothelial cell PANoptosis, macrophage inflammatory polarization, and vascular smooth muscle cell (VSMC) fibrosis. Pseudo-time sequencing, differential expression, and regulation network analyses revealed the association of potential hub genes Klf2, ETS2, Elavl1, C3, and Nr4a1 with the mentioned pathological processes. It is demonstrated that hypoglycemia induces VSMC fibrosis in vivo, whereas Angptl4 knockdown can attenuate VSMC fibrosis in vitro. These findings demonstrate the hypoglycemic macroangiopathy mechanism and provide important references for future disease intervention and treatment. Show less

In this study, we investigated the therapeutic effects and mechanisms of umbilical cord mesenchymal stem cells (UCMSCs) in diabetic nephropathy (DN) ZDF (FA/FA) rats. The therapeutic effects were assessed by renal function tests, the urinary albumin-creatinine ratio, PAS staining, electron microscopy, and TGF- Show less

D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in breast cancer remains largely unexplored. We applied an advanced biosensor approach to detect the D-2HG levels in breast cancer samples. We then investigated the biological functions of D-2HG through multiple in vitro and in vivo assays. A joint MeRIP-seq and RNA-seq strategy was used to identify the target genes regulated by D-2HG-mediated N6-methyladenosine (m We found that D-2HG accumulated in triple-negative breast cancer (TNBC), exerting oncogenic effects both in vitro and in vivo by promoting TNBC cell growth and metastasis. Mechanistically, D-2HG enhanced global m Our study unveils a previously unrecognized role for D-2HG-mediated RNA modification in TNBC progression and targeting the D-2HG/FTO/m Show less

Renal fibrosis is a common pathological process in various chronic kidney diseases. The accumulation of senescent renal tubular epithelial cells (TECs) in renal tissues plays an important role in the development of renal fibrosis. Eliminating senescent TECs has been proven to effectively reduce renal fibrosis. Procyanidin C1 (PCC1) plays a senolytic role by specifically eliminating senescent cells and extending its overall lifespan. However, whether PCC1 can alleviate unilateral ureteral obstruction (UUO)-induced renal fibrosis and the associated therapeutic mechanisms remains unclear. Here, we observed a marked increase in senescent TECs within obstructed human renal tissue and demonstrated the positive correlation between the accumulation of senescent TECs and renal fibrosis in UUO-induced renal fibrosis in mice. We found that PCC1 reduced the number of senescent TECs, restored the regenerative phenotype in kidneys with reduced fibrosis, and improved tubular repair after UUO-induced injury. In vitro, PCC1 effectively cleared senescent HK2 cells by inducing apoptosis via ANGPTL4/NOX4 signaling. Incubation with culture medium from senescent HK2 cells promoted fibroblast activation, whereas PCC1 impeded profibrotic effects by downregulating senescence-associated secretory phenotype (SASP) factors from senescent HK2 cells. Therefore, PCC1 alleviated interstitial renal fibrosis not only by clearing senescent TECs and improving tubular repair but also by indirectly attenuating myofibroblast activation by reducing the level of SASP. In summary, PCC1 may be a novel therapeutic senolytic agent for treating renal fibrosis. Show less

To date, glucocorticoids remain the mainstay of treatment of nephrotic syndrome (NS). However, serious side effects and development of drug-resistance following long-term use limit the application of glucocorticoids. Protopanaxadiol (PPD) possesses activity of dissociating transactivation from transrepression by glucocorticoid receptor (GR), which may serve as a potential selective GR modulator. However, steroid-like effects of PPD in vivo are unclear and not defined. How to translate PPD into clinical practice remains to be explored. The current study explored the renoprotection and potential mechanism of PPD and its combination with steroid hormones using adriamycin-induced NS rats. Adriamycin was given intravenously to rats to induce nephropathy. The determination of proteinuria, biochemical changes and inflammatory cytokines were performed, and pathological changes were examined by histopathological examination. Immunostaining and PCR were used to analyze the expression of interesting proteins and genes. The results showed that PPD, alone and in combination with prednisone, efficiently alleviate the symptoms of NS, attenuate nephropathy, improve adriamycin-induced podocyte injury by reducing desmin and increasing synaptopodin expression. In addition, the combined treatment reduced the expression of NF-κB protein and mRNA, as well as cytokine levels, and yet increased the expression of GR protein and mRNA. PPD modulated the transactivation of GR, manifested as repressing TAT, PEPCK and ANGPTL4 mRNA expressions mediated by GR. Meanwhile, PPD inhibited elevation of blood glucose and immune organ atrophy induced by prednisone. In summary, PPD increases the therapeutic effect of prednisone in NS while effectively prevents or decreases the appearance of side effects of glucocorticoids. Show less

JOURNAL/nrgr/04.03/01300535-202512000-00030/figure1/v/2025-01-31T122243Z/r/image-tiff Studies have shown that vascular dysfunction is closely related to the pathogenesis of Alzheimer's disease. The middle temporal gyrus region of the brain is susceptible to pronounced impairment in Alzheimer's disease. Identification of the molecules involved in vascular aberrance of the middle temporal gyrus would support elucidation of the mechanisms underlying Alzheimer's disease and discovery of novel targets for intervention. We carried out single-cell transcriptomic analysis of the middle temporal gyrus in the brains of patients with Alzheimer's disease and healthy controls, revealing obvious changes in vascular function. CellChat analysis of intercellular communication in the middle temporal gyrus showed that the number of cell interactions in this region was decreased in Alzheimer's disease patients, with altered intercellular communication of endothelial cells and pericytes being the most prominent. Differentially expressed genes were also identified. Using the CellChat results, AUCell evaluation of the pathway activity of specific cells showed that the obvious changes in vascular function in the middle temporal gyrus in Alzheimer's disease were directly related to changes in the vascular endothelial growth factor (VEGF)A-VEGF receptor (VEGFR) 2 pathway. AUCell analysis identified subtypes of endothelial cells and pericytes directly related to VEGFA-VEGFR2 pathway activity. Two subtypes of middle temporal gyrus cells showed significant alteration in AD: endothelial cells with high expression of Erb-B2 receptor tyrosine kinase 4 (ERBB4 high ) and pericytes with high expression of angiopoietin-like 4 (ANGPTL4 high ). Finally, combining bulk RNA sequencing data and two machine learning algorithms (least absolute shrinkage and selection operator and random forest), four characteristic Alzheimer's disease feature genes were identified: somatostatin ( SST ), protein tyrosine phosphatase non-receptor type 3 ( PTPN3 ), glutinase ( GL3 ), and tropomyosin 3 ( PTM3 ). These genes were downregulated in the middle temporal gyrus of patients with Alzheimer's disease and may be used to target the VEGF pathway. Alzheimer's disease mouse models demonstrated consistent altered expression of these genes in the middle temporal gyrus. In conclusion, this study detected changes in intercellular communication between endothelial cells and pericytes in the middle temporal gyrus and identified four novel feature genes related to middle temporal gyrus and vascular functioning in patients with Alzheimer's disease. These findings contribute to a deeper understanding of the molecular mechanisms underlying Alzheimer's disease and present novel treatment targets. Show less

Genome-wide association studies (GWAS) have identified nearly 100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but the molecular functions of these variant alleles remain elusive, particularly when they occur in non-coding regions. Here we profiled the chromatin accessibility landscape of liver nuclei from MASLD individuals, and demonstrated these accessible genomic sites were bound by cell type-specific transcription factors (TFs) and enriched for MASLD risk variants, highlighting lineage- and disease state-specific regulation. Using a massively parallel reporter assay (MPRA), we identified hundreds of differential activity variants (DAVs) that operate in a cell type-specific manner or in a stimulus-dependent context by disrupting liver pathogenesis-associated transcriptional regulatory network. Integrative analyses combining liver eQTLs, chromatin looping, and single-cell CRISPRi screening linked these DAVs to functional target genes. Notably, we demonstrated that DAVs located near Show less

Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of VLDL particles in vivo. One way APOA5 exerts its effects is through the modulation of LPL activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 KO and WT mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 KO mice was cleared significantly more slowly by cultured hepatocytes. VLDL proteomics experiments from two independent laboratories identified altered contents of 23 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including reductions in APOE and serum amyloid A1. Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response. Show less

Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, overshadowing its influence on the biological effects of formulations. In this study, we reevaluated the delivery effect of CH using widely applied lipid microspheres (LM) as a model DDS. We conducted comprehensive investigations into the impact of CH on the distribution, cell uptake, and protein corona (PC) of LM at sites of cardiovascular inflammatory injury. The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage. Then, the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy. Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in vascular endothelial cells and estrogen receptor alpha (ERα) protein levels in myocardial cells, thereby enhancing LM uptake at cardiovascular inflammation sites. Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V (Apoa5); this may be a major contributing factor to their prolonged circulation Show less

To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships between TCM constitutions, uric acid levels, and various cardiovascular risk factors. A cross-sectional study involving 683 patients diagnosed with HUA was conducted. Patients' TCM constitutions were classified using the standardise "Classification and Determination of TCM Constitution" questionnaire. Serum uric acid (UA), lipid profiles, ApoB, and homocysteine (Hcy) levels were measured. Among 683 HUA patients, phlegm-dampness (22.99% ) and damp-heat constitution (20.06% ) were the most common TCM constitution types. UA, ApoB, and Hcy levels in patients with phlegm-damp constitution were significantly higher than those in other constitutions (P< 0.05). UA levels were negatively correlated with HDL-C (r=-0.472, P= 0.027) and positively correlated with ApoB (r= 0.618, P= 0.012) and Hcy (r= 0.492, P= 0.018). Phlegm-damp and damp-heat constitutions are the most common TCM constitution types in HUA patients and are associated with higher levels of UA, ApoB, and Hcy. These constitutional types are independently associated with increased cardiovascular risk. Show less

Cholecystectomy alters lipid profiles and is associated with the risk of major adverse cardiac and cerebrovascular events (MACCE), yet the results are ambiguous. To assess the causal effects of cholecystectomy on blood lipid levels and risks of MACCE, we performed Mendelian randomization (MR) aiming to reduce confounding. We used genetic data on gallbladder removal, lipid levels, and MACCE from public databases. MR analysis estimated causal effects using genetic variants as instruments. Enrichment analysis identified relevant metabolic pathways, while multivariable MR evaluated specific lipid subtypes. Expression Quantitative Trait Loci MR pinpointed key genes, with cellular distribution insights from single-cell sequencing. Cholecystectomy was associated with delayed onset of angina, coronary heart disease, heart failure, myocardial infarction, and stroke. The ApoB/ApoA1 ratio was a key mediator, and the LPL gene influenced lipid-related cardiovascular risk. Cholecystectomy may reduce cardiovascular risks by lowering the ApoB/ApoA1 ratio, which highlights the role of lipid regulation in mitigating cardiovascular risk post-cholecystectomy. Show less

The contribution of circulating group 3 innate lymphoid cells (ILC3s) to lipid dysregulation has remained poorly defined, and the mechanisms through which washed microbiota transplantation (WMT) improves lipid metabolism require further clarification. Peripheral ILC subsets and plasma IL-22 were assessed in hyperlipidemia patients and healthy controls. The lipid-lowering effects of WMT were evaluated in a prospective cohort without lipid-lowering medications. Gut microbial and plasma metabolite profiles before and after WMT were analyzed. A hyperlipidemic mouse model was used to determine whether healthy microbiota promote hepatic ILC3 homing via integrin α4. Hyperlipidemia was characterized by reduced circulating ILC3s, integrin α4 Hyperlipidemia is associated with depletion of circulating ILC3s and reduced IL-22. Restoration of ILC3 subsets and enhancement of integrin α4-dependent hepatic homing are achieved after WMT, accompanying improvements in lipid metabolism. Show less