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Climate change creates major challenges in livestock industry, making chickens vulnerable to heat stress because they can tolerate a narrow range of temperatures. Heat stress disrupts metabolic and physiological homeostasis, leading to reduced growth, productivity, reproduction, and immune function, thereby threatening the economic viability of poultry farming. This review explores the multifaceted impacts of heat stress on poultry, including physiological responses, production performance, and immune function. Recent advances in transcriptomic and genomic research have shed light on the molecular mechanisms underlying heat stress resilience in poultry. Key genes such as HSP70, HSP90, HSP27, and HSP47 are significantly upregulated under heat stress, playing vital roles in protein folding, preventing aggregation, and protecting cellular integrity. Additionally, genes like SOD and CAT enhance antioxidant defenses, mitigating oxidative damage. Genes such as RB1CC1, BAG3, and TRMT1L regulate apoptosis and oxidative stress, promoting cell survival. In the liver, CCK, DIO3, and ANGPTL4 improve energy homeostasis and reduce metabolism-related heat production, while BMP10 and MYH7 in the heart contribute to cardiac adaptation during thermal stress. Genetic adaptations such as the Naked neck, Frizzle, and Dwarf gene provide intrinsic thermotolerance by reducing feather mass, altering feather structure, and minimizing body size, thereby improving heat dissipation. These genetic traits, combined with transcriptomic insights into heat resilience genes, offer opportunities for developing heat-tolerant chicken breeds. By integrating molecular genetics, transcriptomics, and management strategies, this review highlights the importance of selective breeding programs to enhance poultry thermotolerance. Future research should focus on leveraging indigenous breeds, advanced molecular tools, and nutritional interventions to mitigate the effects of rising global temperatures. Enhancing heat stress resilience in poultry is imperative to ensure sustainable production and global food security in this climate change. Show less

Idiopathic nephrotic syndrome (INS) is a significant kidney disorder in pediatrics. Early diagnosis of minimal change disease (MCD) is difficult in children with nephrotic syndrome (NS). Angiopoietin-like protein 4 (ANGPTL4), found on the surface of podocytes, has been linked to nephrotic syndrome (NS) and plays a role in triggering proteinuria. Macrophage migration inhibitory factor (MIF) functions as a crucial modulator of the innate immune system and partly counteracts glucocorticoid-induced immune system inhibition. This study aimed to assess the role of ANGPTL4 and MIF as biomarkers in steroid responsiveness of INS. This cross-sectional comparative study involved 70 children with NS and 40 healthy children as a control group. Urinary MIF/creatinine levels were significantly elevated in steroid-resistant nephrotic syndrome (SRNS) relative to in steroid-sensitive nephrotic syndrome (SSNS) and controls (p < 0.001). However, ANGPTL4 levels were significantly elevated in the SSNS group relative to the SRNS and control groups (p < 0.001). Regarding plasma MIF and urinary MIF/creatinine levels, there were no significant differences between MCD and FSGS, whereas ANGPTL4 levels were significantly elevated in MCD relative to FSGS (p < 0.001). Elevated levels of serum and urinary MIF levels were consistent with SRNS. Furthermore, ANGPTL4 was found to be highly upregulated in SSNS, unlike SRNS, which serves as a potential marker to distinguish between these two diseases. Show less

Human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are known to exert immunomodulatory and pro-reparative effects in vivo. This makes hBM-MSCs an enticing therapeutic candidate for inflammatory diseases, such as acute respiratory distress syndrome (ARDS). The ARDS microenvironment is complex and contains an abundance of free fatty acids (FFAs), which are known to differentially impact MSC functionality. PPARβ/δ is a ubiquitously expressed nuclear receptor that is activated in response to FFA-binding. PPARβ/δ has been shown to impact the therapeutic efficacy of mouse MSCs. This study sought to investigate the impact of PPARβ/δ-modulation on human MSC functionality in vitro and in vivo. hBM-MSCs were exposed to a synthetic PPARβ/δ agonist/antagonist in the presence or absence of ARDS patient serum and the immunomodulatory and pro-reparative capacity of the MSC secretome was investigated using in vitro assays and a pre-clinical model of LPS-induced acute lung inflammation (ALI). Our results highlighted enhanced pro-reparative capacity of PPARβ/δ-agonized hBM-MSCs secretome in CALU-3 lung epithelial cells, mediated by MSC derived angiopoietin-like 4 (ANGPTL4). PPARβ/δ-induced ANGPTL4-high MSC secretome facilitated enhanced endothelial barrier integrity in the lungs of ALI mice. Therapeutic effects of PPARβ/δ-agonized hBM-MSCs secretome were further enhanced by licensing MSCs with human ARDS patient serum. ARDS-licensed PPARβ/δ-induced ANGPTL4-high MSC secretome had reduced clinical score and weight loss. The role ANGPL4 in these protective effects was confirmed using an anti-ANGPTL4 antibody. These findings conclude that the MSC secretome therapeutic effects can be enhanced both in vitro and in vivo through licensing strategies that upregulate the angiogenic factor ANGPTL4. Show less

Volatile fatty acids (VFAs) provide more than 70% of the energy source for the ruminants. Understanding the host-microbiota regulation of VFAs production and utilization is highly important for optimizing the feed energy utilization efficiency of ruminants. Here, we conducted whole-genome resequencing, rumen transcriptome sequencing, 16S rRNA gene amplicon sequencing, and VFA concentration determination in 530 Holstein bulls. We treated VFA concentrations as complex traits to perform multi-omics association analyses. The host genetics, rumen microbiota, and rumen expressed genes, on average, explained 23%, 58%, and 61% of the variations in VFAs with the same diet, respectively. We found that the rumen microbial composition and community structure differed significantly between the high and low VFA individuals. We further identified 11 microbes with potential causal relationships with rumen VFAs via the Mendelian randomization method, among which Bacteroidales_RF16_group, Prevotella, Clostridia_UCG-014, and [Eubacterium]_ventriosum_group were positively correlated with acetic acid, propionic acid, and butyric acid. Conversely, rumen epithelial genes involved in fatty acid β-oxidation (e.g., HSD17B4, ACADVL, ACADL, CPT1A, and ANGPTL4) were negatively correlated with the main VFAs and VFA-producing bacteria. These candidate microbes and genes suggest that the host-microbe coregulating mechanism facilitates the efficient production and utilization of rumen VFAs in ruminants. Our study provides a comprehensive perspective on the complex dynamic regulatory patterns of rumen VFAs, highlighting the crucial role of host-microbe interactions in optimizing the feed utilization of ruminants. Show less

Pancreatic cancer (PC) exhibits an extremely poor prognosis due to its high heterogeneity. The senescence-associated secretory phenotype (SASP), a distinct secretory profile displayed by senescent cells, has been increasingly studied. However, the role of SASP in PC prognosis and treatment remains unclear. Transcriptomic sequencing data from PC patients were analyzed using consensus clustering based on SASP genes. A prognostic signature was subsequently constructed Consensus clustering based on SASP genes identified two SASP-associated clusters (SASPclusters), with cluster B demonstrating significantly worse prognosis than cluster A. Thirty-three SASP genes showed significant associations with PC prognosis, and a 7-gene SASP-based prognostic signature was established. High-risk patients exhibited significantly higher mutation rates. Distinct immune cell infiltration patterns, immune functions, checkpoint expression levels, and chemosensitivity profiles were observed between risk groups. Besides, we found that ANGPTL4 could promote PC cell proliferation, migration, and invasion. Molecular subtyping and risk stratification based on SASP genes effectively predict PC prognosis and reveal heterogeneity in mutational burden, immune microenvironment, and therapeutic sensitivity. These computational findings deepen our understanding of potential role of SASP in PC and provide a theoretical foundation for personalized treatment strategies. Show less

Exposure to mono(2-ethylhexyl) phthalate (MEHP) during pregnancy has been associated with adverse pregnancy and birth outcomes characterized by extravillous trophoblast (EVT) abnormal function. Previous reports have suggested that MEHP can activate the PI3K/AKT pathway in EVT cells, a pathway known to regulate inflammation and angiogenesis in these cells. However, the molecular effects of MEHP on crucial EVT functions such as inflammatory and angiogenic homeostasis remain unexplored. This study aimed to characterize the role of the PI3K/AKT pathway as a mechanism of action of MEHP activity, as well as its effects on inflammatory and angiogenic soluble molecules in HTR-8/Svneo EVT human-derived cells. The results showed that a low (5 μM) MEHP concentration increased AKT phosphorylation, but a high (200 μM) concentration did not. Conversely, a high MEHP concentration, but not a low concentration, promoted nuclear translocation of p65 in a PI3K-dependent manner. Notably, distinct patterns of cytokines were transcriptionally and secretorily activated by high and low concentrations of MEHP. IL1B, CXCL8, and TNF were transcriptionally upregulated by MEHP 5 μM, while gene expression and secretion of IL-6 were induced by MEHP 200 μM, suggesting a biphasic inflammatory dose response. In addition, both MEHP concentrations upregulated the expression of angiogenic molecules (VEGF, PGF, and ANGPTL4) and impaired migration and tube formation in HTR-8/Svneo cells. Both inflammatory and angiogenic responses induced by MEHP were inhibited by the PI3K inhibitor LY294002. Collectively, these data demonstrate that MEHP induces inflammation and impairs angiogenesis partly via PI3K/AKT in HTR-8/SVneo cells. These findings may help to understand previous clinical associations between MEHP exposure and placental pathophysiology. Show less

Protein feed resource shortage is a major constraint to the sustainable development of the livestock industry and a bottleneck problem hindering the growth of the Tibetan pig industry in China's Qinghai-Tibet Plateau region. Walnut meal, rich in protein, holds promise as a substitute for soybean meal. However, the effects and underlying mechanisms of walnut meal substitution on Tibetan pigs in Diqing remain unclear. The study showed that substituting 50% of soybean meal with walnut meal in the diet of Diqing Tibetan pigs significantly reduced backfat thickness and increased intramuscular fat content ( This study reveals that walnut meal can serve as a substitute for soybean meal, and a 50% substitution ratio is conducive to intramuscular fat deposition in Diqing Tibetan pigs. The findings provide valuable insights for the development and application of unconventional protein feed resources, and offer new perspectives for the production of marbled pork. Show less

Hepatocellular carcinoma (HCC) exhibits high recurrence rates and limited therapeutic options. Endothelial cell-specific molecule 1 (ESM1) and angiopoietin-like 4 (ANGPTL4) are implicated in tumor progression, yet their synergistic role in HCC lipid metabolism and angiogenesis remains unexplored. We integrated multi-omics approaches, including RNA sequencing, metabolomics, and immunoprecipitation-mass spectrometry, in HCC cell lines and patient-derived xenograft models. Key experiments involved Co-IP, Western blotting, tube formation assays, and clinical tissue microarray analysis to validate the ESM1-ANGPTL4-FASN-trioleate axis. ESM1 and ANGPTL4 formed a positive feedback loop, stabilizing fatty acid synthase (FASN) to promote trioleate synthesis. Trioleate activated the NF-κB/IL-17 pathway in HCC cells and upregulated CD99 in endothelial cells, driving angiogenesis. In vivo, ESM1/ANGPTL4 knockdown suppressed tumor growth, which was rescued by trioleate supplementation. Clinical data revealed elevated ESM1/ANGPTL4 expression in bevacizumab-resistant HCC, correlating with poor prognosis. The ESM1-ANGPTL4-FASN-trioleate axis orchestrates metabolic reprogramming and endothelial activation, representing a promising therapeutic target. Future studies should explore combination therapies targeting this axis and overcoming bevacizumab resistance in HCC. Show less

Damp-heat gout (DHG) is a highly certified type of disease integrated with syndrome in TCM. The ambiguity of its pathomechanism and the lack of quantifiable indicators limit its clinical accurate diagnosis and treatment. This study aimed to elucidate the pathological mechanism of DHG and establish a symptom-centered diagnostic and therapeutic model. We recruited 136 participants, comprising healthy controls (HCs) and DHG patients. Serum metabolomics and proteomics analyses were performed to screen common pathways. Based on the biological significance of these common pathways, a symptom-pathway correlation network was constructed to clarify the pathological mechanisms driving DHG occurrence and progression. Enrichment scores and correlations with key DHG symptoms were used to identify critical pathways. Differential metabolites and proteins associated with these critical pathways served to establish a multi-index diagnostic model and identify potential therapeutic protein targets. Integrated metabolomic and proteomic analyses revealed 21 common pathways associated with DHG. Four crucial pathways, such as Bile secretion, Cholesterol metabolism, Purine metabolism, Arachidonic acid metabolism, were exhibited significant correlations with core DHG symptoms. Furthermore, six pathway-related biomarkers were identified: Hypoxanthine, Prostaglandin E2, Uric acid, Deoxycholic acid, Taurochenodeoxycholic acid, and Bilirubin. The combined diagnostic efficacy of these biomarkers was optimal (discovery cohort: AUC = 0.987; validation cohort: AUC = 0.997). Six protein targets were identified from the crucial pathways, including ATP1A1, APRT, ANGPTL4, GLUT1, PTGES3 and LIPA. This study establishes a symptom-centered diagnostic and therapeutic model for DHG utilizing the identified biomarkers and clarifies the involvement of critical metabolic pathways in DHG pathogenesis, providing novel targets for improved clinical diagnosis and therapy. Show less

The rising demand for high-quality pork among consumers has driven interest in genetic improvement strategies. Crossbreeding is well known to influence carcass performance and meat quality; however, the molecular mechanisms underlying these effects are still poorly understood. In this study, the F1 generation of the Songlei Crossbred Pig (SL) was developed through crossing the Songliao Black Pig (male) (SS) and the Leixiang Pig (female) (LL). We integrated the transcriptomes and metabolomes of the longissimus dorsi (LD) muscle of SS and SL under identical conditions to identify key mechanisms regulating the quality of crossbred meat. Compared with those of SS, the slaughter weight, carcass weight, and dressing percentage of SL were significantly lower, but the backfat thickness was greater; however, meat quality traits, including intramuscular fat (IMF), colour, and pH The meat quality of SL was better than that of their male parents, but not the carcass traits were not. Additionally, several critical genes and pathways related to lipid metabolism were identified. These findings provide new insights into how meat quality can be improved by hybridization. Show less

Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting from tumor formation, their accumulation is deleterious during aging as it promotes age-related diseases, including cancer initiation and progression. Although the SASP has a critical role, its composition, regulation and dual role in cancer remain largely misunderstood. Here, we show that ANGPTL4 is one of the rare secreted factors induced in many different types of senescent cells. Importantly, ANGPTL4 knockdown during senescence or its constitutive expression, respectively inhibits or induces classical proinflammatory SASP factors, such as IL1A, IL6 and IL8. The latter effect is mediated upstream of IL1A, an early SASP factor, suggesting an upstream role of ANGPTL4 in SASP induction. This ANGPTL4-dependent proinflammatory SASP can promote human neutrophil activation in ex vivo assays, or tumor initiation in a KRAS-dependent lung tumorigenesis model in mice. This upstream activity of ANGPTL4 in regulating the proinflammatory SASP depends on its upregulation following a hypoxia-like response and HIF2A activation, and its proteolytic processing by the FURIN proprotein convertase. Altogether these findings shed light on a two-step activation of ANGPTL4 by HIF2A and FURIN in senescent cells and its upstream role in promoting the proinflammatory SASP, cancer and potentially other senescence-associated diseases. Show less

Angiopoietin-like proteins (ANGPTLs) are key regulators of lipid metabolism; however, their response to lipid-lowering therapies remains incompletely understood. The PRESTIGE study compared the effects of pemafibrate add-on versus statin dose doubling on small dense low-density lipoprotein-cholesterol (sdLDL-C) in patients with type 2 diabetes and hypertriglyceridemia receiving statins. This post-hoc analysis investigated changes in circulating ANGPTL levels. Participants were randomized to receive either pemafibrate (0.2 mg/day; n = 48) or double-dose statin therapy (n = 49). Plasma ANGPTL levels and lipid parameters were assessed at baseline and after 12 weeks. ANGPTLs were quantified using specific human ELISA kits. sdLDL-C, LDL-triglycerides (TG), and HDL3-C were measured using the homogeneous assays. Pemafibrate treatment significantly increased circulating ANGPTL3 (+71%) and ANGPTL4 (+143%) levels, with no change in ANGPTL8, whereas statin dose doubling had no effect on ANGPTL levels. Pemafibrate markedly reduced TGs and sdLDL-C, while increasing large buoyant LDL-C, LDL-TG, HDL2,3-C, apolipoprotein AI, and apolipoprotein AII. The increase in ANGPTL3 was not correlated with changes in LDL subspecies but was positively associated with changes in HDL2,3-C. When participants were stratified by baseline ANGPTL3 levels, those in the low ANGPTL3 group showed an increase in LDL-C and LDL-TG in response to pemafibrate. The substantial elevation in ANGPTL4 induced by pemafibrate did not show associations with lipid changes. Pemafibrate markedly elevated circulating ANGPTL3 and ANGPTL4 levels, but these increases were not associated with pro-atherogenic changes in lipoprotein profiles. Notably, baseline ANGPTL3 concentrations may influence the effect of fibrates on LDL-C levels. Show less

The prevalence of Type 2 diabetes mellitus (T2DM) is rapidly increasing in India, yet molecular markers that reflect early disease susceptibility remain limited. Epigenetic modifications such as DNA methylation may reflect early metabolic vulnerability preceding overt dysglycemia. In this study, we examined genome-wide DNA methylation patterns in a pilot subset nested within a prospective Indian cohort using Nanopore sequencing and assessed their associations with previously identified metabolite predictors from the same cohort. Genome-wide DNA methylation profiling was performed on buffy-coat DNA from 12 participants who were normoglycemic at baseline and later classified into normoglycemia, prediabetes, or T2DM based on their glycemic status at 6-year follow-up. At baseline, gene-level aggregation of CpG methylation revealed directionally consistent hypermethylation of seven genes (ABCG1, ADARB2, BCL2, DLC1, EGFLAM, SYK, ZNF516) in individuals who later developed T2DM, while those progressing to prediabetes exhibited six hypermethylated (ABCG1, FLT3, LCP1, MBP, NCOA2, TCF7L2) and five hypomethylated genes (ZFHX3, PAX6, PTPRN2, ERC1, HIPK1). ABCG1 showed consistent hypermethylation across both groups. Longitudinal within-individual comparisons identified additional gene-associated methylation changes, including ANK1, IQSEC1, and RUNX1, and shared alterations in CACNA1C, KANSL1, PTPRN2, and TTC34, while six genes showed stage-dependent directional shifts in methylation (ASB3, EFR3A, PCSK5, KLHL14, PDE4C, UNC5C). Correlation analyses at baseline suggested associations between ABCG1 and EGFLAM methylation, fasting glucose, phosphatidylethanolamine [PE (20:3₁₈:0)] and insulin sensitivity indices. This pilot longitudinal study suggests that gene-associated DNA methylation changes in blood may be detectable prior to the onset of dysglycemia. These findings are exploratory and hypothesis-generating, highlighting candidate genes and epigenetic-metabolic associations for targeted validation in larger, independent cohorts using alternative analytical approaches. Show less

Numerous genetic variants have been identified by genome-wide association studies as being associated with colorectal cancer (CRC) risk. Metabolome-wide association analysis was performed for 187 CRC-associated genetic variants using genomic data and untargeted Show less

Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer's Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA. Show less

Negative Emotional symptoms such as depression and anxiety do not exist independently, often co-occurring in the same individual, and heterogeneity exists between individuals suffering from depression and anxiety; however, prior research has rarely investigated heterogeneity in a person-centered manner and from the perspective of college students. The main purpose of this study was to explore this heterogeneity and its association with e-Health literacy (e-HL) using Latent profile analysis (LPA), a person-centered statistical method. A total of 7,503 Chinese college students from 10 regions (including Guangdong Province, Shanghai Municipality, and Jiangsu Province) were surveyed using the Generalized Anxiety Disorder Scale (GAD-7) and Patient Health Questionnaire (PHQ-9) to assess anxiety and depressive symptoms. LPA was employed to identify potential profiles of negative emotional symptoms and validate their robustness; binary logistic regression was used to explore differences in demographic characteristics (sex, grade ranking), sociological factors (family residential background, per capita monthly family income), and lifestyle factors (adherence to physical activity, smoking status, alcohol consumption) across profiles; analysis of variance (ANOVA) was applied to compare e-HL levels among different profiles. The two-class model was identified as the optimal classification of negative emotional symptoms: low/no negative emotional symptoms (61.49%) and high negative emotional symptoms (38.51%). Female college students, those with low per capita monthly family income, lack of regular physical exercise, and alcohol consumption habits were more likely to be categorized into the high negative emotional symptoms group (all Reliance on self-report measures may lead to recall bias and social desirability bias; the cross-sectional design cannot establish causal relationships between variables; digital addiction, a potential confounding factor that may co-occur with negative emotional symptoms and influence e-HL, was not included in the analysis. This study identified two distinct latent profiles of negative emotional symptoms among Chinese college students and their key predictive factors using LPA. The findings highlight the need for stratified early screening for high-risk groups (females, low-income families, inactive individuals, and drinkers) and the development of targeted interventions. Enhancing e-HL could be a potential pathway to improve mental health outcomes, providing actionable insights for scientific and effective mental health management in colleges and universities. Show less

Butyrate is one of the three main short-chain fatty acids, and it provides energy, controls the state of the intestinal microbiota and mediates the immune response. Sodium butyrate supplementation improves poultry production and changes the intestinal microbiota dynamically. These changes may affect the liver directly and indirectly through pathways in the gut-liver axis, the bidirectional relationship between the liver and intestines. The study analysed gene expression and methylation in the broiler liver after Incubated Ross 308 broiler eggs were injected on day 12 with saline as the control group or with sodium butyrate as SB groups at three doses: 0.1%, 0.3% and 0.5%. Chicks' livers were collected postmortem on day 42 of rearing for RNA and DNA extraction. Gene expression was analysed by reverse-transcription qPCR, and gene methylation by methylation-specific qPCR for a panel of lipid metabolism and immune regulation genes comprising Sodium butyrate stimulation changed gene expression levels. Upregulation was noted of The obtained results suggest that sodium butyrate affected both gene expression and methylation in the liver, indicating its potential epigenetic effects. Show less

Lipoprotein(a) [Lp(a)] has been recognized as a genetically determined and independent contributor to atherosclerotic cardiovascular disease. However, its role in lower extremity arterial disease (LEAD) among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains insufficiently studied. Given the overlapping metabolic disturbances in both conditions, such as insulin resistance and lipid abnormalities, a potential relationship between Lp(a) and peripheral vascular injury in MASLD is biologically plausible. This study aimed to investigate the cross-sectional association between circulating Lp(a) concentrations and the presence of LEAD in a well-characterized MASLD population. A total of 468 MASLD patients undergoing routine health check-ups were included. Lp(a) levels were stratified into three categories: <10 mg/dL, 10–30 mg/dL, and ≥ 30 mg/dL. LEAD was diagnosed using duplex ultrasonography. Multivariable logistic regression models were used to assess the relationship between Lp(a) levels and the presence of LEAD, with adjustments for demographic variables, metabolic conditions, and lipid-related parameters. Subgroup analyses were conducted to assess potential effect modification. LEAD was diagnosed in 61.5% ( Elevated Lp(a) levels were associated with a higher prevalence of LEAD in patients with MASLD. Although the magnitude of association per unit increase was modest, higher Lp(a) concentrations were associated with greater LEAD prevalence. These findings should be interpreted cautiously and viewed as hypothesis-generating, particularly with respect to subgroup analyses. Prospective studies are needed to clarify causality and clinical relevance. The online version contains supplementary material available at 10.1186/s12872-026-05600-7. Show less

Diabetic refractory wounds are a severe complication of diabetes, often synchronized with diabetic peripheral neuropathy. In this study, we demonstrated a significantly downregulated expression of calcitonin gene-related peptide (CGRP) in the skin tissues of both diabetic patients and diabetic mouse models. This observation implies the crucial role of CGRP in diabetic wound healing. Based on this discovery, we engineered glucose-responsive along with sustained-release antibacterial hydrogel microspheres (BA-HPCS@CGRP) for the controlled delivery of CGRP and conducted systematic evaluation of its therapeutic efficacy. In vitro findings demonstrated that microspheres not only directly enhanced the migration and tube formation capabilities of endothelial cells impaired by high glucose but also further facilitated the restoration of endothelial cell function by promoting the secretion of angiopoietin-like protein 4 (Angptl4) by macrophages after switching to M2 phenotype by CGRP. The results from diabetic mouse models showed that BA-HPCS@CGRP accelerated diabetic wound healing by modulating macrophage polarization towards to M2 phenotype and reduced inflammation, promoted neurovascular regeneration and restored the local CGRP expression. These findings suggest that sustained releasing of low concentration of CGRP provides novel therapeutic approaches for diabetic wounds via modulating macrophage. Moreover, BA-HPCS@CGRP achieves comprehensive sequential therapy through the synergistic modulation of the "neuro-immune-vascular" axis, which might open new perspective to chronic wounds and regenerative medicine. Show less

Angiopoietin-like protein 3 (Angptl3), a factor secreted by the liver, inhibits lipoprotein lipase and other lipases by forming a complex with Angptl4 and 8. However, whether inhibition of Angptl3 can alleviate hepatic lipid accumulation and atherosclerosis remains unclear. Therefore, this study explored the effect of small interfering RNA (siRNA)-based inactivation of Angptl3 on metabolic dysfunction-associated fatty liver disease (MAFLD) and atherosclerosis in male LDLR-deficient hamsters. Recombinant adeno-associated virus serotype 9 (AAV9) encoding Angptl3-siRNA or empty AAV (AAV9-null) were injected into male 4-month-old LDLR On HFD, Angptl3-siRNA-treated hamsters displayed significantly decreased plasma triglyceride (TG), total cholesterol, high-density lipoprotein-cholesterol, and glucose levels, compared with the AAV9-null hamsters. FPLC analysis further revealed a marked reduction of TG and cholesterol contents in VLDL/LDL fractions. Plasma apolipoprotein analysis showed relatively lower ApoB/ApoE levels and higher ApoA1 levels. Moreover, Angptl3-siRNA markedly accelerated the clearance of triglyceride-rich lipoproteins in LDLR These findings demonstrated that siRNA-based inactivation of Angptl3 alleviated MAFLD and atherosclerosis induced by HFD in LDLR The online version contains supplementary material available at 10.1186/s12944-026-02916-3. Show less

Lipoprotein(a) [Lp(a)] is a novel biomarker for Atherosclerotic cardiovascular disease prediction. Yet, given the scarcity in high-quality evidence, its use in routine primary prevention screening is lacking. For this reason, we aimed to assess Lp(a) prognostic utility during routine screening. A retrospective cohort of adults with available Lp(a) measurement, taken during a screening program (2008-2024) in a tertiary care center. Major adverse cardiovascular events (MACE) was the study primary outcome. The optimal Lp(a) threshold was evaluated using spline curve analysis and validated by Cox regression models adjusted for clinical and laboratory covariates. Subgroup analyses were performed in patients with SCORE2 and PCE data. 3052 people were included with a median (IQR) follow-up of 6.4 (3.5-12) years. Lp(a) threshold of 50 mg/dL was identified as a risk inflection point. High Lp(a) (> 50 mg/dL) was associated with increased MACE risk, independent of clinical data (HR 1.55, 95% CI 1.10-2.17, p = 0.011) or different laboratory variables (HR 1.62, 95% CI 1.07-2.46). High Lp(a) remained a predictor for MACE in models incorporating the SCORE2 and PCE scores, and its incorporation into these scores improved their performance in high-risk patients. In people with cardiovascular comorbidities, the optimal Lp(a) threshold for MACE prediction was 61 mg/dL, while it was 48.4 mg/dL in those without (n = 2778). In a large ambulatory and mostly healthy cohort, Lp(a) showed a strong predictive utility for cardiovascular events. These findings support the integration of Lp(a) into primary cardiovascular risk assessment and role in guiding emerging targeted therapies. Show less

Type 1 diabetes (T1D) is an autoimmune disease resulting in the destruction of pancreatic β-cells leading to insulin deficiency and hyperglycemia. Single cell transcriptomic analysis of human islets demonstrated profound β-cell changes and revealed heterogeneity in endocrine and exocrine cells in T1D. Pancreatic stellate cells (PSCs), the resident mesenchymal cells of the pancreas, regulate extracellular matrix homeostasis and drive fibrosis in aging, pancreatitis, and pancreatic cancer. By secreting cytokines and growth factors, PSCs contribute to local immunity and inflammation that affect pancreatic exocrine and endocrine functions. However, cell-cell communication from single cell transcriptomics analyzing the role of PSCs in T1D has not been explored. We analyzed single-cell RNA sequencing data from human pancreatic islets of 20 donors with and without T1D from the Human Pancreas Analysis Program database using the CellChat R package, focusing on activated-PSCs (aPSCs) signaling pathways. In addition, we performed aPSCs differential expression gene and gene set enrichment analyses. CellChat analysis revealed aPSCs demonstrated major changes increasing the number and strength of cellular communications in T1D compared to control pancreata. Signaling pathways upregulated in cell-to-cell communication involving aPSCs include TGFB, FGF, CXCL, ANGPTL, and NGF, and their respective ligands TGFB1/3, FGF7, CXCL12, ANGPTL4 and NGF. In contrast, PTN signaling from aPSCs was blunted in T1D. Our study revealed novel intercellular communication signatures involving aPSCs in T1D. Identification of the changes in cellular communication between aPSCs and other cells in T1D suggest a role in T1D pathogenesis or progression which might lead to the development of novel therapeutics. Show less

The incidence of osteoarthritis (OA) is strongly correlated with aging. It has been shown that the accumulation of senescent cells in the synovium precedes chondrocyte senescence and cartilage degradation, suggesting that synovial cell senescence plays a key role in OA pathogenesis. This study aimed to investigate the mechanisms underlying synovial cell senescence and its influence on intercellular communication within the joint. Using multiplex immunofluorescence, gene regulatory network reconstruction, and single-cell RNA sequencing analyses, we identified senescent cells and characterized the senescence-associated secretory phenotype in the synovium. A series of in vivo and in vitro functional experiments is conducted to elucidate the mechanisms of fibroblast senescence and its effects on macrophages and chondrocytes. We found that synovial intimal fibroblasts (SIF) display more marked premature senescence compared to other synovial cell types. A specific senescent subpopulation within SIF is identified, and we demonstrated that the transcription factors EGR1 and ATF3 regulate senescence-related pathways in these cells. Furthermore, we showed that senescent SIF promote M1 macrophage polarization and cartilage degeneration through paracrine secretion of ANGPTL4. Additionally, senescent SIF may facilitate OA progression through direct cell-cell contact with macrophages. Show less

Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial-derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascular-osteogenic coupling during bone regeneration. CGRP, a bone sensory neuron-derived peptide, contributes to bone formation, but the potential mechanism by which it improves bone regeneration via angiogenesis is unclear. Here, we demonstrate that CGRP may contribute to bone repair in the elderly, as human CGRP levels are inversely proportional to age and proportional to bone mass in clinical data and bulk transcriptome data. Based on single-cell RNA sequencing data and experimental analyses, CGRP is found to promote the angiogenesis of human microvascular endothelial cell line-1 in vitro through the FAK-AKT-VEGF pathway. CGRP gene deletion in mice reduced bone vascular density and bone mass, and delayed angiogenesis and bone regeneration at the bone defect site. Recombinant CGRP restored bone repair after defect introduction. It also promoted Angptl4 secretion by bone vascular endothelial cells, thereby driving osteogenic differentiation of bone marrow mesenchymal stem cells and enhancing bone regeneration after bone injury. Treatment with recombinant Angptl4 enhanced bone healing in a mouse bone defect model. These integrated analysis reveal the important role and mechanism of CGRP in vascular-mediated osteogenesis, suggesting a novel therapeutic strategy for promoting bone regeneration. Show less

Tinnitus is a complex neurological condition affecting 10-15% of adults worldwide, characterized by phantom auditory perception without external sound sources. While traditional investigations have focused on discrete auditory structures, emerging evidence suggests tinnitus involves broader alterations across central auditory regions. This study employed transcriptomic analysis to investigate molecular mechanisms underlying salicylate-induced tinnitus across multiple brain regions simultaneously. Male C57BL/6 N mice received daily intraperitoneal injections of sodium salicylate (350 mg/kg) for five consecutive days to induce tinnitus-like behavior, assessed using gap-prepulse inhibition of acoustic startle reflex. RNA sequencing was performed on auditory cortex, inferior colliculus, and cochlear nucleus tissues. Differential gene expression analysis, weighted gene co-expression network analysis, and functional annotation were conducted to identify shared molecular signatures and pathways across auditory centers. Principal component analysis revealed region-specific transcriptomic changes following salicylate treatment. Differential gene expression analysis identified Depp1 and Angptl4 as consistently upregulated genes across multiple brain regions, particularly within the inferior colliculus and cochlear nucleus. Weighted gene co-expression network analysis revealed a 215-gene module increased across all auditory regions in tinnitus mice, with functional annotation indicating enrichment for vasculature-related biological processes. Depp1 emerged as a central hub gene linking oxidative stress responses to autophagy mechanisms. This study shows that tinnitus pathology involves not only neuronal hyperactivity but also oxidative stress, neuroinflammation, and autophagy in the central auditory pathway. Depp1 acts as a molecular hub linking redox imbalance to cellular clearance, highlighting its potential as a therapeutic target and offering new insights for intervention. Show less

Microtubule organization plays a central role in cell differentiation, orchestrating essential processes such as cell polarization, mechanotransduction, organelle positioning and intracellular transport. A hallmark of many differentiated cells is the transition from a centrosomal to a non-centrosomal microtubule-organizing center (MTOC). Here, we demonstrate that both centrosomal and nuclear envelope (NE)-associated MTOCs coexist in osteoclasts. We show that the key players for NE-MTOC formation, the AKAP6 and nesprin-1 (SYNE1) isoforms AKAP6β and nesprin-1α, previously considered muscle specific, are upregulated during osteoclast differentiation, suggesting a conserved role in NE-MTOC assembly across cell types. Targeted depletion of AKAP6 in RAW264.7-derived osteoclasts led to the displacement of the Golgi and MTOC-associated proteins PCM1, pericentrin and CDK5RAP2 from the NE, while their centrosomal localization remained intact. This selectively impaired microtubule nucleation from the NE without disrupting centrosomal microtubule activity, enabling a functional dissection of the two MTOCs. Loss of NE-MTOC activity, through AKAP6 depletion, impaired podosome formation and significantly reduced bone resorption capacity, highlighting the distinct and essential role of NE-derived microtubules in osteoclast function. Show less

Urban particulate matter (UPM) is a major air pollutant affecting public health, with maternal exposure potentially leading to cardiac developmental disorders in offspring. However, the exact mechanisms underlying the intergenerational effects of UPM remain unclear. This study aimed to investigate the molecular mechanisms involved in cardiac developmental defects caused by maternal UPM exposure in offspring zebrafish. Female zebrafish were exposed to UPM for 21 days to examine intergenerational effects. The results indicated that maternal zebrafish in the exposed group exhibited ovarian damage and a reduced number of embryos and fertilization rates. Zebrafish offspring exhibited abnormal cardiac development, including pericardial edema and pathological heart injury. Mechanistically, transcriptomic analysis of the offspring indicated that UPM exposure induced significant modifications in the mitochondrial biogenesis pathway, with altered expression of mitochondrial function-related genes. Maternal UPM exposure impaired respiration in zebrafish embryos and increased angiopoietin-like 4 (ANGPTL4) expression in offspring hearts. In vitro, Angptl4 knockdown alleviated UPM-induced mitochondrial membrane potential reduction and mitochondrial reactive oxygen species overproduction in cardiomyocytes, whereas Angptl4 overexpression exacerbated UPM-induced mitochondrial toxicity. These findings show that maternal UPM exposure disrupts mitochondrial homeostasis by upregulating ANGPTL4 expression, leading to abnormal cardiac development in zebrafish offspring. Show less