As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, Show more
As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, particularly atherosclerosis, remain unclear. This study aimed to explore the effects of IL-38 on atherosclerosis progression and its mechanisms in regulating macrophage function during the atherosclerotic process. To evaluate the therapeutic potential of IL-38 in atherosclerosis, we performed histopathological examinations and biochemical analyses in vivo. In vitro, we used primary bone marrow-derived macrophages (BMDMs) stimulated with oxidized low-density lipoprotein (ox-LDL) to assess the anti-inflammatory effects of IL-38 and quantified its impact on ox-LDL-induced macrophage polarization. To further elucidate the specific mechanisms by which IL-38 regulates macrophage function, we conducted mRNA sequencing and validated downstream regulatory signaling pathways. IL-38 exhibited therapeutic potential in atherosclerosis by reducing atherosclerotic plaque formation, modulating plaque composition, suppressing the production of proinflammatory cytokines within plaques, and potentially regulating macrophage cholesterol metabolism. Moreover, IL-38 exerted significant anti-inflammatory effects on macrophages both in vivo and in vitro. Notably, it inhibited the polarization of macrophages toward the proinflammatory M1-like phenotype in both settings. Additionally, IL-38 impeded the phosphorylation and nuclear translocation of p65 in BMDMs and reduced ox-LDL-induced macrophage apoptosis. IL-38 holds therapeutic potential for atherosclerosis, as it alleviates disease progression, inhibits macrophage polarization toward the M1-like phenotype, suppresses nuclear factor-κB (NF-κB) signaling activation, and reduces macrophage apoptosis. This study provides new insights into the anti-inflammatory mechanisms by which IL-38 mitigates atherosclerosis. Show less
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic mo Show more
Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic modalities to revolutionize clinical management and enhance patient outcomes. The recent seminal discovery by Swamynathan et al. has unveiled menadione, a vitamin K precursor, as a potent inducer of triaptosis-a novel regulated cell death pathway mediated through the oxidative modulation of phosphatidylinositol 3-kinase PIK3C3/VPS34. This mechanistically distinct cell death paradigm, characterized by its intimate association with endosomal dysfunction and oxidative stress-induced cellular catastrophe, has demonstrated remarkable therapeutic efficacy in preclinical prostate cancer models, outperforming conventional therapeutic regimens and emerging as a potential paradigm-shifting strategy in oncology. This comprehensive review provides a critical synthesis of the triaptosis discovery landscape, elucidating its molecular intricacies and pathophysiological implications. We systematically examine the multifaceted roles of endosomal biology in oncogenesis and tumor progression, while offering a nuanced perspective on redox homeostasis in malignant cells and the therapeutic potential of oxidative stress modulation. Furthermore, we address the inherent dichotomy of oxidative stress induction in cancer therapy, balancing its therapeutic promise against potential adverse effects. Looking toward the horizon of cancer research, we explore transformative therapeutic strategies leveraging triaptosis induction and its potential applications beyond oncology, aiming to catalyze a new era of precision medicine that ultimately enhances patient survival and quality of life. Show less
To explore neurodynamic bases underlying subjective cognitive decline (SCD) based on edge-centric functional network. 211 SCD patients and 210 healthy controls (HC) were recruited from the Alzheimer's Show more
To explore neurodynamic bases underlying subjective cognitive decline (SCD) based on edge-centric functional network. 211 SCD patients and 210 healthy controls (HC) were recruited from the Alzheimer's Disease Neuroimaging Initiative. Edge time series (ETS) were obtained based on resting-state functional magnetic resonance data. The top 10% co-fluctuation signals of all time points in ETS were extracted to construct the high-amplitude frame networks, and the co-fluctuation signals from the remaining time points were used to construct the low-amplitude frame networks. In both network states, the graph theory and network-based statistics (NBS) analyses were used to compare SCD and HC. The correlation of the imaging indicators with cognitive scores and apolipoprotein E (APOE) ε4 genes was performed by Spearman correlation analysis. SCD exhibited lower peak amplitude and longer trough-to-trough duration (TTD) compared to HC. In both network states, the normalized clustering coefficient, normalized characteristic path length, small-worldness, and global efficiency of SCD were significantly reduced, and the altered nodal centralities of SCD predominantly exhibited a decreasing trend. However, the high-amplitude frame network identified more altered brain regions compared to the low-amplitude frame network. Furthermore, a SCD-related subnetwork was found in the high-amplitude frame network, which was composed of 11 brain regions and 13 edges. TTD was positively related to the number of APOE ε4 genes; the normalized characteristic path length, the betweenness centrality of right postcentral gyrus, and the connection between bilateral angular gyrus were correlated with cognitive scores. Our findings demonstrate that the edge-centric network framework reveals details of brain network alterations in SCD through different perspectives, and these alterations hold potential as novel biomarkers for SCD. Show less
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, infla Show more
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less
To investigate the effects of Qihuang Jianpi Zishen Granules (QJZG) on renal injury in SLE mice, focusing on macrophage M1/M2 polarisation mediated by the AMPK/ULK1 signalling pathway. Parameters of r Show more
To investigate the effects of Qihuang Jianpi Zishen Granules (QJZG) on renal injury in SLE mice, focusing on macrophage M1/M2 polarisation mediated by the AMPK/ULK1 signalling pathway. Parameters of renal function and proteinuria were assessed. Pathological changes in the kidney were examined using H&E, periodic acid-Schiff and Masson's trichrome staining. Serum inflammatory factor levels were quantified using ELISA. The expression levels of the glycolysis rate-limiting enzymes hexokinase 2 (HK2) and glucose transporter 1 (GLUT1) were determined, and the transcriptional levels of AMPK/ULK1 pathway components were measured using quantitative PCR. The abundance of proteins associated with AMPK/ULK1 signalling was assessed via immunoblotting. Flow cytometry was used to quantify CD86+ M1 type and CD206+ M2 type macrophage populations. Dual immunofluorescence staining was employed to visualise F4/80+CD86+ and F4/80+CD206+ coexpression patterns. Compared with the Untreated group, mice in the PRED (prednisone acetate), QJZG and 2-Deoxy-D-glucose groups exhibited improved renal histopathology, reduced levels of creatinine, blood urea nitrogen, 24-hour RRO (24-hour urinary protein), ACR (Albumin-to-Creatinine Ratio), TPCR (Urine Total Protein-to-Creatinine Ratio), tumour necrosis factor alpha, interleukin (IL)-1β, IL-12, IL-23, IL-27, HK2, GLUT1, mTOR, CD86 and iNOS messenger RNA (mRNA), CD86 and iNOS proteins, M1 macrophages, M1/M2 macrophages and F4/80+CD86 expression (p<0.05). They also displayed increased expression of transforming growth factor-beta, IL-4, IL-10, C-C motif chemokine ligand 18, AMPK, ULK1, Atg13, CD206 and Arg-1 mRNA, AMPK, ULK1, CD206 and Arg-1 proteins, M2 macrophages and F4/80+CD206 (p<0.05). QJZG effectively improved renal injury in SLE by reducing inflammation and modulating the AMPK/ULK1 signalling pathway to suppress M1 macrophage polarisation. Show less
The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed Show more
The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed beak bean phenotypes of duck at 10, 20, 30 and 40 days of age, revealing that the most common type is the black beak bean, characterized by melanin deposition on the beak surface. This study performed single nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) to investigate the genetic basis of beak bean color, identifying signals on chromosome 1. The copy number variation region-based GWAS revealed a consistent candidate region overlapping with the SNP-based GWAS signals, further supporting the importance of this genomic region. Locus zoom analysis further refined the candidate regions to 48.5-50.5 and 50.8-52.8 Mb. Functional enrichment analysis highlighted six candidate genes within these regions: KITLG, DUSP6, GALNT4, MGAT4C, ATP2B1 and NTS. Notably, KITLG and DUSP6, which are linked to melanin production, were identified as key candidate genes for beak bean color. Our finding revealed the genetic basis of the bean color traits for the first time in ducks, providing a theoretical foundation and technological framework for enhancing duck beak coloration. Show less
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathologic Show more
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty Show more
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Show less
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safet Show more
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safety of treatment with pemigatinib, an oral, potent, selective FGFR1-3 inhibitor, in patients with advanced FGFR-altered CNS tumors. FIGHT-207 was a single-arm, open-label, phase 2 study of pemigatinib in patients with advanced solid tumors harboring FGFR fusions/rearrangements or other mutations. Patients received pemigatinib 13.5 mg once daily until disease progression or unacceptable toxicity. Endpoints included tumor response and safety. Of the 13 patients with CNS tumors in FIGHT-207, 10 had glioblastoma. Fibroblast growth factor receptor alterations were FGFR3-TACC3 fusions (n = 9), FGFR1 K656E mutations (n = 2), FGFR1 N546K mutation (n = 1), and FGFR1-MITF fusion (n = 1). Three patients (23%) displayed objective responses (1 complete, 2 partial). Safety was consistent with the overall FIGHT-207 population. Pemigatinib had antitumor activity and a manageable safety profile in patients with CNS tumors. Show less
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a m Show more
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a multifaceted role in the progression of cardiac hypertrophy and HF. Here, it is identified that a lncRNA forkhead box O6, opposite strand (Foxo6os) is significantly downregulated in murine HF model induced using transverse aortic constriction (TAC). Knockdown of Foxo6os accelerates cardiomyocyte hypertrophy, reflects as elevated expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and myosin heavy chain 7 (MYH7). Conversely, Foxo6os overexpression can improve cardiac function and alleviate adverse cardiac remodeling. Mechanistically, Foxo6os directly interacts with myosin-binding protein-C (MYBPC3), which then recruits protein kinase C alpha (PKC-α) to facilitate MYBPC3 phosphorylation, resulting in maintaining myocardial contractility and postponing HF progression. Therefore, these findings underscore the critical role of Foxo6os in preserving cardiomyocyte contractile function, suggesting a potential for Foxo6os as a novel therapeutic target of HF. Show less
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute config Show more
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute configurations were unambiguously elucidated by analysis of extensive NMR spectroscopy, ECD, and HRESIMS, as well as enzymatic hydrolysis. In vitro bioassay, compound 7 showed obvious inhibitory effects on the production of Aβ40 and Aβ42, with IC Show less
Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfuncti Show more
Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfunction in endothelial cells (ECs). Endothelial cell-specific molecule 1 (ESM1), has been identified as a marker for activated ECs. Nevertheless, the mechanisms underlying ESM1-induced endothelial cell proliferation remain elusive. The expression of ESM1, ANGPTL4 and autophagy related protein were confirmed by western blot. Proliferation ability was tested by MTT and EdU. Lipids level was confirmed by Oil red staining. Autophagic flux was confirmed by Monodansylcadaverine (MDC) staining and pCMV-mCherry-GFP-LC3B fluorescence staining assay. The mouse model of AS was used to observe the effect of PA on the ESM1-ANGPTL4-autophagy signaling axis. This study elucidates ESM1-ANGPTL4 axis in maintaining proliferation of ECs and lipid reprogramming. Furthermore, it has been observed that PA has the ability to stimulate EC to autonomously increase the expression of ESM1, which in turn can counteract the detrimental effects of PA on ECs. Conversely, when ESM1 is suppressed, the damaging effects of PA on ECs are exacerbated. Mechanistically, our findings indicate that ESM1 facilitates EC proliferation and lipids homeostasis by up-regulating autophagy through ANGPTL4. This effect of ESM1 on ECs can be attenuated by ATG7 inhibiting. Additionally, the serum levels of ESM1 were found to be elevated in AS mice. ESM1 was found to enhance ECs proliferation and mitigate endothelial cell injury induced by PA through the upregulation of autophagy. This mechanism potentially serves as a protective factor against atherosclerosis progression. Show less
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompl Show more
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of Show more
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn Show less
The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a Show more
The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a reference for exploring the hypoxic adaptation mechanism of other animals. To grope for the genetic mechanism of adaptation to the hypoxic environment at the transcriptional level in Tibetan sheep testicular tissue, and to identify candidate genes and key pathways related to sheep adaptation, histological observation of testicular tissues from two sheep breeds was carried out using haematoxylin-eosin (HE) conventional staining. A total of 103 differentially expressed genes (DEGs) were authenticated in high altitude Tibetan sheep (ZYH) and low altitude Tibetan sheep (ZYM) by RNA sequencing technology (RNA-Seq), which included 50 up-regulated genes and 53 down-regulated genes. Functional analyses revealed several terms and pathways that were closely related to testis adaptation to the plateau. Several genes (including GGT5, AGTR2, EDN1, LPAR3, CYP2C19, IGFBP3, APOC3 and PKC1) were remarkably enriched in several pathways and terms, which may impact the Plateau adaptability of sheep by adjusting its reproductive activity and sexual maturation, and protecting Sertoli cells, various spermatocytes, and spermatogenesis processes. The results make a reasonable case for a better understanding of the molecular mechanisms of adaptation to altitude in sheep. Show less
The treatment and prognosis of cardiac amyloidosis (CA) depend heavily on the accurate identification of amyloid protein types. Histopathological methods are the most commonly used approach, but often Show more
The treatment and prognosis of cardiac amyloidosis (CA) depend heavily on the accurate identification of amyloid protein types. Histopathological methods are the most commonly used approach, but often produce inconclusive results. The application of mass spectrometry with laser microdissection mass spectrometry based on non-targeted proteomics in CA diagnosis is gradually being recognized, but it is expensive, time-consuming, and still in the early stages of scientific research applications. This study aims to establish a novel typing method based on targeted semi-quantitative proteomics to address the shortcomings of existing methods. Formalin-fixed, paraffin-embedded (FFPE) myocardial tissue samples from 52 CA and 52 hypertrophic cardiomyopathy (HCM) patients were analyzed. A semi-quantitative typing method was developed using triple quadrupole mass spectrometry, with laser microdissection mass spectrometry (LMD-MS) serving as the reference standard. A total of 52 peptides were analyzed. Key amyloid-associated proteins (AAPs) -apolipoprotein A-IV (apo A-IV), apolipoprotein E (apo E), and serum amyloid P component (SAP) - showed high diagnostic accuracy, with AUC values of 0.964, 0.999, and 0.923, respectively. Transthyretin (TTR), immunoglobulin light chains- κ (IGL - κ), and IGL-λ were semi-quantified using normalized scores (NS) adjusted for microdissection and peptide peak areas. An NS This targeted semi-quantitative mass spectrometry method has high consistency with non-targeted LMD-MS typing, with an accuracy higher than IHC (100 % vs. 30.8 %), while compensating for the shortcomings of non-targeted proteomics. It provides a practical method for CA typing in routine clinical laboratories and may help identify rare subtypes of amyloidosis in the future. Show less
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of le Show more
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of lean meat percentage, and a slower growth rate. Crossbreeding with lean-type breeds, such as Large White, Landrace, and Berkshire can enhance offspring traits, and increase genetic diversity. In this study we employed RNA-seq technology to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (SAT) samples from HN pigs and their crosses with multiple breeds (with three replicates per group). In the SAT of Huainan × Berkshire pigs (BH), Huainan × Yorkshire pigs (YH), and Huainan × Landrace pigs (LH), numerous key functional genes were identified, including In conclusion, these findings offer valuable insights and provide a foundation for future research on the molecular mechanisms underlying fat deposition in pigs. Show less
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on c Show more
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on coagulation remains unclear. To investigate the effects of ApoA-IV on the coagulation system, including its interactions with potential targets and the underlying mechanisms. Plasma ApoA-IV levels in deep vein thrombosis patients were tested by enzyme-linked immunosorbent assay. The effects of ApoA-IV on coagulation were assessed through thromboelastography. Potential interactions and mechanisms were analyzed using surface plasmon resonance and AlphaFold 3. Mice bleeding and stroke models were employed to evaluate the effects on hemostasis and thrombosis. ApoA-IV levels were reduced in deep vein thrombosis patients and correlated with increased thrombotic risk. Thromboelastography showed that ApoA-IV treatment delayed clot reaction and kinetic times while decreasing thrombus generation angle and maximum amplitude, highlighting its crucial role in inhibiting coagulation and platelet aggregation. We identified ApoA-IV as a functional activator of activated protein C (APC), with critical interactions occurring at residues 144 to 148 within the exosite loop of the APC protease domain. In animal models, anti-ApoA-IV antibody administration shortened bleeding time but exacerbated ischemic stroke outcomes. Notably, inhibitory peptide HE5, which inhibits ApoA-IV-APC interaction, effectively counteracted the anticoagulant activity of ApoA-IV. These findings establish ApoA-IV as a pivotal regulator of coagulation and hemostasis, primarily through enhancing APC activity. This research advances our understanding of the interplay between inflammation, lipid metabolism, and thrombosis, offering insights for developing novel antithrombotic therapies. Show less
The benefits of plant essential oils (EO) on the health of animals have been frequently reported, but their alteration of lipid metabolism in obese pigs has yet to be explored. This study aimed to ass Show more
The benefits of plant essential oils (EO) on the health of animals have been frequently reported, but their alteration of lipid metabolism in obese pigs has yet to be explored. This study aimed to assess the impact of EO blends (oregano, cinnamon and lemon oils) on growth performance, meat physicochemical parameters, intestinal health and lipid metabolism in the small intestine of weaned Bamei (a kind of obese-type pig) piglets. One hundred and forty-four male 60-day-old weaned Bamei piglets were randomly assigned to three groups of six replicates each: CON (basal diet), T1 (basal diet + 250 mg/kg EO), and T2 (basal diet + 500 mg/kg EO) over 28 days. The results showed that T1 trended to improve the average daily gain and feed intake to body gain ratio (p < 0.1), reduced water loss (p < 0.05), and increased the redness of meat (p < 0.05) compared to the CON. In addition, a significant change in the proportion of C17:0 and C20:1 was observed in the meat of T1 (p < 0.05). Improved intestinal health was evidenced by the reduced crypt depth, improved villi-to-crypt length ratio, and better superoxide dismutase activity in T1 (p < 0.05). Further study on intestinal lipid metabolism showed that duodenal lipase activity and the mRNA expression levels of lipid transport-related genes in the jejunum (FABPs, APOA1, APOB and ACSL3) were significantly reduced, alongside diminished serum lipid metabolites (Total protein and triglyceride) in the groups fed with EO (p < 0.05). In short, EO supplementation especially at 250 mg/kg improved intestinal health and inhibited lipid metabolism, which had a positive effect on the overall performance of Bamei piglets. This new evidence contributes to understanding the early regulatory role of EO in obese pigs and their potential to alleviate adolescent obesity. Show less
Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, Show more
Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, more than 30% of patients either fail to respond initially or lose response over time, underscoring the need for a deeper mechanistic understanding of immunogenetic pathways and the development of individualized therapeutic strategies. We first discuss how newly identified susceptibility genes (e.g., IL23R, NOD2, BDNF, SLC) and their polymorphisms influence immune cell function and epithelial barrier integrity. Single-cell technologies have further revealed novel cell subsets and interactions underlying disease heterogeneity. We then explore the clinical efficacy of classical and emerging targeted therapies, including cytokine-specific biologics, JAK inhibitors, and novel strategies aimed at restoring regulatory T-cell function or blocking integrin-mediated lymphocyte trafficking. Additionally, we highlight promising therapeutic approaches such as fecal microbiota transplantation, microbial metabolite-based interventions, and nanotherapeutics. We further discuss how genetic insights and immune biomarkers can facilitate treatment personalization and improve prognostic stratification. Ultimately, this review emphasizes the transition from broad immunosuppression to precision medicine and proposes integrated approaches-combining multiomics profiling, immune monitoring, and novel therapeutics-to achieve sustained remission and improve long-term outcomes in IBD patients. Show less
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing Show more
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium. Show less
Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP Show more
Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout of NUP85, NUP107, or NUP133 in immortalized human podocytes activates CDC42, an important effector of SRNS pathogenesis. However, it is unknown whether or not loss of NUP160 dysregulates CDC42 in the podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter genes using CRISPR/Cas9 and Cre/loxP technologies. We investigated nephrotic syndrome-associated phenotypes in the Nup160podo-/- mice, and performed single-cell transcriptomic and proteomic analysis of glomerular suspension cells and cultured primary podocytes, respectively. The Nup160podo-/- mice exhibited progressive proteinuria and fusion of podocyte foot processes. We found decreased Cdc42 protein and normal Cdc42 transcriptional level in the podocytes of the Nup160podo-/- mice using analysis of single-cell transcriptomes and proteomes. We subsequently observed that Cdc42 protein decreased in both kidney tissues and cultured primary podocytes of the Nup160podo-/- mice, although Cdc42 mRNA levels were elevated in the cultured primary podocytes of the Nup160podo-/- mice. We also found that Cdc42 activity was significantly reduced in the cultured primary podocytes of the Nup160podo-/- mice. In conclusion, loss of Nup160 dysregulated Cdc42 in the podocytes of the Nup160podo-/- mice with proteinuria and fusion of podocyte foot processes. Our findings suggest that the dysregulation of CDC42 may contribute to the pathogenesis of SRNS in patients with mutations in NUP160. Show less
Qianzhu Jiang, Huiting Li · 2025 · Journal of bioenergetics and biomembranes · Springer · added 2026-04-24
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific Show more
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific enhancer factor 2 A (MEF2A) is implicated in cardiac fibroblast activation, its role in MF remains unclear. We manipulated MEF2A expression in cardiac fibroblasts (CFs) through knockdown and overexpression, and assessed fibrosis markers, migration, and RhoA signaling. Binding of MEF2A to the Snail1 promoter was predicted using JASPAR and validated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Rescue experiments with Snail1 overexpression and RhoA inhibition were performed. An angiotensin II (Ang II)-induced MF mouse model was used to evaluate cardiac function by echocardiography and to assess collagen deposition through picrosirius red (PSR) staining. MEF2A was significantly upregulated in Ang II-induced fibrotic hearts and CFs. MEF2A knockdown reduced α-SMA and Col1a1 expression, inhibited CF migration, and suppressed activation of the Snail1/RhoA/α-SMA pathway. ChIP and luciferase assays confirmed the direct binding of MEF2A to the Snail1 promoter. Inhibition of RhoA signaling reversed MEF2A-induced myofibroblast activation and migration. Rescue experiments showed that Snail1 overexpression restored the fibrotic phenotype suppressed by MEF2A knockdown. In vivo, MEF2A knockdown improved left ventricular function, reduced collagen deposition (PSR staining), and lowered heart weight/tibia length ratios. MEF2A promotes myocardial fibrosis by directly activating Snail1 and engages the RhoA/α-SMA pathway. Targeting MEF2A offers a promising therapeutic strategy to attenuate MF and improve heart function. Show less
The comorbidity of major depressive disorder (MDD) and Parkinson's disease (PD) were prevalent and has a profound impact on patients. However, whether this comorbidity results from specific pathologic Show more
The comorbidity of major depressive disorder (MDD) and Parkinson's disease (PD) were prevalent and has a profound impact on patients. However, whether this comorbidity results from specific pathological processes or a mutual cause-and-effect relationship was largely controversial. Additionally, although MDD can appear before or after PD, the health impact of the comorbidity sequence is poorly understood. We used mendelian randomization (MR) and UK biobank (UKB) cohort to explore the associations between MDD and PD. MR was also utilized to investigate potential confounders. By classifying UKB patients into MDD first and PD first groups, we evaluated the health impact of the comorbidity sequence using Cox regression. Bidirectional MR and cohort study showed conflicting results. MR did not find associations between MDD followed by PD (odds ratio [OR] = 1.28, 95 % confidence interval [CI] = 0.85-1.94) or PD followed by MDD (OR = 0.99, 95 % CI = 0.97-1.01). However, the cohort study found a significant effect of MDD on PD (hazard ratio [HR] = 1.75, 95 % CI = 1.55-1.97) and PD on MDD (HR = 4.35, 95 % CI = 3.65-5.19). By performing MR on 4709 proteins, we identified ESD, LEAP2, NDRG3, NRXN3, and PLXNB2 as potential common causes of MDD and PD. Additionally, PD first group had higher risks of all-cause mortality (HR = 1.65, 95 % CI = 1.03-1.90), dementia (HR = 1.88, 95 % CI = 1.16-3.04), and aspiration pneumonia (HR = 1.89, 95 % CI = 1.09-3.27). Our study suggested the comorbidity of MDD and PD is likely the result of certain pathological processes. Additionally, patients with PD first had higher risks of several adverse outcomes. Show less
To investigate the effects and the underlying mechanism(s) of conbercept on the phagocytosis of hard exudates (HEs) by Müller glia in diabetic retinopathy (DR). Twenty-one eyes from 17 patients with d Show more
To investigate the effects and the underlying mechanism(s) of conbercept on the phagocytosis of hard exudates (HEs) by Müller glia in diabetic retinopathy (DR). Twenty-one eyes from 17 patients with diabetic macular edema (DME) underwent optical coherence tomography (OCT) imaging to examine the changes of HEs before and after intravitreal conbercept injection (IVC). The area of HEs showed minimal change after the first IVC (1.39±1.41 to 1.38±1.3 mm Conbercept reduces HEs in DR by enhancing Müller glia phagocytosis possibly through activating PPARγ-CD36 axis, which is mediated by inhibition of VEGF signaling. Modulation of Müller glia phagocytic capacity might provide a novel therapeutic strategy to treat DR and DME. Show less
The color of rice leaves are important agronomic traits that directly influence the proportion of sunlight energy utilization and ultimately affect the yield and quality, so it is crucial to excavate Show more
The color of rice leaves are important agronomic traits that directly influence the proportion of sunlight energy utilization and ultimately affect the yield and quality, so it is crucial to excavate the mechanism of regulating rice leave color. To investigate the molecular mechanism that triggers the purple color in rice leaf, phenotypic characterization and genome-wide transcriptome analysis were conducted using the japonica rice cultivar nipponbare (Nip) and its two purple leaf mutants, A total of 2247, 5484, 4525, 2103, 4375 and7029DEGs (differentially expressed genes) were identified in nip-a vs These results not only revealed the molecular mechanism triggering leaf purple color in the rice mutants Show less
Angiopoietin-like proteins (ANGPTLs) represent a family of secreted glycoproteins that are extensively expressed in vivo and are integral to various pathophysiological processes, including glucose and Show more
Angiopoietin-like proteins (ANGPTLs) represent a family of secreted glycoproteins that are extensively expressed in vivo and are integral to various pathophysiological processes, including glucose and lipid metabolism, stem cell proliferation, local inflammation, vascular permeability, and angiogenesis. Particularly interesting is ANGPTL4, which has been identified as a significant factor in the development and progression of diabetic retinopathy (DR), thus becoming a central focus of DR research. ANGPTLs modulate metabolic pathways, enhance vascular permeability, and facilitate pathological angiogenesis, in addition to causing intraocular inflammation. As promising molecular targets, ANGPTLs not only serve as biomarkers for predicting the onset and progression of DR but also present therapeutic potential through antibody-based interventions. This paper discusses the pathogenesis of DR and the potential applications of ANGPTLs in early diagnosis and targeted therapy. It provides references for advancing precision diagnosis and personalized treatment strategies through more profound ANGPTLs research in the future. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying ef Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)-a bioactive glycoside from Show less