Search Results (7,515)

Diabetic wounds are a common and severe complication of diabetes mellitus, characterized by delayed healing due to persistent inflammation, impaired angiogenesis, and cellular dysfunction. Conventional therapeutic approaches remain limited in efficacy. In recent years, exosomes have attracted considerable attention in wound healing and regenerative medicine because of their crucial role in intercellular communication and tissue repair. However, rapid clearance of exosomes in vivo greatly limits their therapeutic efficacy. To address this critical limitation, we engineered a decellularized extracellular matrix (dECM)-based hydrogel system functionalized with exosomes derived from skin-derived precursor cells (SKPs). This biomimetic scaffold was designed to serve as a local exosome-delivery platform at the wound site, with the aim of improving exosome utilization and augmenting their regenerative effects. Comprehensive in vitro characterization demonstrated that the exosome-loaded composite hydrogels exhibited robust pro-angiogenic activity, as evidenced by enhanced endothelial cell proliferation, migration, and tube formation. Moreover, the hydrogels displayed significant antibacterial effects against wound-relevant pathogens and potent reactive oxygen species (ROS)-scavenging capacity, thereby mitigating oxidative damage. Notably, the composite hydrogels also promoted the phenotypic polarization of macrophages toward the pro-regenerative M2 phenotype. In parallel, in vivo studies using a streptozotocin-induced diabetic rat wound model confirmed that treatment with the composite hydrogels significantly accelerated wound closure rates compared to control groups. Histological and immunohistochemical analyses revealed enhanced angiogenesis, as evidenced by increased CD31-positive microvessel density, as well as improved collagen deposition, re-epithelialization, and an attenuated local inflammatory microenvironment characterized by reduced pro-inflammatory cytokine expression and elevated M2 macrophage infiltration. Collectively, the SKPs exosome-loaded dECM based composite hydrogels developed in this study represent a potential therapeutic strategy for the treatment of diabetic wounds. Full article

Background: The CD163+ macrophage is considered a key component of the tumor immune microenvironment (TIME) in osteosarcoma (OS) in relation to tumor progression and chemotherapy resistance. However, the relationship between CD163+ macrophage infiltration and the efficacy of neoadjuvant chemotherapy (NACT) in OS remains unexplored. Methods: This study collected a total of 195 biopsy samples from newly diagnosed, pretreated OS patients. The infiltration of CD163+ macrophages was evaluated using immunohistochemical (IHC) staining with anti-CD163 antibody. Additionally, multiplex fluorescence staining (CD8, CD68, CD163, and PDL1) was employed to further characterize the TIME profiles associated with different levels of CD163+ macrophage infiltration. The relationships between various clinical characteristics, survival outcomes, and CD163+ macrophage infiltration levels were also assessed. Results: CD163+ macrophages in biopsy tissues ranged from 2.25 cells/mm² to 3974.79 cells/mm² and 1.37 cells/mm² to 3027.20 cells/mm² in the training and validation cohorts respectively. Multivariate analysis identified that CD163+ macrophage density was an independent predictor for NACT response. Importantly, patients with high CD163+ macrophage infiltration exhibited poorer DFS, DMFS, and RFS than their counterparts. Conclusions: CD163+ macrophage infiltration was an independent predictor for NACT response. Patients with high CD163+ macrophage density benefited less from NACT and exhibited a more immunosuppressive TIME than low-density patients. Full article

Manganese-based cathodes offer high capacity, low cost, and safety for aqueous zinc-ion batteries (AZIBs), yet suffer from Mn dissolution, Jahn–Teller distortion, and sluggish Zn²⁺ kinetics. Herein, a Zn/Co co-doped MnO nanoporous carbon composite (denoted as ZnCo-MnO@NPC) derived from a bimetallic ZnCoMn metal–organic framework (ZnCoMn-MOF-74) is successfully synthesized and proposed as a high-performance cathode to address these challenges. The introduction of Zn²⁺ increases the initial specific capacity of MnO, while Co doping effectively suppresses the Jahn–Teller distortion and improves the integrity of the structure. Furthermore, the nanoporous carbon matrix facilitates electrolyte infiltration and accelerates ionic transport. To further suppress dendrite growth and enhance cycling stability, a zeolitic imidazolate framework (ZIF-8) protective layer is engineered on the zinc anode (denoted as ZIF-8@Zn), effectively mitigating dendrite formation. The ZnCo-MnO@NPC//ZIF-8@Zn full cell demonstrates superior electrochemical performance, delivering 281.3 mAh g⁻¹ at 0.1 A g⁻¹ and retaining 98.7% of this value after 3500 long-term cycles at 2.0 A g⁻¹, a remarkable finding that underscores its potential for high-performance energy storage. Collectively, this work highlights that transition metal ion doping represents an effective way to design efficient high-performance MOF-derived cathodes of AZIBs. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) involves complex interactions between immune evasion and metabolic reprogramming. This study aimed to characterize ccRCC through integrated immunometabolic profiling, develop a prognostic signature, and investigate the functional role of the key driver gene UCN using in vitro and in vivo approaches. Methods: Integrated immunometabolic profiling was performed to identify molecular subtypes and establish a prognostic gene signature. Two distinct molecular subtypes were identified, and a 9-gene Immune Metabolic Index (IMI) was constructed. The functional role of the key driver gene UCN was investigated through in vitro functional assays and in vivo xenograft models in BALB/c mice, including combination with PD-1 blockade. Results: Two molecular subtypes with significant survival differences (p < 0.001) were identified. The established IMI demonstrated high prognostic accuracy, with Area Under the Curve (AUC) values of 0.813, 0.751, and 0.779 at 1-, 3-, and 5-year intervals, respectively. UCN was identified as the highest-risk gene in the signature. Functional assays showed that UCN silencing significantly inhibited cell proliferation and migration (p < 0.05). In BALB/c mouse xenograft models, UCN silencing remodeled the tumor microenvironment by increasing CD8+ T cell infiltration and reducing regulatory T cells (p < 0.01). Furthermore, UCN knockdown significantly suppressed tumor growth and synergized with PD-1 blockade to enhance antitumor efficacy (p < 0.001). Conclusions: The IMI is a robust tool for risk stratification in ccRCC. Targeting the UCN-driven immunometabolic axis represents a promising therapeutic strategy to overcome immune resistance in ccRCC. Full article

Background/Objectives: Zebrafish fin regeneration serves as a classic model for investigating vertebrate tissue regeneration, yet the core regulatory networks and their crosstalk with the immune microenvironment remain incompletely characterized. This study aimed to identify hub genes, and elucidate the underlying molecular mechanisms and immune microenvironment dynamics during zebrafish fin regeneration. Methods: We integrated multiple bulk RNA-seq datasets of zebrafish fin regeneration from the GEO database, followed by data standardization with batch effect removal. Hub genes were screened via differential expression analysis, weighted gene co-expression network analysis (WGCNA), and predictive models constructed with 13 classic machine learning algorithms. Functional enrichment, time-ordered gene co-expression network (TO-GCN) method, immune infiltration analyses and RT-qPCR validation were further performed. Results: We identified upregulated differentially expressed genes, regeneration-correlated gene modules and their overlapping genes, including 82 candidate genes and 10 hub genes enriched in cytoskeleton remodeling, extracellular matrix organization, and focal adhesion. Temporal analysis uncovered hierarchical gene regulation and functional switching during regeneration. Hub gene expression was significantly correlated with the infiltration of B cells, M1/M2 macrophages and CD8+ T cells, revealing a stage-specific immune microenvironment. RT-qPCR validation showed high consistency with the multi-omics data. Conclusions: This study provides potential gene targets for understanding zebrafish fin regeneration, and offers a valuable reference for investigating the crosstalk between regulatory networks and the immune microenvironment in vertebrate tissue regeneration. Full article

Background/Objectives: Extraintestinal pathogenic Escherichia coli (ExPEC) is a major pathogen that causes septicemia, meningitis, and polyserositis in pigs. The increasing prevalence of antimicrobial resistance and the diverse serotypes of ExPEC highlight the urgent need for broadly protective vaccines. Methods and Results: In this study, an OmpC epitope vaccine based on the T4 phage display system was developed and evaluated. Two B-cell epitopes (OmpC-1 and OmpC-2) were identified by bioinformatic analysis and displayed on recombinant T4 phages. Immunization induced strong antigen-specific IgG responses, with the OmpC-1-T4 group showing significantly higher antibody titers than the OmpC protein group. In the O11 serotype PCN033 challenge model, survival rates reached 100% in the OmpC-1-T4 group, 60% in the OmpC-2-T4 group, and approximately 80% in the OmpC protein group. In the O18 serotype 2103 challenge model, both recombinant phage groups had survival rates of approximately 60%, whereas all the mice in the OmpC protein group died within three days. OmpC-1-T4 immunization also significantly reduced bacterial loads in lung and brain tissues after PCN033 infection and decreased TNF-α and IL-6 expression in lung tissues, accompanied by reduced inflammatory infiltration and tissue damage. Conclusions: Overall, the T4 phage-displayed OmpC epitope vaccine induced strong humoral immunity and provided protection against different ExPEC serotypes. Among the candidates, OmpC-1-T4 showed superior immune protection, bacterial clearance, and inflammation control, supporting its potential as a vaccine candidate against porcine ExPEC infection. Full article

Cardiovascular disease represents the primary cause of morbidity and mortality among patients with chronic kidney disease (CKD). Emerging evidence suggests that coronary artery pathology in CKD diverges from the traditional atherosclerotic phenotype seen in individuals with maintained renal function. This review delineates coronary artery-specific alterations in CKD, focusing on mechanisms that expedite atherogenesis, characteristics of plaques, calcific remodeling, and dysfunction of the coronary microvasculature. CKD fosters a pro-inflammatory, pro-oxidative, and pro-calcific environment, which results in endothelial damage and vascular calcification remodeling. Furthermore, coronary plaques in CKD are more likely to exhibit larger lipid-rich necrotic cores, heightened inflammatory cell infiltration, a significant calcific burden, and vulnerability indicators such as cholesterol crystals and microdisruptions. Impaired coronary microvascular function is also prevalent and may account for ischemia with non-obstructive coronary arteries. In summary, CKD is linked to a rapid, calcification- and inflammation-driven form of coronary disease characterized by both macrovascular plaque remodeling and microvascular dysfunction. This underscores the necessity of early identification and prevention of cardiovascular risk, targeting CKD-specific mechanisms in conjunction with conventional risk factors. Full article

Vitiligo is characterized by epidermal melanocyte destruction, with autoreactive CD8⁺ T cells playing a central pathogenic role, yet the mechanisms driving their hyperactivation remain unclear. Lactate has emerged as a key immunometabolite that functions as both a signaling molecule and an epigenetic modulator via protein lactylation. Nevertheless, the role of lactate in vitiligo pathogenesis has not been explored. Here, we report that serum lactate levels are significantly elevated in vitiligo patients and correlate positively with disease activity. In a mouse model, lactate administration accelerated vitiligo progression, accompanied by increased CD8⁺ T cell infiltration and melanocyte destruction in lesional skin. In vitro, lactate enhanced CD8⁺ T cell effector molecule expression (granzyme B, perforin, IFN-γ, CD107a) and cytotoxic function. Mechanistically, lactate increased global protein lactylation in CD8⁺ T cells, with marked enrichment at histone H3 lysine 9 (H3K9). H3K9 lactylation (H3K9la) was associated with enhanced chromatin accessibility and transcriptional activation of effector genes, as revealed by RNA sequencing and CUT&Tag analyses. Pharmacological inhibition of lactate production or lactylation abrogated these effects. Collectively, our findings identify lactate as a critical driver of CD8⁺ T cell pathogenicity in vitiligo through H3K9la-mediated epigenetic reprogramming, highlighting lactate metabolism and lactylation as potential therapeutic targets. Full article

In the hepatobiliary system, the majority of neoplasms grow within the hepatic parenchyma; however, some arise, grow, and/or spread within the lumen of the intrahepatic large bile ducts and the perihilar/distal bile ducts (collectively referred to as large bile ducts), representing specialized ductal organs associated with unique peribiliary glands and being distinct from the intrahepatic small bile ducts and bile ductules embedded within the hepatic parenchyma. Precursors of cholangiocarcinoma (CCA) arising within the lumen of large bile ducts have recently been proposed. Neoplasms growing and spreading within the lumen of large bile ducts have been categorized into four groups and are discussed here in light of updated pathological findings. (i) Precursor(s) of CCA arising in the large bile ducts (large-duct-type intrahepatic CCA and perihilar/distal CCA): These precursors include high-grade biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile duct (IPNB), and intraductal oncocytic papillary neoplasm (IOPN). High-grade BilIN presents as a flat, microscopic lesion with dysplastic cytoarchitectural alterations and grows along the luminal surface of large bile ducts, whereas the latter two present as grossly visible polypoid or tumorous lesions composed of papillary, villous, or tubular proliferation of neoplastic epithelium with delicate fibrovascular cores. These lesions may eventually progress to invasive CCA. Intraductal tubulopapillary neoplasm of the bile duct (ITPN), previously categorized as another precursor of CCA arising in large bile ducts, appears to represent a heterogeneous group of neoplasms with respect to progression and presumed cell of origin. Some ITPNs are frequently associated with nodular invasive carcinoma resembling small-duct-type intrahepatic CCA (SD-iCCA) and share genetic alterations with SD-iCCA; such cases may arise in association with small bile ducts or bile ductules. In contrast, other ITPNs exhibit cystic changes with tubulopapillary features and may arise in association with peribiliary glands or cysts. (ii) Secondary growth and spread of biliary neoplasms: This category comprises several patterns. First, intraepithelial neoplastic spread directly and continuously from the primary neoplastic lesion is observed in almost all cases of high-grade BilIN, IPNB, and IOPN; it spreads laterally along the luminal surface of the proximal and distal bile ducts and extends vertically into the adjacent peribiliary glands. Intraluminal cast-like spread in the bile ducts adjacent to the primary neoplastic lesion also occurs in some precursor lesions, particularly in ITPN. Implantation of a biliary neoplasm from one part of the biliary tract to another results in discontinuous, multifocal biliary neoplasms, particularly in IPNB, and occurs mainly in the distal bile ducts relative to the main tumor. Multicentric tumorigenesis may contribute to the multifocal development of precursors and CCA in the bile ducts. The accumulation of additional genetic alterations, beyond the common mutations detected in primary tumors, may contribute to metachronous recurrence of CCA after curative resection of the primary biliary tumor. Cancerization of the duct (COD) by CCA may also contribute to secondary growth and spread within the bile duct lumen. Specifically, flat-type cancerization of pre-existing non-neoplastic bile ducts, resembling high-grade BilIN, occurs in approximately one-third of hilar CCA cases. Intraductal polypoid, cast-like cancerization within the lumen of adjacent bile ducts, resembling polypoid precursors of CCA, can also occur in approximately one-tenth of SD-iCCA. (iii) Prominent intraductal polypoid growth of invasive CCA: Invasive CCA rarely presents with predominant intraductal polypoid carcinoma that is continuous with periductal infiltrating CCA; this pattern can be referred to as polypoid invasive CCA. (iv) Nonbiliary neoplasms presenting bile duct tumor thrombus (BDTT): BDTT associated with hepatocellular carcinoma and with extrahepatic malignancies extending into the bile duct lumen can mimic the intraluminal growth and spread patterns of the above-mentioned biliary neoplasms. In conclusion, intraluminally growing biliary neoplasms in the large bile ducts comprise a heterogeneous group that can be reasonably classified into four categories. This categorization may facilitate understanding of these intrabiliary growing neoplasms. Full article

Background and Clinical Significance: Chromothripsis represents a catastrophic genomic event in plasma cell myeloma (PCM) associated with poor prognosis. We report a case of newly diagnosed PCM with complex cytogenetic abnormalities indicative of genomic instability. Case Presentation: A 67-year-old man presented with acute dyspnea and was found to have severe acute kidney injury, anemia, hypercalcemia, and IgG lambda monoclonal gammopathy. Bone marrow biopsy revealed plasma cell infiltration. Comprehensive FISH analysis demonstrated a complex pattern with gain of 1q, monosomy 13, and multiple numeric and structural abnormalities affecting chromosomes 5, 9, and 15, suggestive of a chromothripsis-like pattern. Despite requiring hemodialysis, the patient achieved complete renal recovery and >99% reduction in serum-free light chains after one cycle of CyBorD plus daratumumab, which was continued for four cycles. Follow-up bone marrow evaluation at three months confirmed complete histologic, flow cytometric, and cytogenetic remission, allowing for preparation for autologous stem cell transplantation. Conclusions: This case demonstrates that exceptional clinical responses can be achieved in high-risk disease with contemporary quadruplet regimens. While the long-term durability of such responses in genomically unstable cases remains uncertain, this case highlights the importance of comprehensive cytogenetic characterization to identify and monitor genomic instability in PCM. Full article

NLRP1 is an inflammasome sensor protein expressed in barrier tissues of humans. Its activation in response to microbes or cellular stress triggers a cascade of molecular events, leading up to IL1β-driven inflammation and pyroptosis. Rare germline mutations of NLRP1 cause its persistent activation, resulting in autoinflammatory syndromes. Multiple self-healing palmoplantar carcinoma (MSPC) is one such syndrome, characterized by the appearance of recurrent keratoacanthomas (KAs) on the palms and soles. Here, we aimed to compare the subcellular localization of mutant NLRP1 in lesions from an MSPC patient to wild-type NLRP1 in non-MSPC-KAs and in skin from healthy donors. Using mass spectrometry, immunohistochemistry and immunoelectron tomography, we found that NLRP1 localized to mast cell granules in all MSPC lesions but also in healthy skin, a novel finding which implicates these cells in NLRP1-associated responses in human skin. Moreover, we found that mast cells expressing the A66V pathogenic variant of NLRP1 overpopulated MSPC-KAs, infiltrated the epidermis and degranulated, a behavior not seen in other lesions from this study. The released granules had the highest NLRP1 protein content and also contained NLRP3 and IL1β, suggesting the coexistence of inflammasome pathways within mast cells. Taken together, our findings propose cutaneous mast cells as a previously unrecognized NLRP1 reservoir in health and disease. Full article

Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by an intrinsic resistance to immunotherapy, primarily due to its low immunogenicity and immune-cold tumor microenvironment. The mechanisms underlying this resistance remain poorly understood. Methods: A systematic screen of 796 epigenetic regulators was performed to identify candidate genes associated with effector CD8⁺ T cell infiltration and clinical outcomes following chemoimmunotherapy in SCLC. This analysis integrated several public SCLC datasets, including single-cell RNA sequencing (scRNA-seq) data from 20 SCLC tumors, bulk RNA-seq data from the IMpower133 cohort, proteomic profiles from the TU-SCLC cohort, and an independent scRNA-seq dataset of 39 SCLC tumors. In vitro and in vivo functional experiments were conducted to investigate the role of the candidate genes in SCLC. Results: The epigenetic regulator TAF1 emerged as a key candidate, with its expression negatively correlating with effector CD8⁺ T cell infiltration in SCLC. Clinically, patients with low TAF1 expression in tumors showed better outcomes following atezolizumab-based chemoimmunotherapy, particularly in ASCL1-high tumors. Additionally, TAF1 expression was inversely correlated with MHC-I expression. Knockdown of TAF1 in SCLC cells restored MHC-I expression, suppressed tumor growth in immunocompetent mice, and increased CD8⁺ T cell infiltration. Conclusions: TAF1 functions as a potential epigenetic suppressor of MHC-I expression in SCLC. Targeting TAF1 may represent a promising therapeutic strategy to enhance immunotherapy efficacy in SCLC. Full article

Increasing evidence suggests pancreatic cancer develops within a host–microbe ecosystem in which microbial communities across anatomical niches interact with tumour biology, immune regulation, metabolism, and therapeutic response. This review examines pancreatic cancer through the lens of humans as holobionts, integrating evidence from the oral, gut, biliary, and intratumoural microbiomes. Epidemiological and sequencing studies demonstrate consistent microbial alterations across these niches in pancreatic cancer, including oral dysbiosis associated with periodontal pathogens, gut microbial shifts toward pro-inflammatory taxa, disease-specific biliary microbial signatures, and the presence of distinct intratumoural microbial communities. Mechanistic studies indicate that intestinal barrier disruption, microbial translocation, immune and metabolite signalling can influence tumour immune architecture, macrophage polarisation, T-cell infiltration, oncogenic signalling pathways, and chemotherapeutic metabolism, particularly inactivation by tumour-associated bacteria. Microbiome-driven shifts in immunometabolism can reprogramme immune-cell metabolic pathways, impairing effective T-cell activation, promoting tumour-supportive macrophage phenotypes. Emerging therapeutic strategies aim to modulate the microbiome–tumour axis, including dietary interventions, probiotics and immunonutrition, faecal microbiota transplantation, engineered microbial therapies, and microbiome-informed antibiotic strategies. While pre-clinical findings are compelling and early-phase clinical studies suggest feasibility, most evidence remains associative and heterogeneous across cohorts and methodologies. Understanding pancreatic cancer as a multi-site ecological system may help explain inter-patient variability in disease progression and treatment response. This could usher in a new era for therapeutic manipulation where future progress will depend on longitudinal, multi-omic, and interventional studies to determine whether microbiome-targeted strategies can produce clinically meaningful improvements in pancreatic cancer outcomes. Full article

Background: Kinkeliba (Combretum micranthum G. Don), commonly used in West African traditional pharmacopeia for its anti-inflammatory and gastrointestinal properties, remains poorly studied regarding its potential role in the prevention or treatment of ulcerative colitis. Objective: This study evaluated the therapeutic potential of the ethanolic extract of Combretum micranthum (EECM) in a murine model of chronic DSS-induced colitis. Methods: Male C57BL/6 mice were subjected to three cycles of 1.5% DSS administration over nine weeks to induce chronic colitis. EECM was administered orally at 50, 100, or 200 mg/kg during the final week. Disease severity was evaluated using the Disease Activity Index (DAI), colon length, biochemical and hematological markers, along with histopathological and immunohistochemical assessment of colonic tissue. Results: EECM treatment significantly improved clinical parameters and prevented colon shortening in chronic DSS-induced colitis. These improvements were associated with the restoration of serum biochemical and hematological profiles, along with reduced histopathological damage and preservation of colonic tissue architecture. Immunohistochemical analysis further demonstrated decreased CD3-positive T-lymphocyte infiltration in colonic tissue, suggesting modulation of local immune cell responses. Conclusions: These findings highlight the therapeutic potential EECM in ulcerative colitis and support further investigations to elucidate its mechanisms of action and evaluate its efficacy in future translational studies. Full article

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease linked to epidermal barrier dysfunction, Th2-skewed immune polarization, and disrupted gut microbiota homeostasis. While probiotic interventions show promise in managing AD, the mechanisms governing strain-specific efficacy—particularly systemic modulation via the “gut–skin axis”—remaining to be fully elucidated. Methods: This study systematically compared the oral therapeutic effects of three Lacticaseibacillus rhamnosus strains (MG-A047, MG-A054, and LGG) in a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. Results: By integrating behavioral, histopathological, and serological assessments with 16S rRNA-based gut microbiota profiling and in vitro functional assays, this study offers a multidimensional evaluation of the strain-specific advantages and potential therapeutic mechanisms of three L. rhamnosus strains. The results demonstrate that MG-A054 most effectively alleviated cutaneous inflammation and pruritus, significantly reduced serum IgE and IL-4 levels, and attenuated epidermal hyperplasia and inflammatory cell infiltration (including mast cells and eosinophils). Mechanistically, this strain may directly inhibit hyaluronidase activity and mast cell degranulation, and specifically remodel the gut microbiota structure, thereby promoting a shift toward a healthier functional profile. Conclusions: These findings suggest that the superior efficacy of MG-A054 may be achieved through coordinated modulation of the gut–skin axis and related pathways. This study offers new mechanistic clues for understanding the strain-specific actions of probiotics and lays a preclinical foundation for the further development of MG-A054 as a potential targeted microecological therapy for AD. Full article