Search Results (1,438)

Chemerin, encoded by the RARRES2 gene, is an adipokine with potent immunometabolic functions mediated through CMKLR1, GPR1, and CCRL2. Its regulation is tissue- and context-dependent, conferring dual protective and pathogenic roles. In the upper GI tract, chemerin facilitates immune tolerance in Barrett’s adenocarcinoma and promotes invasion in esophageal and gastric cancers. In pancreatic disease, it acts as a biomarker of acute and chronic injury, while modulating β-cell function and carcinogenesis. In the liver, chemerin contributes to NAFLD/NASH pathogenesis with both anti-inflammatory and pro-steatotic actions, predicts prognosis in cirrhosis, and demonstrates tumor-suppressive potential in hepatocellular carcinoma. In IBD, chemerin exacerbates colitis via impaired macrophage polarization, yet protects epithelial antimicrobial defense, underscoring its context-specific biology. Collectively, these findings position chemerin as a versatile regulator bridging metabolic dysfunction, inflammation, and gastrointestinal malignancy, and as a potential candidate for biomarker development and therapeutic intervention. Full article

Dysregulated redox signaling, mitochondrial dysfunction and impaired autophagy form an interconnected network that drives inflammatory and immune responses in cardiovascular disease. Among these, disturbances in redox balance, largely mediated by reactive oxygen species (ROS), serve as key drivers linking inflammatory signaling to adverse cardiovascular outcomes. Mitochondria are essential for energy production and cellular homeostasis, but their dysfunction leads to the accumulation of excessive ROS, which triggers inflammation. This pro-oxidative milieu disrupts immune regulation by activating inflammasomes, promoting cytokine secretion, triggering immune cell infiltration and ultimately contributing to cardiovascular injury. Conversely, intracellular degradation processes such as mitophagy alleviate these effects by selectively eliminating dysfunctional mitochondria, thereby decreasing ROS levels and maintaining immune homoeostasis. These interconnected processes influence myeloid cell function, including mitochondrial reprogramming, macrophage polarization and autophagic activity. The modulation of these immune responses is crucial for determining the severity and resolution of cardiac and vascular inflammation, and consequently the extent of cellular injury. This review examines the latest developments and understanding of the intricate relationships between redox signaling, mitochondrial dysfunction, autophagy and oxidative stress in modulating inflammation and immune responses in cardiovascular diseases. Understanding these interrelationships will inform future studies and therapeutic solutions for the prevention and treatment of cardiovascular diseases. Full article

Background: Diabetic wound healing has always been a clinical challenge with minimal response or efficacy to standard treatment. This study aims to assess the therapeutic potential of hypoxia-induced extracellular vesicles (hy-EVs) produced by human umbilical cord mesenchymal stem cells (HUCMSCs) to treat diabetic wounds. Methods: HUCMSCs were isolated from umbilical cord tissue, cultured under hypoxic conditions to induce the release of extracellular vesicles (EVs) and compared with normoxia-induced extracellular vesicles (n-EVs). We assessed the functions of hy-EVs on human skin fibroblasts (HSFs) and human umbilical vein endothelial cells (HUVECs) in vitro. Simultaneously, we analyzed the pro-angiogenic effects of hy-EVs, their effects on macrophage polarization, and their ability to scavenge endogenous reactive oxygen species (ROS). In addition, a diabetic wound model was established to assess the curative effect of hy-EVs in diabetic wound healing. Results: We found by in vitro study that hy-EVs markedly improved the functional activities of HSFs, thus significantly promoting wound repair. Remarkably, it was determined that hy-EVs greatly enhanced the proliferation and migration ability as well as the angiogenic ability of HUVECs, while promoting the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial-generation-associated factor A (VEGFA), and platelet endothelial adhesion molecule (CD31), which suggested that hy-EVs can effectively activate the HIF-1α pathway to promote angiogenesis. Above all, we found that hy-EVs promoted the expression of CD206 while decreasing the expression of CD86, suggesting that hy-EVs could induce macrophages to shift from M1-type (pro-inflammatory) to M2-type (anti-inflammatory), thereby modulating the inflammatory response. Additionally, hy-EVs inhibited ROS production in both HSFs and HUVECs to reduce oxidative stress. In vivo results showed that hy-EVs enhanced collagen deposition and angiogenesis, modulated macrophage polarization, and inhibited immune response at the wound spot, which significantly enhanced diabetic wound healing. Conclusions: Our study shows that hy-EVs significantly promote angiogenesis through activation of the HIF-1α pathway, modulate macrophage polarization and attenuate cellular oxidative stress, possibly through delivery of specific miRNAs and proteins. Our discoveries offer a key theoretical basis and potential application to develop novel therapeutic strategies against diabetes-related tissue injury. Full article

Hepatocellular carcinoma (HCC) is the most prevalent primary malignancy of the liver. Characterized by rapid progression and poor overall survival rates, HCC requires effective and streamlined treatment regimens. It predominantly occurs in East Asia and sub-Saharan Africa, where it has historically been managed with herbal formulas. We previously observed that the herbal formula HO-1089 exerts potent anti-HCC effects both in vitro and in vivo. In this study, we investigated the anticancer efficacy and mechanisms of HO-1197, a reconstituted herbal formulation derived from HO-1089. HO-1197 selectively inhibited the viability of HCC cell lines without hepatotoxicity and demonstrated superior anticancer activity compared with both HO-1089 and sorafenib. Mechanistically, HO-1197 induced apoptosis and G2/M arrest through reactive oxygen species-mediated DNA damage, independent of p53 status. Transcriptomic analysis revealed downregulation of mitosis-related genes, particularly those regulated by FOXM1, a key driver of HCC proliferation and metastasis. HO-1197 suppressed FOXM1 expression and nuclear translocation, reducing its downstream targets and diminishing angiogenic and metastatic potential. Furthermore, HO-1197 modulated the tumor immune microenvironment by promoting pro-inflammatory macrophage polarization and enhancing natural killer cell-mediated cytotoxicity. HO-1197 exhibited potent antitumor efficacy, and combination therapy with HO-1197 and sorafenib exhibited synergistic effects in both two-dimensional and immune-activated multicellular spheroid models. These findings suggest that HO-1197 is a promising multifunctional therapeutic candidate with antitumor, antiangiogenic, antimetastatic, and immunomodulatory properties. Its combination with sorafenib may offer effective treatment for HCC. HO-1197, which demonstrated strong efficacy, is a novel herbal medicine developed by H&O Biosis and is referred to as an Integrated Natural Medicine. Full article

Introduction: Sarcopenia, the progressive age-related decline in skeletal muscle mass, strength, and function, represents a major contributor to morbidity, frailty, and reduced quality of life in older adults. Oxidative stress and chronic low-grade inflammation are increasingly recognized as central mechanisms driving its onset and progression, through pathways involving mitochondrial dysfunction, impaired satellite cell activity, and dysregulated protein turnover. Objective: The purpose of the following manuscript is to summarize current research on the molecular and cellular interactions between oxidative stress and inflammation in sarcopenia, as well as to assess Aronia melanocarpa’s potential as a nutritional intervention. Methods: A narrative review was conducted by searching PubMed, Scopus, and Web of Science for peer-reviewed literature published between 2000 and 2024. Keywords included “sarcopenia”, “oxidative stress”, “inflammation”, “Aronia melanocarpa”, “polyphenols”, and even “functional foods”. Eligible publications provided mechanistic, preclinical, or clinical findings on skeletal muscle biology and A. melanocarpa bioactivity. Results: This narrative review examines the relationship between oxidative stress and inflammation in sarcopenia, focusing on NF-κB-mediated inflammatory signaling, Nrf-2-dependent antioxidant defenses, myokines like myostatin and irisin, and macrophage polarization in muscle homeostasis. Aronia melanocarpa (black chokeberry) is highlighted as a polyphenol-rich fruit with a distinct profile of anthocyanins and proanthocyanidins that have strong antioxidant and anti-inflammatory properties. According to preclinical, clinical, and nutritional studies, A. melanocarpa bioactives modulate redox balance, suppress pro-inflammatory cytokine production, increase antioxidant enzyme activity, and regulate metabolic and regenerative signaling pathways important for skeletal muscle health. Conclusions: Overall, the data suggest A. melanocarpa’s potential as a functional food and nutraceutical candidate for the prevention and treatment of sarcopenia. However, further translational and clinical research is needed to determine the appropriate intake, bioavailability, and long-term efficacy in human populations. Full article

Background: The human acellular amniotic membrane (HAAM) is widely used as a decellularized bioscaffold in tissue engineering to promote wound healing, but its clinical application is limited by poor mechanical properties, rapid degradation, and handling difficulties. This study aimed to develop a modified amniotic membrane-based composite material loaded with vascular endothelial growth factor (VEGF) and the Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-Lalanylhydrazide]-Sphenylglycine t-butyl ester (DAPT) to enhance wound healing by modulating macrophage polarization and cytokine secretion. Methods: VEGF-loaded gellan gum-hyaluronic acid (GG-HA) hydrogels (VEGF-GG-HA) and DAPT-loaded HAAM (DAPT-HAAM) were prepared and combined to form a novel composite material (VEGF-GG-HA & DAPT-HAAM). The morphology and microstructure of the materials were characterized using scanning electron microscopy. In vitro studies were conducted using the human monocytic cell line (Tohoku Hospital Pediatrics-1, THP-1) to evaluate the effects of the materials on cell viability, cytokine secretion, and protein expression. Assessments included CCK-8 assays, ELISA, quantitative real-time PCR, Western blot analysis, and immunohistochemical staining. Results: The composite material VEGF-GG-HA & DAPT-HAAM exhibited good biocompatibility and significantly promoted THP-1 cell proliferation compared to control and single-component groups. It enhanced the secretion of IL-10, TNF-α, TGF-β, MMP1, and MMP3, while suppressing excessive TGF-β overexpression. The material also modulated macrophage polarization, showing a trend toward anti-inflammatory M2 phenotypes while maintaining pro-inflammatory signals (e.g., TNF-α) for a balanced immune response. Conclusions: The modified amniotic membrane hydrogel composite promotes wound healing through a phased immune response: it modulates macrophage polarization (balancing M1 and M2 phenotypes), enhances cytokine and matrix metalloproteinase secretion, and controls TGF-β levels. These effects contribute to improved vascular remodeling, reduced fibrosis, and prevention of scar formation, demonstrating the potential for enhanced wound management. Full article

Atherosclerosis is characterized by atherosclerotic plaque formation in large and medium vessels, mediated by endothelial cell (EC) dysfunction, altered contractility of Vascular Smooth Muscle Cells (VSMCs) and recruitment of blood leukocytes to the injured vascular endothelium. These include macrophages (MØ), T lymphocytes, and dendritic cells, which drive the production of many inflammatory mediators and the process of chronic inflammation. Also, de-differentiation or phenotypic switching of VSMCs contributes to vascular remodeling and the pathogenesis of atherosclerosis. Likewise, MØ plasticity and the presence of different phenotypes have a major effect on atherosclerotic plaque formation. The multi-functional transcriptional regulator and pluripotency factor Krüppel-like factor 4 (KLF4) acts as a gatekeeper of VSMC phenotypic switching and MØ polarization during vascular inflammation and atherosclerosis. Similarly, pro-inflammatory pathways activated by Toll-like receptor (TLR)4 and Interferon gamma (IFNγ) emerge as key components of VSMC and MØ plasticity, tightly regulated by Signal Transducer and Activator of Transcription (STAT)s, Interferon Regulatory Factor (IRF)s, and Nuclear factor-κB (NF-κB). Recent discoveries predict a collaborative role of these transcription factors in different transcriptional mechanisms connected to inflammation and atherosclerosis. This review provides novel insight into the transcriptional regulatory interplay between KLF4, STATs, IRFs, and NF-κB in VSMC phenotypic switching and MØ polarization during atherogenesis. Detailed understanding of these transcriptional networks will enable us to develop novel diagnostic and therapeutic strategies to combat vascular proliferative diseases, including atherosclerosis. Full article

The immunosuppressive and anti-inflammatory potential of mesenchymal stromal cells (MSCs) underpins their therapeutic value in musculoskeletal disorders. However, the underlying mechanisms remain ill-defined. Traditionally associated with immune cells, immunometabolism (the cellular metabolism–immune system interplay) is now recognized as central in a broader range of processes, including tissue homeostasis, repair, and chronic inflammation. Depending on the context and cell type, distinct metabolic pathways (e.g., fatty acid oxidation, lipid mediator biosynthesis) can drive pro-inflammatory/pro-resolving immune phenotypes. This dynamic is salient in musculoskeletal tissues: macrophage polarization, T-cell activation, and MSC immunomodulation are governed by metabolic cues. Emerging evidence highlights lipid-driven immunometabolism as a key player in MSC function, particularly in post-traumatic osteoarthritis (PTOA) and osteoporosis (OP). Unlike immune cells, MSCs rely on distinct metabolic programs (e.g., lipid sensing, uptake, and signaling) to exert context-dependent immunoregulation. In PTOA, persistent inflammation triggers lipid-centric metabolic pathways, enhancing MSC-driven immunomodulation and therapeutic outcomes. In OP, low-grade inflammation and altered lipid metabolism impair bone regeneration, modulating lipid-driven routes that can restore MSC osteogenic function and influence osteoclast precursors. This review explores how lipid-derived mediators and signaling contribute to MSCs’ immunosuppressive capacity, positioning lipid immunometabolism as a novel axis for rebalancing the inflamed joint microenvironment and encouraging musculoskeletal regeneration. Full article

Autoimmune liver diseases (AILDs) represent a diverse spectrum of chronic inflammatory conditions characterized primarily by compromised hepatic immune tolerance, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Recent evidence positions macrophages as pivotal players in AILDs pathogenesis, attributable to their multifaceted roles in inflammation amplification, immune regulation, and fibrogenesis. In the context of AILDs, macrophages exhibit marked polarization imbalance, increased recruitment of monocytes, and impaired clearance of apoptotic cells. Through complex interactions with T lymphocytes and hepatic stellate cells, macrophages orchestrate a pathological milieu promoting inflammation and fibrosis. Notably, diverse programmed cell death (PCD) modalities—autophagy, necroptosis, pyroptosis, and ferroptosis—not only determine macrophage survival and functional phenotype but also significantly impact cytokine release, phenotypic plasticity, and the trajectory of immunopathological progression. This review synthesizes current understandings of macrophage-driven immunoregulatory mechanisms in AILDs, characterizes the regulatory attributes of various macrophage-related PCD processes, and evaluates their relevance in experimental disease models. Furthermore, we highlight recent advancements in biomarker identification and targeted therapeutic strategies. Comprehensive elucidation of the interplay between macrophage immunological activity and programmed cell death pathways promises to inform novel, personalized therapeutic approaches for patients with AILDs. Full article

Interstitial lung disease associated with connective tissue disease (CTD-ILD) is a severe condition characterized by inflammation and progressive lung fibrosis, with limited treatment options. Previous studies have demonstrated the anti-inflammatory and antifibrotic properties of human umbilical cord-derived mesenchymal stem cells (huMSCs), suggesting their potential as novel therapeutic agents. Therefore, we investigated the dose-dependent therapeutic effects of huMSCs on CTD-ILD. A bleomycin-induced mouse model of interstitial lung disease, in which female C57BL/6J mice developed diffuse pulmonary lesions following continuous subcutaneous infusion of bleomycin, was used. Mice subsequently received intravenous huMSCs at doses of 1.0 × 10³, 1.0 × 10⁴, or 1.0 × 10⁵ cells. The medium dose (1.0 × 10⁴ cells) showed the most pronounced effects on pulmonary fibrosis and collagen deposition, while significantly suppressing pro-inflammatory cytokines, including interleukin-1β and interleukin-6; however, this effect was not consistent across all measured outcomes. The treatment also enhanced beneficial matrix remodeling by downregulating TIMP-1 and upregulating MMP-9 expression. Furthermore, huMSC administration modulated macrophage polarization and inhibited the pro-inflammatory M1 phenotype. These findings highlight the therapeutic potential of huMSCs for CTD-ILD and underscore the importance of dose optimization to balance efficacy and safety. Full article

Background/Objectives: Liver cirrhosis is a major global health challenge and a key risk factor for hepatocellular carcinoma (HCC), a malignancy with high mortality due to late diagnosis. This study aimed to integrate single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data, using single-cell data to identify macrophage-associated transcriptomic changes during the progression from cirrhosis to HCC, and using bulk data to validate these findings in independent cohorts, while developing predictive models for early risk assessment. Methods: We integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets derived from liver tissues of cirrhosis and HCC patients. Single-cell data were used to identify macrophage subtypes and their dynamic transcriptional changes, while bulk data provided validation in independent cohorts. Gene expression and network analyses were performed, and candidate genes were used to construct diagnostic models with Lasso regression, Random Forest, and Extreme Gradient Boosting (XGBoost). Model performance was evaluated using receiver operating characteristic curves. Results: We identified eleven macrophage-associated genes, among which KLK11, MARCO, CFP, KRT19, GAS1, SOD3, and CYP2C8 were downregulated in HCC, indicating loss of tumor-suppressive and pro-apoptotic functions, while TOP2A, CENPF, MKI67, and NUPR1 were upregulated, reflecting enhanced cell cycle progression, proliferation, and M2 polarization. These are all associated with the progression from liver cirrhosis to HCC. Based on these findings, we established predictive models using Lasso, Random Forest, and XGBoost, which stratified cirrhotic patients into high- and low-risk groups according to cutoff values using liver tissue transcriptomic data. All three models demonstrated high diagnostic performance. Conclusions: This study highlights the critical role of macrophage-associated transcriptomic remodeling in liver disease progression. The machine learning–based predictive models offer a promising approach for early diagnosis and clinical decision-making in patients with cirrhosis. Full article

Background and Objectives: TAM receptors—Tyro3, Axl, and Mer—and their ligand Growth Arrest-Specific 6 (Gas6) represent a pleiotropic system implicated in fibrosis. Increased Gas6 and Axl expression have previously been observed in lung samples and fibroblast cultures from Idiopathic Pulmonary Fibrosis (IPF) patients. The study explored the contribution of Gas6/TAM system in fibrosis development and the impact of its pharmacological inhibition in fibroblasts. Materials and Methods: IPF fibroblasts (IPF FBs) and control human pulmonary fibroblasts (HPFs) were treated with R428 (Axl-specific inhibitor), LDC1267 (TAM inhibitor), or Nintedanib (an IPF-approved drug) to evaluate the influence of these drugs on cell proliferation, migration, and the expression of pro-inflammatory and pro-fibrotic genes. Fibroblast-to-myofibroblast differentiation was induced by TGF-β. The impact of IPF FBs and HPF on macrophage polarization was investigated through a co-culture of fibroblasts with monocyte-derived macrophages, with the further gene expression analysis of markers of the M1 (pro-inflammatory) or M2 (pro-fibrotic) polarization forms. Results: Cell proliferation was monitored in fibroblasts treated with TGF-β, the drugs, and their combination. In the presence of LDC1267 and Nintedanib, minor differences in cell confluence were detected between IPF FBs and HPFs; R428 (1 μM) seemed to have a higher inhibitory impact on IPF FBs. Regarding cell migration, the fibroblasts treated with LDC1267 exhibited slower wound closure. R428 treatment led to a relative wound closure of 76% in HPFs but only 56% in IPF FBs (60 h). R428 (1 μM) significantly reduced the expression of the pro-fibrotic markers ACTA2, COL1A1, and FN1 in HPFs and IPF FBs compared to TGF-β treatment. HPFs and IPF FBs co-cultured with monocyte-derived macrophages demonstrated a significantly increased expression of MRC1 while the expression of FN1, TNFα, and CXCL10 was moderately increased. Conclusions: These findings suggest that R428 and LDC1267 modulate the proliferation, migration, and gene expression of activated fibroblasts via TAM signaling. Fibroblast-mediated effects on macrophage polarization underscore the relevance of intercellular crosstalk in fibrotic disease. Full article

This study investigated the protective effects of Gardenia jasminoides Ellis polysaccharides (GP) on lipopolysaccharide (LPS)-induced immunosuppression and oxidative stress in mice and explored how GP modulates macrophage polarization through the TLR4/NF-κB signaling axis. The results showed that GP notably restored thymus and spleen indices in LPS-treated mice, markedly decreased the serum concentrations of malondialdehyde, and enhanced superoxide dismutase activity and total antioxidant capacity. In RAW 264.7 macrophage cultures, GP displayed immunostimulatory effects by improving phagocytic activity, promoting NO synthesis, and enhancing the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. These effects were observed in cells not pretreated with TAK-242 or PDTC; however, they were not observed in cells pretreated with these inhibitors. At 300 µg/mL concentration, GP markedly enhanced the transcriptional levels of iNOS and cytokine genes. Protein analysis revealed significant upregulation of TLR4, MyD88, TRAF6, NF-κB RelA/p65, and phosphorylated p65. Fluorescence imaging confirmed the nuclear translocation of p65. Collectively, these findings indicated that GP reversed systemic immunosuppression and oxidative stress, offering foundational insights for developing natural immune regulators. The observed immunomodulatory properties of GP are likely mediated through the TLR4/NF-κB signaling pathway. Full article

Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections in infants, the elderly, and immunocompromised persons. Innate immune responses to RSV, which are crucial for containment of the infection yet may also be linked to severe disease, are well-studied in the main RSV target cells, respiratory epithelial cells, but the role of pulmonary macrophages (MΦs), key innate immune regulators, remains incompletely defined. This review addresses the interaction of RSV with MΦ, discussing the susceptibility of these cells to productive infection, and MΦ responses to RSV, including cytokine and chemokine release and inflammasome activation. Furthermore, factors contributing to variability in MΦ infectivity and responses, such as MΦ polarization, age, differences in RSV isolates, co-infections, and prior innate priming, are presented. Finally, the review highlights discrepancies observed across experimental models, MΦ origins, and RSV isolates used, complicating the interpretation of MΦ-RSV interactions, thereby underscoring the need for standardized methodologies. Full article

Autoimmune diseases result from dysregulated immune responses that mistakenly attack the body’s own tissues, causing chronic inflammation and progressive damage. Macrophages, with their remarkable plasticity, play key roles in both promoting and resolving inflammation, with pro-inflammatory M1 and anti-inflammatory M2 states shaping disease outcomes. Macrophage-derived exosomes have emerged as important mediators of intercellular communication, reflecting the functional state of their parent cells while influencing recipient cell behavior. Exosomes from M1 macrophages amplify inflammation through cytokines and microRNAs, whereas M2-derived exosomes support tissue repair and immune regulation. Studies in rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel disease, type 1 diabetes, and psoriasis highlight their dual roles in pathology and resolution. In addition, macrophage exosomes can be engineered to deliver targeted therapeutic molecules, offering cell-free interventions with advantages in specificity, biocompatibility, and immunomodulation. This review summarizes current insights into macrophage-derived exosomes, their role in autoimmune pathogenesis, and emerging strategies to harness their therapeutic potential, highlighting their promise as precision-guided treatments for autoimmune diseases. Full article