Search Results (941)

Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance. Full article

Background/Objectives: The prolonged M1-like pro-inflammatory polarization of macrophages is a key factor in the delayed healing of diabetic ulcers (DU). SIRT3, a primary mitochondrial deacetylase, has been identified as a regulator of inflammation and represents a promising new therapeutic target for DU treatment. Nonetheless, the efficacy of existing SIRT3 agonists remains suboptimal. Methods: Here, we introduce a novel compound, SZC-6, demonstrating promising activity levels. Results: SZC-6 treatment down-regulated the expression of inflammatory factors in LPS-treated RAW264.7 cells and reduced the proportion of M1 macrophages. Mitosox, IF, and JC-1 staining revealed that SZC-6 preserved cellular mitochondrial homeostasis and reduced the accumulation of reactive oxygen species. In vivo experiments demonstrated that SZC-6 treatment accelerated wound healing in diabetic mice. Furthermore, HE and Masson staining revealed increased neovascularization at the wound site with SZC-6 treatment. Tissue immunofluorescence results indicated that SZC-6 effectively decreased the proportion of M1-like cells and increased the proportion of M2-like cells at the wound site. We also found that SZC-6 significantly reduced MyD88, p-IκBα, and NF-χB p65 protein levels and inhibited the nuclear translocation of P65 in LPS-treated cells. Conclusions: The study concluded that SZC-6 inhibited the activation of the NF-χB pathway, thereby reducing the inflammatory response and promoting skin healing in diabetic ulcers. SZC-6 shows promise as a small-molecule compound for promoting diabetic wound healing. Full article

Liver fibrosis, a critical pathological feature of chronic liver injury, is closely associated with macrophage-mediated inflammatory responses and metabolic reprogramming. Blocking the fibrosis process will be beneficial to the treatment and recovery of the disease. Liver macrophages are a remarkably heterogeneous population of immune cells that play multiple functions in homeostasis and are central to liver fibrosis. Glycolysis-mediated macrophage metabolic reprogramming leads to an increase in the proportion of M1 macrophages and the release of pro-inflammatory cytokines. The present study aimed to investigate the therapeutic effect and mechanism of acid B (SAL B) against carbon tetrachloride (CCl₄)-induced liver fibrosis. Here, we demonstrate that SAL B reduced the production of inflammatory factors in CCl₄-induced liver fibrosis. Mechanistically, SAL B increased the expression of migration inhibitor 1 (MIG1) by inhibiting DNMT1-mediated methylation of the MIG1 promoter. Subsequently, MIG1 reduced the transcription of lactate dehydrogenase A (LDHA) and hexokinase 2 (HK2) which blocked glycolysis-mediated macrophage M1 polarization. In summary, our results suggested that SAL B is a promising intervention for ameliorating liver fibrosis. Full article

This review explores the emerging role of functionalized hydrogels in modulating the microbiome for therapeutic applications in tissue regeneration and infection control. The skin and gut microbiomes play crucial roles in maintaining tissue homeostasis, regulating immune responses, and influencing the healing process. Disruptions in microbial balance—such as those observed in chronic wounds, autoimmune conditions, or post-surgical environments—can impair regeneration and increase susceptibility to infection. Hydrogels, due to their tunable physical and chemical properties, serve as versatile platforms for delivering probiotics, prebiotics, antimicrobials, and immune-modulatory agents. The encapsulation of beneficial bacteria, such as Lactobacillus plantarum or Prevotella histicola, within hydrogels could enhance bacterial viability, targeted delivery, and immune tolerance. Additionally, hydrogels functionalized with silver nanoparticles, nitric oxide donors, and bacteriocins have demonstrated effective biofilm disruption and pathogen clearance. These systems also promote favorable immune responses, such as M2 macrophage polarization and the induction of regulatory T cells, which are essential for tissue repair. Innovative approaches, including 3D bioprinting, self-healing materials, and photothermal-responsive hydrogels, expand the clinical versatility of these systems. Full article

Tumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment (TME), interacting with cancer cells and other components to promote tumor growth. Given the influence of TAMs on tumor progression and resistance to therapy, regulating the activity of these macrophages is crucial for improving cancer treatment outcomes. TAMs often exhibit immunosuppressive phenotypes (commonly referred to as M2-like macrophages), which suppress immune responses and contribute to drug resistance. Therefore, inhibiting immunosuppressive polarization offers a promising strategy to impede tumor growth. This study revealed retinoic acid receptor gamma (RARγ), a nuclear receptor, as a key regulator of immunosuppressive polarization in THP-1 macrophages. Indeed, the inhibition of RARγ, either by a small molecule or gene silencing, significantly reduced the expression of immunosuppressive macrophage markers. In a three-dimensional tumor spheroid model, immunosuppressive macrophages enhanced the proliferation of HCT116 colorectal cancer cells, which was significantly hindered by RARγ inhibition. These findings suggest that targeting RARγ reprograms immunosuppressive macrophages and mitigates the tumor-promoting effects of TAMs, highlighting RARγ as a promising therapeutic target for developing novel anti-cancer strategies. Full article

Extracellular vesicles (EVs) have emerged as promising acellular tools for modulating immune responses for tissue engineering applications. This study explores the potential of human fibroblast-derived EVs delivered within a three-dimensional (3D) injectable scaffold composed of polycaprolactone (PCL) nanofibers and collagen (PNCOL) to reprogram macrophage behavior and support scaffold integrity under inflammatory conditions. EVs were successfully isolated from human fibroblasts using ultracentrifugation and characterized for purity, size distribution and surface markers (CD63 and CD9). Macrophage-laden PNCOL scaffolds were prepared under three conditions: macrophage-only (MP), fibroblast co-encapsulated (F-MP), and EV-encapsulated (EV-MP) groups. Structural integrity was assessed via scanning electron microscopy and Masson’s trichrome staining, while immunomodulatory effects were evaluated through metabolic assays, gene expression profiling, and immunohistochemistry for macrophage polarization markers (CD80, CD206). When co-encapsulated with pro-inflammatory (M1) macrophages in PNCOL scaffolds, fibroblast-derived EVs preserved scaffold structure and significantly enhanced macrophage metabolic activity compared to the control (MP) and other experimental group (F-MP). The gene expression and immunohistochemistry data demonstrated substantial upregulation of anti-inflammatory markers (TGF-β, CD163, and CCL18) and surface protein CD206, indicating a phenotypic shift toward M2-like macrophages for EV-encapsulated scaffolds relative to the other groups. The findings of this study demonstrate that fibroblast-derived EVs integrated into injectable PCL–collagen scaffolds offer a viable, cell-free approach to modulate inflammation, preserve scaffold structure, and support regenerative healing. This strategy holds significant promise for advancing immuno-instructive platforms in regenerative medicine, particularly in settings where conventional cell therapies face limitations in survival, cost, or safety. Full article

Metastases are the leading cause of cancer-related deaths. The spread of neoplasms involves multiple mechanisms, with metastatic tumors exhibiting molecular behaviors distinct from their primary counterparts. The key hallmarks of metastatic lesions include chromosomal instability, copy number alterations (CNAs), and a reduced degree of subclonality. Furthermore, metabolic adaptations such as enhanced glycogen synthesis and storage, as well as increased fatty acid oxidation (FAO), play a critical role in sustaining energy supply in metastases and contributing to chemoresistance. FAO promotes the infiltration of macrophages into the tumor, where they polarize to the M2 phenotype, which is associated with immune suppression and tissue remodeling. Additionally, the tumor microbiome and the action of cytotoxic drugs trigger neutrophil extravasation through inflammatory pathways. Chemoresistant neutrophils in the tumor microenvironment can suppress effector lymphocyte activation and facilitate the formation of neutrophil extracellular traps (NETs), which are linked to drug resistance. This article examines the genomic features of metastatic tumors, along with the metabolic and immunological dynamics within the metastatic tumor microenvironment, and their contribution to drug resistance. It also discusses the molecular mechanisms underlying resistance to chemotherapeutic agents commonly used in the treatment of metastatic cancer. Full article

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic inflammation, endothelial dysfunction, and placental insufficiency. While inadequate trophoblast invasion and impaired spiral artery remodeling have long been recognized as central to its pathogenesis, emerging evidence underscores the critical roles of dysregulated iron metabolism and its crosstalk with immune responses, particularly macrophage-mediated inflammation, in driving PE development. This review systematically explores the dynamic changes in iron metabolism during pregnancy, including increased maternal iron demand, placental iron transport mechanisms, and the molecular regulation of placental iron homeostasis. We further explore the contribution of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, to trophoblast dysfunction and pregnancy-related diseases, including PE. Macrophages, pivotal immune regulators at the maternal–fetal interface, exhibit distinct polarization states that shape tissue remodeling and immune tolerance. We outline their origin, distribution, and polarization in pregnancy, and emphasize their aberrant phenotype and function in PE. The bidirectional crosstalk between iron and macrophages is also dissected: iron shapes macrophage polarization and function, while macrophages reciprocally modulate iron homeostasis. Notably, excessive reactive oxygen species (ROS) and pro-inflammatory cytokines secreted by M1-polarized macrophages may exacerbate trophoblast ferroptosis, amplifying placental injury. Within the context of PE, we delineate how iron overload and macrophage dysfunction synergize to potentiate placental inflammation and oxidative stress. Key iron-responsive immune pathways, such as the HO-1/hepcidin axis and IL-6/TNF-α signaling, are discussed in relation to disease severity. Finally, we highlight promising therapeutic strategies targeting the iron–immune axis, encompassing three key modalities—iron chelation therapy, precision immunomodulation, and metabolic reprogramming interventions—which may offer novel avenues for PE prevention and treatment. Full article

Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have provided strong evidence supporting its effectiveness in alleviating chronic pain and its potential for sustaining long-term pain relief. In addition to that, there has been ongoing research with clinical evidence relating to the role of small non-coding ribonucleic acids known as microRNAs in regulating gene expressions affecting pain signals. The signal pathway involves alterations in neuronal excitation, synaptic transmission, dysregulated signaling, and subsequent pro-inflammatory response activation and pain development. When microRNAs are dysregulated in the dorsal root ganglia neurons, they polarize macrophages from anti-inflammatory M2 to inflammatory M1 macrophages causing pain signal generation. By reversing this polarization, a therapeutic activity can be induced. However, the direct delivery of these nucleotides has been challenging due to limitations such as rapid clearance, degradation, and reduction in half-life. Therefore, safe and efficient carrier vehicles are fundamental for microRNA delivery. Here, we present a comprehensive analysis of miRNA-based nano-systems for chronic neuropathic pain, focusing on their impact in dorsal root ganglia. This review provides a critical evaluation of various delivery platforms, including viral, polymeric, lipid-based, and inorganic nanocarriers, emphasizing their therapeutic potential as well as their limitations in the treatment of chronic neuropathic pain. Innovative strategies such as hybrid nanocarriers and stimulus-responsive systems are also proposed to enhance the prospects for clinical translation. Serving as a roadmap for future research, this review aims to guide the development and optimization of miRNA-based therapies for effective and sustained neuropathic pain management. Full article

Background: Natural products are key sources of anti-inflammatory agents, yet the potential of fish visceral extracts remains largely unexplored. This study evaluated the anti-inflammatory activity of a spleen extract from rainbow trout (Oncorhynchus mykiss). Methods: A crude spleen extract and its four solvent fractions were tested in LPS-stimulated RAW264.7 macrophages. Nitric oxide production and expression of iNOS, COX-2, and cytokines were assessed by qRT-PCR and Western blotting. The most active fraction, OSB (n-butanol layer), was further analyzed for its effects on NF-κB signaling, macrophage polarization, and ROS generation. Results: The crude spleen extract significantly reduced NO production and downregulated iNOS and COX-2 expression at both the transcriptional and translational levels. Among the four fractions, the OSB fraction exhibited the most potent and consistent anti-inflammatory effects. OSB markedly suppressed LPS-induced expression of iNOS, COX-2, and pro-inflammatory cytokines, while enhancing anti-inflammatory cytokines. Mechanistic analyses demonstrated that OSB inhibited NF-κB activation by preventing the nuclear translocation of the p65 subunit. Additionally, OSB attenuated LPS-induced ROS production and reduced the expression of M1 macrophage markers, indicating inhibition of M1 polarization. Conclusions: The OSB fraction from rainbow trout spleen exhibits potent anti-inflammatory activity by modulating the NF-κB pathway and suppressing M1 macrophage polarization, suggesting its potential as a natural therapeutic agent. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

C-reactive protein (CRP) has long been recognized as a biomarker of systemic inflammation and cardiovascular disease (CVD) risk. However, emerging evidence highlights the distinct and potent pro-inflammatory role of its monomeric form (mCRP), which is predominantly tissue-bound and directly implicated in vascular injury and plaque destabilization. This narrative review explores the interactions and overlapping pathways that converge within and modulate CRP, mCRP, the associated pathophysiology of diabetes mellitus, and cardiovascular disease. We examine how mCRP promotes endothelial dysfunction, leukocyte recruitment, platelet activation, and macrophage polarization, thereby contributing to the formation of unstable atherosclerotic plaques. Furthermore, we discuss the critical influence of diabetes in amplifying mCRP’s pathogenic effects through metabolic dysregulation, chronic hyperglycemia, and enhanced formation of advanced glycation end products (AGEs). The synergistic interaction of mCRP with the AGE-receptor for AGE (RAGE) axis exacerbates oxidative stress and vascular inflammation, accelerating atherosclerosis progression and increasing cardiovascular risk in diabetic patients. Understanding these mechanistic pathways implicates mCRP as both a biomarker and therapeutic target, particularly in the context of diabetes-associated CVD. This review highlights the need for further research into targeted interventions that disrupt the mCRP-[AGE-RAGE] inflammatory cycle to reduce plaque instability and improve cardiovascular outcomes in high-risk populations. Full article

The immunomodulatory polysaccharide CPP-3a, purified from Chlorella pyrenoidosa, was investigated for its effects on RAW264.7 macrophages and underlying mechanisms, revealing that CPP-3a significantly enhanced phagocytic capacity and nitric oxide production while upregulating pro-inflammatory cytokines TNF-α and IL-6 and elevating the co-stimulatory molecule CD86, collectively driving robust M1 polarization. Mechanistically, TLR4-, TLR2-specific inhibitors, and TLR4-knockout cells confirmed TLR4 as the primary receptor for CPP-3a, with TLR2 playing a secondary role in cytokine modulation. CPP-3a activated NF-κB and p38 MAPK signaling pathways via the MyD88-dependent pathway, evidenced by phosphorylation of NF-κB/p65 with its nuclear translocation and increased phosphorylation of p38 MAPK, with these signaling activations further validated by specific pathway inhibitors that abolished M1 polarization phenotypes. Collectively, CPP-3a emerges as a potent TLR4-targeted immunomodulator with adjuvant potential for inflammatory and infectious diseases. Full article

Background: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells in hepatocellular carcinoma (HCC). However, it remains unclear whether MICA expression correlates with TAMs and influences the switch in macrophage phenotype by mediating metabolic alterations. Methods: Various biostatistical tools, qPCR, and IHC staining experiments were utilized to analyze data from The Cancer Genome Atlas (TCGA) and collected HCC tumor tissues. Single-cell RNA sequencing (scRNA-seq) analyses and a co-culture model of HCC cells with macrophages were performed to validate the findings from the biostatistical analyses. Results: Through the intersection of differentially expressed genes (DEGs), metabolism-related genes (MRGs), and co-expression genes (CEGs) with MICA in HCC, the EHHADH gene was identified. Gene set enrichment analyses were conducted to further confirm the role of EHHADH. EHHADH expression is decreased in HCC tumors and can serve as a prognostic biomarker for HCC. Expressions of MICA and EHHADH exhibited significant correlations with various phenotypic macrophages and exerted opposing effects on M1-like and M2-like macrophages infiltrating HCC. The underlying metabolic and molecular mechanisms revealed that MICA in tumor cells induced M2-like polarization through the PPAR/EHHADH pathway, which regulates the fatty acid oxidation (FAO) in macrophages. Conclusions: The metabolic gene EHHADH, which is associated with MICA, led to alterations in M2-like macrophages by promoting heightened fatty acid uptake and augmenting levels of FAO within macrophages. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article