Search Results (1,225)

Diabetic wound healing presents significant challenges due to impaired angiogenesis, chronic inflammation, and cellular dysfunction. Building on previous research, this study further explores the potential of a plant-derived glucosyloxybenzyl 2-isobutylmalates (B-CGT) hydrogel in promoting diabetic wound healing. Network pharmacology and molecular docking analyses suggest that B-CGT may regulate key mechanisms, such as apoptosis, inflammation, and matrix remodeling, through core targets including SIRT1, CASP8, and MMP8. In vivo studies further demonstrated that B-CGT hydrogel significantly accelerated wound closure in diabetic mice, enhanced angiogenesis, promoted collagen deposition, and achieved immune balance by modulating macrophage polarization, thereby shifting the inflammatory environment toward a repair state. Moreover, B-CGT hydrogel significantly improved the wound microenvironment by upregulating VEGF expression and exerting antioxidant effects. By combining theoretical predictions with experimental validation, this study elucidates the multi-target synergistic regulatory mechanisms of B-CGT hydrogel. These findings provide new research directions for addressing immune imbalance and angiogenesis defects in diabetic wound healing and lay a scientific foundation for the optimization and application of chronic wound treatment strategies. Full article

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a pulmonary disease with high mortality associated with inflammation. During the development of ALI/ARDS, macrophages usually polarize toward M1 pro-inflammatory macrophages, promoting the inflammatory response in ALI/ARDS and aggravating lung tissue damage. Natural compounds with anti-inflammatory activity have achieved excellent results in the treatment of ALI/ARDS through different regulatory modes, including macrophage polarization. Of note, flavonoid, brevilin A, and tetrahydropalmatine play an important role in the treatment of ALI/ARDS by modulating the phenotypic polarization of macrophages and their pro-inflammatory cytokine expression in innate immune cells of the lung. Flavonoids are a kind of naturally occurring polyphenol compound, which has antioxidant and anti-inflammatory activities. Studies have found that some flavonoids can alleviate ALI/ARDS through inhibiting the expression of inflammatory cytokines in macrophages. Among them, 5-methoxyflavone, acacetin, grape seed proanthocyanidins, and luteolin can also regulate macrophage polarization. Therefore, the in-depth exploration of the regulatory mechanism of macrophages can lay the foundation for the application of flavonoids in alleviating inflammation-related lung injury. This review focuses on the macrophage polarization effects of different natural compounds and their potential anti-inflammatory mechanisms in the treatment of ALI/ARDS. Full article

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods: Cancer cell-secreted proteins were detected by using liquid chromatography–mass spectrometry (LC-MS). Neutralizing antibodies (nAbs) were used to assess which proteins were involved in MΦs polarization and differentiation. The protein–protein interaction was characterized using co-immunoprecipitation and immunofluorescence assays. Cancer-secreted heat shock protein 70 (Hsp70) protein was quantified using an enzyme-linked immunosorbent assay (ELISA). MΦ polarization and tumor growth were assessed in vivo with subcutaneous LLC-GFP tumor models and toll-like receptor 2 (TLR2) knockout mice; in vitro assessments were conducted using TLR2 knockout and both LLC-GFP and LN227 lentiviral-mediated knockdown (KD) cells. Results: Cancer cells released a secreted form of Hsp70 that acted on MΦ TLR2 to upregulate Mer receptor tyrosine kinase (MerTK) and induce MΦ M2 polarization. Hsp70 nAbs led to a reduction in CD14 expression by 75% in THP-1 cells in response to Gli36 EMD-CM. In addition, neutralizing TLR2 nAbs resulted in a 30% and 50% reduction in CD14 expression on THP-1 cells in response to MiaPaCa-2 and Gli36 exosome/microparticle-depleted conditioned media (EMD-CMs), respectively. Hsp70, TLR2, and MerTK formed a protein complex. Tumor growth and intra-tumor M2 MΦs were significantly reduced upon cancer cell Hsp70 knockdown and in TLR2 knockout mice. Conclusions: Cancer-secreted Hsp70 interacts with TLR2, upregulates MerTK on MΦs, and induces immunosuppressive MΦ M2 polarization. This previously unreported action of secreted Hsp70 suggests that disrupting the Hsp70-TLR2-MerTK interaction could serve as a promising immunotherapeutic approach to mitigate TME immunosuppression in solid cancers. Full article

Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease and ulcerative colitis, are complex chronic disorders characterized by an intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures. This review aims to synthesize recent advances in IBD pathogenesis, exploring key mechanisms and potential avenues for prevention and personalized therapy. A comprehensive literature search was conducted across major bibliographic databases, selecting the most recent and impactful studies on IBD pathogenesis. The review integrates findings from multi-omics analyses, single-cell transcriptomics, and longitudinal cohort studies, focusing on immune regulation, gut microbiota dynamics, and environmental factors influencing disease onset and progression. Immune dysregulation, including macrophage polarization (M1 vs. M2) and Th17 activation, emerges as a cornerstone of IBD pathogenesis. Dysbiosis, as a result of reduced alpha and beta diversity and overgrowth of harmful taxa, is one of the main contributing factors in causing inflammation in IBD. Environmental factors, including air and water pollutants, maternal smoking, and antibiotic exposure during pregnancy and infancy, significantly modulate IBD risk through epigenetic and microbiota-mediated mechanisms. While recent advances have supported the development of new therapeutic strategies, deeply understanding the complex dynamics of IBD pathogenesis remains challenging. Future efforts should aim to reduce the burden of disease with precise, personalized treatments and lower the incidence of IBD through early-life prevention and targeted interventions addressing modifiable risk factors. Full article

This study aimed to investigate the innate immune response of human macrophages to Porphyromonas gingivalis W83 using a novel in vitro infection model. The growth kinetics of P. gingivalis W83 were analyzed, revealing an exponential growth phase at 8 h (optical density = 0.70). To establish a reliable macrophage model, the differentiation of THP-1 monocytes into macrophages was optimized using low concentrations of phorbol 12-myristate 13-acetate (PMA). This approach induced enhanced adherence and morphological changes, with full differentiation achieved after 48 h of PMA treatment followed by 24 h of rest. Polarization towards the pro-inflammatory M1 phenotype was successfully induced with interferon-γ (IFN-γ) and lipopolysaccharide (LPS), as confirmed using cytokine profiling. Cytokine analysis using Luminex^® technology demonstrated significant increases in interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6, indicating the effective activation of macrophages towards a pro-inflammatory phenotype. Building upon this macrophage model, this study investigated the interactions between macrophages and P. gingivalis W83 during its exponential growth phase. After a one-hour infection period, bacterial DNA quantification in supernatants and lysed macrophages revealed minimal levels of internalized or adherent bacteria, supporting the hypothesis that P. gingivalis effectively evades immune detection. These findings emphasize the utility of this model in uncovering the sophisticated immune evasion strategies employed by P. gingivalis, with significant implications for the development of targeted therapeutic interventions. Full article

Atherosclerosis is a complex inflammatory process associated with high-mortality cardiovascular diseases. Today, there is a growing body of evidence linking atherosclerosis to mutations of mitochondrial DNA (mtDNA). But the mechanism of this link is insufficiently studied. Atherosclerosis progression involves different cell types and macrophages are one of the most important. Due to their high plasticity, macrophages can demonstrate pro-inflammatory and pro-atherogenic (macrophage type M1) or anti-inflammatory and anti-atherogenic (macrophage type M2) effects. These two cell types, formed as a result of external stimuli, differ significantly in their metabolic profile, which suggests the central role of mitochondria in the implementation of the macrophage polarization route. According to this, we assume that mtDNA mutations causing mitochondrial disturbances can play the role of an internal trigger, leading to the formation of macrophage M1 or M2. This review provides a comparative analysis of the characteristics of mitochondrial function in different types of macrophages and their possible associations with mtDNA mutations linked with inflammation-based pathologies including atherosclerosis. Full article

Research on serum amyloid A (SAA) has seen major advancement in recent years with combined approaches of structural analysis and genetically altered mice. Initially identified as an acute-phase reactant, SAA is now recognized as a major player in host defense, inflammation, lipid metabolism and tumor metastasis. SAA binding and the neutralization of LPS attenuate sepsis in mouse models. SAA also displays immunomodulatory functions in Th17 differentiation and macrophage polarization, contributing to a pro-metastatic tumor microenvironment. In spite of the progress, the regulatory mechanisms for these diverse functions of SAA remain unclear. This review provides a brief summary of recent advances in SAA research on immunity, inflammation, tumor microenvironment and in vivo models. Full article

Zika virus (ZIKV), a member of the Flaviviridae family, is primarily transmitted through mosquito bites, but can also spread via sexual contact and from mother to fetus. While often asymptomatic, ZIKV can lead to severe neurological conditions, including microcephaly in fetuses and Guillain–Barré Syndrome in adults. ZIKV can infect placental macrophages and fetal microglia in vivo as well as human monocytes and monocyte-derived macrophages (MDMs) in vitro. Here, we observed that both human monocytes, and MDM particularly, supported ZIKV replication without evident cytopathicity, with virions accumulating in cytoplasmic vacuoles. We also investigated whether the cytokine-induced polarization of MDMs into M1 or M2 cells affected ZIKV replication. The stimulation of MDMs with pro-inflammatory cytokines (interferon-γ and tumor necrosis factor-α) polarized MDMs into M1 cells, significantly reducing ZIKV replication, akin to previous observations with a human immunodeficiency virus type-1 infection. In contrast, M2 polarization, induced by interleukin-4, did not affect ZIKV replication in MDMs. M1 polarization selectively reduced the expression of MERTK, a TAM family putative entry receptor, and increased the expression of several interferon-stimulated genes (ISGs) previously associated with the containment of ZIKV infection; of interest, ZIKV infection transiently boosted the expression of some ISGs in M1-MDMs. These findings suggest a dual mechanism of ZIKV restriction in M1-MDMs and highlight potential antiviral strategies targeting innate immune responses. Full article

Dental socket repair theoretically involves a constructive inflammatory immune response, which evolves from an initial M1 prevalence to a subsequent M2 dominance. In this scenario, the MEK1/2 signaling pathway is allegedly involved in M2 polarization. This study aimed to evaluate the impact of MEK1/2 pharmacological inhibition in the local host response and repair outcome. C57Bl/6-WT 8-week-old male mice were submitted to the extraction of the right upper incisor and treated (or not, control group) with MEK1/2 inhibitor PD0325901 (10 mg/kg/24 h/IP, MEK1/2i group) and analyzed at 0, 3, 7, and 14 days using microcomputed tomography, histomorphometry, birefringence, immunohistochemistry, and PCR array analysis. The results demonstrate that MEK1/2 inhibition limits the development of M2 response over time, being associated with lower expression of M2, MSCs, and bone markers, lower levels of growth and osteogenic factors, along with a higher expression of iNOS, IL-1b, IL-6, and TNF-α, as well inflammatory chemokines, indicating a predominantly M1 pro-inflammatory environment. This modulation of local inflammatory immune response is associated with impaired bone formation as demonstrated by microtomographic and histomorphometric data. The results show that MEK1/2 inhibition delays bone repair after tooth extraction, supporting the concept that M2 macrophages are essential elements for host response regulation and proper repair. Full article

In solid tumors, tumor-associated macrophages (TAMs) are one of the most numerous populations and play an important role in the processes of tumor cell invasion, metastasis, and angiogenesis. Therefore, TAMs are considered promising diagnostic and prognostic biomarkers of tumors, and many attempts have been made to influence these cells as part of antitumor therapy. There are several key principles of action on ТАМs: the inhibition of monocyte/macrophage transition; the destruction of macrophages; the reprogramming of macrophage phenotypes (polarization of M2 macrophages to M1); the stimulation of phagocytic activity of macrophages and CAR-M therapy. Despite the large number of studies in this area, to date, there are no adequate approaches using antitumor therapy based on alterations in TAM functioning that would show high efficacy when administered in a mono-regimen for the treatment of malignant neoplasms. Studies devoted to the evaluation of the efficacy of drugs acting on TAMs are characterized by a small sample and the large heterogeneity of patient groups; in addition, in such studies, chemotherapy or immunotherapy is used, which significantly complicates the evaluation of the effectiveness of the agent acting on TAMs. In this review, we attempted to systematize the evidence on attempts to influence TAMs in malignancies such as lung cancer, breast cancer, colorectal cancer, cervical cancer, prostate cancer, gastric cancer, head and neck squamous cell cancer, and soft tissue sarcomas. Full article

Intracerebral hemorrhage (ICH) is a significant health problem with high mortality and morbidity rates, partly due to limited treatment options. Hematoma after ICH causes neurological deficits due to the mass effect. Hemorrhage catalyzes secondary damage, resulting in increased neurological damage, poor prognosis, and treatment problems. This review evaluates the role of immunotherapeutic approaches in ICH based on original full-text and review articles on the pathophysiology and immunotherapy of ICH, with emphasis on the modulation of microglia/macrophage polarization to the M2 subtype. In this review, we concluded that the pathophysiology of injury progression after ICH is complex and multifaceted. Inflammation plays a dominant role in secondary injuries. Furthermore, cells involved in the inflammatory process have dual roles in pro-inflammatory/destructive and anti-inflammatory/healing. While the role of inflammation in the pathophysiology makes the immune system a therapeutic target in ICH, the dual role of cells makes them a therapeutic target that can modulate anti-inflammatory/healing. Resident microglia (and even macrophages migrating from a peripheral source) are important therapeutic targets for modulation because of their role in the initiation phase and in shaping immunity. Although clinical results remain poor, experimental and clinical trial data seem promising for deciphering the pathophysiology of ICH and providing treatment options. Full article

Interactions between bacteriophages with mammalian immune cells are of great interest and most phages possess at least one molecular pattern (nucleic acid, sugar residue, or protein structure) that is recognizable to the immune system through pathogen associated molecular pattern (PAMP) receptors (i.e., TLRs). Given that phages reside in the same body niches as bacteria, they share the propensity to stimulate or quench immune responses depending on the nature of their interactions with host immune cells. While most in vitro research focuses on the outcomes of direct application of phages to immune cells of interest, the potential impact of their transcytosis through the intestinal barrier has yet to be considered. As transcytosis through intestinal cells is a necessary step in healthy systems for access by phage to the underlying immune cell populations, it is imperative to understand how this step may play a role in immune activation. We compared the activation of macrophages (as measured by TNFα secretion) following direct phage application to those stimulated by incubation with phage transcytosed through a polarized Caco2 epithelial barrier model. Our results demonstrate that phages capable of activating TNFα secretion upon direct contact maintain the stimulatory capability following transcytosis. Furthermore, activation of macrophages by a transcytosed phage is enhanced as compared to that occurring with an equivalent multiplicity of directly applied phage. Full article

The interpretation of the biochemistry of immune metabolism could be considered an attractive scientific field of biomedicine research. In this review, the role of glycolysis in macrophage polarization is discussed together with mitochondrial metabolism in cancer cells. In the first part, the focus is on the Warburg effect and redox metabolism during macrophage polarization, cancer development, and management of the immune response by the cancer cells. The second part addresses the possibility of impacts on the Warburg effect through targeting peroxisome proliferator-activated receptors (PPARs). This could be an activator of native immune responses. Because of the reported serious adverse effects of using synthetic ligands for PPARs in combination with chemotherapeutics, searches for less toxic and more active PPAR inhibitors, as well as blocking undesirable cellular PPAR-dependent processes, are in progress. On the other hand, recent research in modern immunotherapy has focused on the search for gentle immune-modulating natural compounds with harmless synergistic chemotherapeutic efficacy that can be used as an adjuvant. It is a well-known fact that the plant kingdom is a source of important therapeutic agents with multifaceted effectiveness. One of these is the known association with PPAR activities. In this regard, the secondary metabolites extracted from plants could change the game. Full article

Background: This study investigated the wound-healing potential of hispolon, a polyphenolic pigment derived from medicinal mushrooms, under diabetic conditions using both in vitro and in vivo models. Methods: In the in vitro assays, L929 fibroblast cells exposed to high glucose (33 mmol/L) were treated with hispolon at concentrations of 2.5, 5, 7.5, or 10 μmol/L. In the in vivo assays, streptozotocin-induced diabetic rats with excision wounds received daily topical applications of 0.2 g of 5% (w/w) hispolon ointment. Results: Hispolon improved cell viability; suppressed oxidative stress by reducing reactive oxygen species, lipid peroxidation, and oxidative DNA damage; and restored the reduced glutathione/oxidized glutathione ratio. The scratch assay demonstrated that hispolon at 10 μmol/L enhanced fibroblast migration impaired by high-glucose conditions. Treatment with 5% (w/w) hispolon ointment accelerated wound contraction, reduced the epithelialization time, and enhanced tissue regeneration with an efficacy comparable to that of Fespixon^® cream, as shown by histological findings of increased fibroblast activity, collagen deposition, and capillary growth. Hispolon ointment also modulated macrophage polarization in diabetic wounds by reducing M1 markers and enhancing M2 markers. In a diabetic rat dead-space-wound model, 5% (w/w) hispolon ointment reduced the levels of pro-inflammatory cytokines, increased those of anti-inflammatory cytokines and growth factors, and stimulated Type I and III collagen synthesis, effectively promoting wound healing. In incisional wounds, hispolon ointment improved the wound-breaking strength, showing results comparable to that of Fespixon^® cream. Safety assessments confirmed that hispolon ointment showed no acute dermal toxicity. These findings underscore hispolon’s potential as a promising candidate for diabetic wound management by mitigating oxidative stress, enhancing tissue regeneration, and accelerating wound healing. Full article

Sarcoidosis and lymphoma share immunopathological characteristics that suggest a complex, interconnected relationship. This article examines the multi-faceted mechanisms linking sarcoidosis to lymphoma, a phenomenon called sarcoidosis-lymphoma syndrome (SLS). SLS is hard to diagnose, requiring distinct criteria and imaging to differentiate overlapping features and histological differences. The co-occurrence of these diseases may be explained by genetic predispositions, immune dysregulation, and environmental factors that enhance malignancy risk. In active sarcoidosis, chronic inflammation and granuloma formation induce the production of cytokines that can contribute to lymphoma development. The role of macrophage polarization is also discussed. Immunosuppressive treatment prescribed in sarcoidosis patients, particularly corticosteroids and biological agents, may increase the susceptibility to lymphoproliferative malignancies. These common mechanisms emphasize the need for vigilant monitoring of lymphoma in patients with sarcoidosis, as this granulomatous disease can mimic and promote the development of lymphoma. Full article