All implanted materials inevitably trigger an acute inflammatory response. The long-term outcome, however, is dependent on the trajectory of this response. This study investigates the effects of aging on the immune response to two commercially available biomaterials. Extracellular matrix-based urinary bladder matrix (UBM) and synthetic polypropylene mesh (PPM) were implanted in young (4 months) and aged (18 months) C57BL/6J mice. Overall, PPM led to a sustained inflammatory response regardless of the age of the mice. In contrast, UBM induced an initial inflammatory response that matured into a pro-regenerative/remodeling response with time, though aged mice exhibited a delayed resolution of inflammation. The PPM-induced response was predominantly pro-inflammatory with consistently higher M1-like macrophage phenotype, whereas the response to UBM was characterized by an anti-inflammatory M2-like phenotype, especially in young mice. RNA sequencing revealed marked age-related differences in gene transcription. At day 7 post-implantation, the young mice with UBM showed a robust upregulation of both pro- and anti-inflammatory pathways as compared to young mice implanted with PPM, however, by day 14, the gene expression profile transitioned into an anti-inflammatory profile. Intriguingly, in aged mice, the response to UBM was distinct with consistent downregulation of inflammatory genes compared to PPM, while the response to PPM in both young and aged animals was largely consistent. Upstream analysis identified cytokines as key drivers of the host response, with IL-4 and IL-13 in young mice, and TNF-α and IL-1β driving chronic inflammation in aged mice. These findings highlight the importance of host age in biomaterial outcome, and the potential of ECM-based materials to mount a favorable response even in the presence of age-related immune dysregulation.

Titanium (Ti) alloys are widely used in bone repair due to their excellent biocompatibility and mechanical properties. However, managing post-implantation inflammatory responses in the defect region and accelerating the healing process remain major challenges in the design of such materials. As a bridge between the innate and adaptive immune systems, macrophages play a pivotal role in bone defect healing through their M2 polarization, which facilitates the secretion of tissue repair-promoting cytokines. Research on the role of copper ions (Cu²⁺) in regulating inflammatory responses at injury sites suggests their potential as active ions for incorporation into alloys as a secondary phase to modulate macrophage polarization. However, the effective concentration and mechanisms in this process remain unclear. Here, we synthesized Ti-xCu (x = 3, 5, 7 wt%) alloys and investigated the effects of copper concentration on macrophage M1/M2 polarization and the underlying mechanisms. In an 8-week rat mandibular bone regeneration experiment, Ti-5Cu demonstrated superior performance compared to pure titanium. At the early stage (2 weeks), Ti-5Cu promoted the dominance of M1 macrophages and upregulated inflammatory cytokines, facilitating the initial inflammatory response. Subsequently, a timely M1-to-M2 phenotype transition was observed, accompanied by elevated expression of the repair-related cytokine IL-10, ultimately leading to improved bone healing. This study provides a theoretical foundation for the development of titanium-copper composite materials with anti-inflammatory and pro-healing properties, paving the way for innovative solutions to promote bone defect repair.

Ideal periodontal regeneration requires the integration of alveolar bone, periodontal ligament, and cementum, along with Sharpey's fibers for occlusal force resistance. However, physiological regeneration remains rare due to its intricate structure, making clinical regeneration a challenge. Periodontal ligament stem cells (PDLSCs), first isolated in 2004, hold the key to multi-directional differentiation into cementoblasts, fibroblasts, and osteoblasts. While traditional therapies like guided tissue regeneration (GTR) aim to activate PDLSCs, clinical outcomes are inconsistent, suggesting the need for additional strategies to enhance PDLSCs' functions. Advancements in molecular biotechnology have introduced the use of recombinant growth factors for tissue regeneration. However, maintaining their efficacy requires high doses, posing cost and safety issues. Multi-layered scaffolds combined with cell sheet technology offer new insights, but face production, ethical, and survival challenges. Immune regulation plays a crucial role in PDLSC-mediated regeneration. The concept of "coagulo-immunomodulation" has emerged, emphasizing the coupling of blood coagulation and immune responses for periodontal regeneration. Despite its potential, the clinical translation of immune-based strategies remains elusive. The "developmental engineering" approach, which mimics developmental events using embryonic-stage cells and microenvironments, shows promise. Our research group has made initial strides, indicating its potential as a viable solution for periodontal complex regeneration. However, further clinical trials and considerations are needed for successful clinical application. This review aims to summarize the strategic transitions in the development of periodontal regenerative materials and to propose prospective avenues for future development.

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

Single-cell metabolomics reveals cell heterogeneity and elucidates intracellular molecular mechanisms. However, general concentration measurement of metabolites can only provide a static delineation of metabolomics, lacking the metabolic activity information of biological pathways. Herein, we develop a universal system for dynamic metabolomics by stable isotope tracing at the single-cell level. This system comprises a high-throughput single-cell data acquisition platform and an untargeted isotope tracing data processing platform, providing an integrated workflow for dynamic metabolomics of single cells. This system enables the global activity profiling and flow analysis of interlaced metabolic networks at the single-cell level and reveals heterogeneous metabolic activities among single cells. The significance of activity profiling is underscored by a 2-deoxyglucose inhibition model, demonstrating delicate metabolic alteration within single cells which cannot reflected by concentration analysis. Significantly, the system combined with a neural network model enables the metabolomic profiling of direct co-cultured tumor cells and macrophages. This reveals intricate cell-cell interaction mechanisms within the tumor microenvironment and firstly identifies versatile polarization subtypes of tumor-associated macrophages based on their metabolic signatures, which is in line with the renewed diversity atlas of macrophages from single-cell RNA-sequencing. The developed system facilitates a comprehensive understanding single-cell metabolomics from both static and dynamic perspectives.

In previous articles, a porcine model for bridging circumferential defects in the intrathoracic esophagus was developed. The aims of this present study were to evaluate the continued healing response after 35 days, avoid stent migration of the esophageal stent, and to investigate whether it would be beneficial to add new extracellular matrix (ECM) to the healing area after 20 days.

Surgery was performed in twelve piglets, and five different types of stents were used. In two piglets, new ECM was added by endoscope to the area of healing after 20 days. After the animals were euthanized, the esophageal tissue was examined.

Histologic examination after 35 days showed clusters of desmin-positive smooth muscle cells and the sprouting of nerves in the area that was healing. Generally, there were fewer M1 classically activated macrophages in specimens after 35 days when we compared them with the 20-day study. The CD 163 positive macrophages (M2-macrophages) were seen in all specimens. Four piglets did not survive to the end of the study period because of adverse events. Out of the eight piglets that were euthanized after 34 to 35 days, six had stents that had migrated to the stomach. Only in two piglets, who had large rilled stents, did the stents remain in place throughout the study period.

After 35 days, the area of healing did not show more signs of regenerative healing than the 20 days study. A procedure to add a new biomatrix by re-stenting endoscopically after 20 days was performed on two pigs. The procedure was feasible, but due to limb pain in the animals, they had to be euthanized prior to the plan, which prevented the evaluation of the effect on the regenerative response. The regenerative healing that was started needs to be further orchestrated in other ways to produce a more functional outcome with time.

Rheumatoid arthritis (RA), defined as Bi Zheng syndrome in traditional Chinese medicine (TCM), is a chronic inflammatory and autoimmune disease that can cause substantial articular degradation and impairment. In RA, the polarization of macrophages to a proinflammatoy phenotype contributes to chronic inflammation and joint injury. Soufeng sanjie formula (SF), a traditional Chinese formula used to treat RA, consists of Scolopendra subspinipes mutilans L. Koch, Buthus martensii Karsch, Astragalus membranaceus (Fisch), and Glycine max (L.) Merr seed coats and plays a role in the regulation of macrophage polarization. Vitamin D (VD), a specific activator of the vitamin D receptor (VDR), promotes the differentiation of M2 macrophages and significantly enhances the therapeutic effects of TCM on arthritis. However, whether SF can be combined with VD to regulate macrophage polarization and alleviate RA remains unclear.

In this study, we examined the regulatory mechanisms and therapeutic effects of the combination of SF and VD on macrophages in RA.

We used network pharmacology to analyze the targets and pathways of SF in RA. Clinical data were analyzed to confirm the expression of key targets. The RA immune landscape for cell-gene correlations was built using bioinformatics. A collagen-induced arthritis (CIA) model was established to evaluate the combined therapeutic effects of SF and VD on joint injury and inflammation. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting (WB), and immunofluorescence were used to assess the expression of key molecules in macrophages. Macrophage polarization was analyzed using flow cytometry.

SF acts on RA through multiple pathways, including hub genes, such as VDR, ABL1, DNMT1, and CXCR4. Immune infiltration analysis of RA showed that a reduction in the number of M2 macrophages significantly affected RA. Clinical data analysis and prognostic assessments corroborated the pivotal roles played by hub genes, such as VDR, ABL1, DNMT1, and CXCR4. Crucially, this study demonstrated a strong association between the key hub gene VDR and M2 macrophages. In vivo and in vitro models of RA showed that VD significantly improved the efficacy of SF against arthritis in CIA mice and stimulated macrophage polarization toward the M2 phenotype via modulation of the NOTCH3/DLL4 pathway. Furthermore, siRNA-mediated interference with the expression of VDR confirmed that the downregulation of VDR significantly activated the NOTCH3/DLL4 signaling pathway and blocked the regulation of SF combined with VD on the polarization of macrophages toward the M2 phenotype.

Our results demonstrate that the combination of SF and VD markedly improves the therapeutic effect of SF on RA via M2 macrophage differentiation through the VDR-NOTCH3/DLL4 signaling pathway. The VD-enhancing effect of SF in improving RA symptoms offers a new strategy and theoretical foundation for the clinical treatment of the condition.

Macrophages are essential immune cells that play crucial roles in inflammation and tissue homeostasis and are important regulators of metabolic processes, such as the metabolism of glucose, lipids, and amino acids. The regulation of macrophage metabolism by circadian clock genes has been emphasized in many studies. Changes in metabolic profiles occurring after the perturbation of macrophage circadian cycles may underlie the etiology of several diseases. Specifically, chronic inflammatory disorders, such as atherosclerosis, diabetes, cardiovascular diseases, and liver dysfunction, are associated with poor macrophage metabolism. Developing treatment approaches that target metabolic and immunological ailments requires an understanding of the complex relationships among clock genes, disease etiology, and macrophage metabolism. This review explores the molecular mechanisms through which clock genes regulate lipid, amino acid, and glucose metabolism in macrophages and discusses their potential roles in the development and progression of metabolic disorders. The findings underscore the importance of maintaining circadian homeostasis in macrophage function as a promising avenue for therapeutic intervention in diseases involving metabolic dysregulation, given its key roles in inflammation and tissue homeostasis. Moreover, reviewing the therapeutic implications of circadian rhythm in macrophages can help minimize the side effects of treatment. Novel strategies may be beneficial in treating immune-related diseases caused by shifted and blunted circadian rhythms via light exposure, jet lag, seasonal changes, and shift work or disruption to the internal clock (such as stress or disease).

Interleukin (IL)-34 is a relatively recently discovered cytokine which binds to colony-stimulating factor-1 receptor (CSF-1R). So far, there has been no clear explanation as to why CSF-1R requires two ligands. While CSF-1 is ubiquitously expressed, the expression of IL-34 is relatively restricted. However, it has been revealed that IL-34 expression increases in various diseases and is associated with their pathology. Naturally, both IL-34 and CSF-1 stimulate CSF-1R, thereby contributing to the differentiation of monocytes into macrophages. In many cases, the induced macrophages significantly influence the disease pathology. In particular, we have demonstrated that IL-34 expression in cancer is deeply involved in tumor progression and therapeutic resistance. We have shown that the blockade of IL-34 significantly improved therapeutic efficacy such as chemotherapy, radiotherapy, and immune checkpoint blockade against IL-34-expressing cancers. Recently, since macrophages induced by IL-34 exhibit immunosuppressive properties, whereas IL-34 can enhance inflammation, there is growing interest in actively regulating inflammation utilizing IL-34. In this review article, we provide an overview of the characteristics and roles of IL-34 and discuss how it could be applied to future diagnostics and therapeutics.

Diabetic foot ulcers (DFUs) are the severe chronic complications of diabetes, amputation is required when ulcers cause severe loss of tissue or evoke a life-threatening infection. Mesenchymal stem cells (MSCs) have shown a good effect in helping DFU healing, though the efficiency needs to be improved. This study aimed to investigate the effects of heat shock pretreatment on the improvement of the therapeutic effects of MSCs.

Primary rat bone marrow MSCs (BMSCs) were isolated and stimulated with heat shock pretreatment and then tested on a DFU rat model. Alkaline phosphatase, Alizarin Red S, and Oil Red O were stained to check the osteogenic differentiation ability of heat shock-pretreated BMSCs. The effect of heat shock pretreatment on the inflammatory response of macrophages was studied with the lipopolysaccharides stimulation model on a mouse macrophage cell line RAW264.7. The impact of heat shock-pretreated BMSCs on dermal fibroblasts was also checked. Last, heat shock-pretreated BMSCs were tested on a DFU rat model.

Heat shock-pretreated BMSCs were characterized by the expression of CD105 and CD44. Heat shock pre-stimulation did not affect cell viability when cultured up to 96 h. Heat shock pre-stimulated BMSCs inhibited the inflammatory response by reducing the pro-inflammatory cytokine production (IL-1β, IL-6, and TNF-α) and enhancing the anti-inflammatory cytokine production (IL-10) (at least all p < 0.01), as well as increasing the ratio of M2 polarization macrophages to M1 polarization in vitro (p < 0.001). Heat shock pre-stimulated BMSCs enhanced the growth and migration of dermal fibroblasts in vitro (p < 0.001). Heat shock-BMSCs promoted the M2 polarization level of macrophages in wound tissues in a DFU rat model.

Heat shock pretreatment could enhance the therapeutic effect of BMSCs on wound healing in a DFU rat model.

Upon cerebral ischemia/reperfusion injury (CIRI), the brain tissue experiences excessive inflammatory responses, which fuel the activation of immune cells, thereby intensifying cellular damage and inflammatory reactions. Naoqing formula (NQ), a traditional Chinese medicinal compound formulated with musk as the primary component, has been extensively utilized in China for the clinical treatment of ischaemic stroke (IS).

The precise pharmacological mechanism underlying NQ's efficacy in managing IS remains elusive. In this study, we investigate the protective effect and molecular mechanism of NQ against CIRI.

C57BL/6 mice were utilized to investigate the protective effects of NQ (130, 260 and 520mg/kg) against middle cerebral artery occlusion (MCAO) induced CIRI and the underlying mechanism. Employing molecular biology techniques, transcriptomics, proteomics, and network pharmacological analyses, the study assessed the role of NQ in the inflammatory response of neuronal cells by establishing a model for neuronal cell and microglia inflammatory injury induced by oxygen-glucose deprivation/reperfusion (OGD/R) and lipopolysaccharide (LPS) stimulation.

NQ demonstrated significant efficacy in mitigating neuronal damage and cerebral infarction induced by CIRI, achieved through the enhancement of cortical blood flow. Transcriptomic and network pharmacological analyses revealed that NQ mitigated the inflammatory damage caused by CIRI by modulating the Csf3-mediated JAK/STAT pathway. Proteomic analysis further corroborated this finding, indicating that NQ reduced the impact of CIRI by regulating macrophage polarization. Notably, in CIRI mice treated with NQ, there was a notable downregulation of Csf3, JAK2, STAT3, and STAT6, along with a co-localization of Csf3 and CD206. These observations suggested that NQ inhibited the activation of the JAK/STAT pathway and exerted its anti-inflammatory effects by orchestrating the transition of macrophages from the M1 phenotype to the M2 phenotype, triggered by Csf3. Consistent with the in vivo findings, NQ also inhibited the activation of the JAK/STAT pathway in neuronal cells and microglial polarization in vitro, thereby protecting against OGD/R- and LPS-induced inflammatory injury.

This study confirmed that NQ prevented CIRI induced inflammatory injury by inhibiting Csf3-mediated activation of the JAK/STAT pathway and modulating Csf3-mediated macrophage polarization. This study provided a new perspective on the use of NQ in the treatment of IS.

Deep vein thrombosis is an acute medical condition, and the molecular basis of this etiology will be crucial in the discovery of more advanced therapies. This review has focused at the Notch signaling pathway, which plays a significant role in different physiological activities such as homeostasis, development, and disease. Also, reveal macrophage function in inflammation and thrombosis in depth, with a focus on their polarization and interaction with the endothelium during thrombosis. In this context, some essential cellular and molecular mechanisms relevant to thrombus pathogenesis, DVT aetiology and risk factors, as well as elements and composition of the Notch pathway, are covered in the end, with a focus on elements that distinguish canonical from non-canonical signaling pathways and their biological relevance to macrophages. Notch signaling has been shown to influence macrophage activation and polarization, influencing their function in thrombosis breakdown and resolution. This interplay between Notch signaling and macrophages may reveal possible treatment targets for DVT. Discuss the physiological role of Notch signaling in vascular biology, as well as how it contributes to thrombosis. The difficulties in implementing these discoveries in clinical practice are discussed, along with the status of ongoing clinical trials and experimental investigations focussing on macrophage-directed treatments and Notch inhibitors. These molecular insights synthesis provides a basis for the creation of novel strategies for the efficient management of DVT.

Macrophages are pivotal in osteoarthritis (OA) pathogenesis, as their dysregulated polarization can contribute to chronic inflammatory processes. This review explores the molecular and metabolic mechanisms that influence macrophage polarization and identifies potential strategies for OA treatment. Currently, non-surgical treatments for OA focus only on symptom management, and their efficacy is limited; thus, mesenchymal stem/stromal cells (MSCs) have gained attention for their anti-inflammatory and immunomodulatory capabilities. Emerging evidence suggests that small extracellular vesicles (sEVs) derived from MSCs can modulate macrophage function, thus offering potential therapeutic benefits in OA. Additionally, the transfer of mitochondria from MSCs to macrophages has shown promise in enhancing mitochondrial functionality and steering macrophages toward an anti-inflammatory M2-like phenotype. While further research is needed to confirm these findings, MSC-based strategies, including the use of sEVs and mitochondrial transfer, hold great promise for the treatment of OA and other chronic inflammatory diseases.

Regenerative endodontic procedures using blood clots (BC-REP) for immature teeth typically exhibit a periodontal ligament-like healing pattern. However, a pulp-like healing pattern is observed in the presence of residual pulp. This study aimed to clarify the healing phenotype according to tooth maturity when performing BC-REP in the presence of residual pulp, focusing on migrated mesenchymal stem/stromal cells (MSCs). BC-REP rat molar models were created in the presence of residual pulp at ages corresponding to tooth developmental stages, from immature to mature (5 wk: immature, root is still growing; 8 wk: near mature, root has finished growing in length but the apex is not formed; 11 wk: mature, the apex is formed). The healing pattern and histological MSC markers (α-smooth muscle actin [α-SMA], CD73, CD90, and CD146) were investigated. The frequency of periodontal ligament-like healing was higher in mature teeth than in immature teeth. In addition, more healing macrophages were observed at the apical site 28 d after BC-REP, which is the final stage of healing. In immature teeth, double-immunopositive cells for proliferation markers (ki67 and proliferating cell nuclear antigen [PCNA]) and α-SMA were frequently observed in the vicinity of the root canal orifice 7 d after treatment, which is the early stage of healing. By contrast, in mature teeth, the number of CD73-, CD90-, and CD146-immunopositive cells increased at the apical site after 7 and 28 d. CD90- and CD146-immunopositive cells expressed cell proliferation markers (ki67 or PCNA) after 7 d. MSC migration after BC-REP likely varies based on tooth maturity, resulting in different healing phenotypes.

Inactivated whole tumor cell-based vaccines (WTVs) are a promising strategy for tumor immunotherapy, but have exhibited limited antitumor effects clinically. Aiming at constructing enhanced WTVs, we developed glycopolymer-engineered WTVs (G-WTVs) using a Halo-Tag protein (HTP) fusion technique and reversible addition-fragmentation chain transfer (RAFT) polymerization. In our study, G-WTVs with varying molecular weights of glycopolymers were constructed. Compared to unmodified tumor cells, all G-WTVs effectively induced the polarization of macrophages toward the M1 phenotype and promoted the secretion of pro-inflammatory cytokines. This enhanced immune response was attributed to the improved interactions between G-WTVs and the macrophages. Among the G-WTVs, the medium molecular weight variant demonstrated the most pronounced enhancement of antitumor immune responses. Notably, the administration of optimized G-WTVs effectively inhibited the growth of B16 melanoma in mice. Our findings provide a new approach to enhance the antitumor efficacy of WTVs via cell membrane glycopolymer engineering, offering a promising strategy for tumor immunotherapy.

Various inflammatory and anti-inflammatory mediators, along with diverse cell types, are implicated in the development and progression of periapical lesions. This work aimed to assess the immuno-expression of transforming growth factor-beta 1 (TGF-β1) and CD68 (a macrophage marker), elucidating their roles and potential correlations. Additionally, histological analysis was conducted to evaluate the intensity of inflammatory infiltrates in chronic periapical lesion samples.

Tissue samples from fifty individuals with chronic periapical lesions [25 radicular cysts (RCs) and 25 periapical granulomas (PGs)] were obtained, along with control samples from four healthy third molars' dental pulp. Histological examination and inflammatory infiltrate categorization were performed. Immunohistochemical analysis of TGF-β1 and CD68 markers, along with morphometric assessment, were conducted.

The control group displayed normal, inflammation-free pulp tissues, while intense inflammation was observed in PGs and RCs (Score 4 and 3, respectively) dominated by macrophages, plasma cells, and lymphocytes. Immunohistochemistry showed higher TGF-β1 and CD68 expression in PGs and RCs versus control (P < 0.001). Moreover, PGs exhibited greater TGF-β1 and CD68 expression than RCs (P < 0.001). However, a negative relationship was detected between the 2 markers (P < 0.05).

This study highlighted varying expressions of TGF-β1 and CD68 in PGs and RCs, indicating their potential roles in lesion pathology. However, a negative correlation between these markers was observed. Accordingly, their precise role in periapical lesion progression and repair requires further investigation.

Psoriasis is a complex immune-mediated disease that has been closely associated with obesity and lipid metabolism disorders. This study investigated the effects of hydrogen-rich water (HRW) on imiquimod-induced psoriasis-like skin inflammation in ApoE-deficient mice. Psoriasis severity as well as the lipid levels and inflammatory markers were evaluated. The results revealed that HRW significantly reduced plasma triglyceride and total cholesterol levels, increased high-density lipoprotein cholesterol levels, and alleviated skin lesions in mice. Transcriptomic data of the skin tissues indicated significant changes in the inflammatory and lipid metabolism pathways after HRW treatment and quantitative PCR validated the regulation of inflammatory cytokine expression. In addition, HRW promoted M2 macrophage polarization and reduced M1 macrophage polarization in the skin. These results suggest that the consumption of HRW may be a potential therapeutic strategy for psoriasis accompanied by abnormal lipid metabolism.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

Macrophages perform an essential role in the body's defense mechanisms and tissue homeostasis. These cells exhibit plasticity and are categorized into two phenotypes, including classically activated/M1 pro-inflammatory and alternatively activated/M2 anti-inflammatory phenotypes. Functional deviation in macrophage polarization occurs in different pathological conditions that need correction. In addition to antidiabetic impacts, metformin also possesses multiple biological activities, including immunomodulatory, anti-inflammatory, anti-tumorigenic, anti-aging, cardioprotective, hepatoprotective, and tissue-regenerative properties. Metformin can influence the polarization of macrophages toward M1 and M2 phenotypes. The ability of metformin to support M2 polarization and suppress M1 polarization could enhance its anti-inflammatory properties and potentiate its protective effects in conditions such as chronic inflammatory diseases, atherosclerosis, and obesity. However, in metformin-treated tumors, the proportion of M2 macrophages is decreased, while the frequency ratio of M1 macrophages is increased, indicating that metformin can modulate macrophage polarization from a pro-tumoral M2 state to an anti-tumoral M1 phenotype in malignancies. Metformin affects macrophage polarization through AMPK-dependent and independent pathways involving factors, such as NF-κB, mTOR, ATF, AKT/AS160, SIRT1, STAT3, HO-1, PGC-1α/PPAR-γ, and NLRP3 inflammasome. By modulating cellular metabolism and apoptosis, metformin can also influence macrophage polarization. This review provides comprehensive evidence regarding metformin's effects on macrophage polarization and the underlying mechanisms. The polarization-inducing capabilities of metformin may provide significant therapeutic applications in various inflammatory diseases and malignant tumors.

This study focuses on the optimization of sterilization methods for bioprinted three-dimensional (3D) corneal stroma patches prepared using cornea-derived decellularized extracellular matrix (Co-dECM) hydrogels and human keratocytes, with the aim of enhancing clinical applications in corneal tissue engineering. An essential aspect of this study is to refine the sterilization processes, particularly focusing on electron beam (EB) sterilization, to maintain the structural and functional integrity of the Co-dECM hydrogels while ensuring sterility. The study reveals that EB sterilization outperformed traditional methods like ethylene oxide (EtO) gas and autoclaving, which tend to degrade the biochemical properties of hydrogels. By optimizing the EB-sterilization process, the essential mechanical and biochemical characteristics needed for successful 3D bioprinting are retained, reducing batch variability in bioprinted 3D corneal stroma patches. Consistency in production is vital for meeting regulatory standards and ensuring patient safety. Moreover, the study investigates the immunomodulatory properties of sterilized hydrogels, emphasizing their potential to minimize inflammatory responses, which is crucial for maintaining keratocyte phenotype. These findings significantly advance biomedical engineering by providing a sterilization method that preserves material integrity, minimizes immunogenicity, and supports the clinical translation of bioprinted corneal stroma patches, offering a promising alternative to donor transplants and synthetic substitutes.

Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified.

We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis.

Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling.

The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.

Atherosclerosis is the leading cause of cardiovascular disease (CVD). Historically, the management of atherosclerosis was focused on decreasing lipid profile levels; however, recent evidence demonstrated that platelets and leukocytes play an important role in forming and exacerbating atherosclerosis. L-arginine (L-Arg), a precursor to nitric oxide (NO), plays a critical role in modulating oxidative stress and influencing platelet-leukocyte recruitment and has been extensively addressed in the context of CVD.

We aimed to perform a comprehensive literature review on l-Arg metabolism in the causative pathway of atherosclerosis compared to conventional treatment and it as a putative therapeutic approach.

L-Arg supplementation has shown promising effects on NO production, improving endothelial function and reducing oxidative stress in preclinical models. Clinical studies have indicated moderate improvements in vascular health markers, including reductions in inflammation and oxidative stress, although results have varied across studies. The potential of l-Arg to modify platelet-leukocyte recruitment and slow the progression of atherosclerotic plaque development has been observed in certain studies. However, these benefits remain inconsistent, and more robust clinical trials are needed to confirm its effectiveness. Additionally, while l-Arg appears to be relatively safe, some studies reported mild gastrointestinal discomfort as a common side effect.

l-Arg holds potential as a complementary or alternative treatment for atherosclerosis, particularly in improving endothelial function and reducing inflammation and oxidative stress. However, the variability in clinical outcomes and the lack of long-term data required further investigation into assessing therapeutic benefits. Future studies should focus on determining optimal dosing regimens, evaluating their long-term safety, and assessing their potential in combination with other therapies to enhance cardiovascular outcomes.

Crohn's disease (CD) is characterized by immune cell dysregulation, with macrophages playing an indisputable role. Macrophages can exhibit opposing polarization under different conditions, resulting in pro- or anti-inflammatory effects. The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is implicated in intestinal inflammation by regulating both innate and adaptive immune responses. However, the regulatory mechanism between AhR and macrophages in colitis has not been thoroughly investigated.

Macrophage polarization in the colonic tissue of active CD patients was assessed. Following colitis induction in mice by 2,4,6-trinitro-benzenesulfonic acid (TNBS), an intraperitoneal injection of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) was administered. The severity of colitis was estimated, and macrophage polarization was detected. In an in vitro setting, bone marrow-derived macrophages (BMDMs) were polarized to the M2 phenotype in the presence or absence of FICZ. Interferon regulatory factor 4 (IRF4) siRNA was applied to knockdown IRF4 expression. M2-specific markers were quantified using quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry.

Compared with healthy controls, active CD patients exhibited a lower presence of M2 macrophages in colonic tissue. Experimentally, FICZ was found to protect mice against TNBS-induced colitis, as evidenced by reduced diarrhea, bloody stool, and weight loss. This effect was associated with an increase in M2 macrophages and the release of IL-10 in the intestine. In BMDMs, FICZ promoted the expressions of M2-specific markers, including Ym1, Fizz1, IL-10, and CD206. Furthermore, FICZ upregulated IRF4 expression. After IRF4 silencing with siRNA, the enhancement of macrophage M2 polarization by FICZ was significantly impaired.

Activation of AhR appears to have a beneficial effect on intestinal inflammation by promoting macrophage M2 polarization. This effect is partially mediated by the upregulation of IRF4 expression and may lead to new insight into the pathogenesis of CD.

Lipopolysaccharide (LPS), also known as an endotoxin, is derived from Gram-negative bacteria. The intravenous administration of LPS induces an inflammatory response and causes systemic inflammation, such as cytokine storm. Gram-negative bacteria that produce LPS are found in the environment and digestive tract. The mucous membrane, the primary barrier between the interior of the body and the external environment, is constantly exposed to LPS. Moreover, no toxicity is observed when administering LPS through the mucous membranes of the mouth or skin. The presence of LPS in the mucous membranes is necessary not only for maintaining health but also for inducing preventive and therapeutic effects against multiple diseases when administered orally or topically. LPS is an environmental substance that is useful when administered to mucous membranes. The general information emphasizes the role of LPS as an inflammatory substance that occurs when administered intravenously. Therefore, the valuable role of LPS is unknown. Thus, mucosal administration of LPS has received little attention, and the mechanism underlying the expression of its beneficial effects has not been fully elucidated. We proposed a comprehensive concept, the "macrophage network," which proposes a regulatory system in which the mucosa receives environmental information, membrane-bound cytokines are expressed in phagocytes (macrophages), and these macrophages migrate distally to exert effects, such as anti-inflammatory and tissue repair effects, on distal tissues through cell-to-cell communication (juxtacrine signaling) with tissue macrophages. This macrophage network is effective not only for preventing and treating diseases but also for increasing the efficacy of pharmaceuticals. This review aims to investigate the preventive and therapeutic effects of oral and transdermal administration of LPS on various diseases and present an introduction to the concept of the macrophage network and the latest findings.

Osteosarcoma, a primary malignant bone tumor commonly found in adolescents, is highly aggressive, with a high rate of disability and mortality. It has a profound negative impact on both the physical and psychological well-being of patients. The standard treatment approach, comprising surgery and chemotherapy, has seen little improvement in patient outcomes over the past several decades. Once relapse or metastasis occurs, prognosis worsens significantly. Therefore, there is an urgent need to explore new therapeutic approaches. In recent years, the successful application of immunotherapy in certain cancers has demonstrated its potential in the field of cancer treatment. Macrophages are the predominant components of the immune microenvironment in osteosarcoma and represent critical targets for immunotherapy. Macrophages exhibit dual characteristics; while they play a key role in maintaining tumor-promoting properties within the microenvironment, such as inflammation, angiogenesis, and immune suppression, they also possess antitumor potential as part of the innate immune system. A deeper understanding of macrophages and their relationship with osteosarcoma is essential for the development of novel therapeutic strategies.

Glioblastomas are the most prevalent primary brain tumors and are associated with a dramatically poor prognosis. Despite an intensive treatment approach, including maximal surgical tumor removal followed by radio- and chemotherapy, the median survival for glioblastoma patients has remained around 18 months for decades. Glioblastoma is distinguished by its highly complex mechanisms of immune evasion and pronounced heterogeneity. This variability is apparent both within the tumor itself, which can exhibit multiple phenotypes simultaneously, and in its surrounding microenvironment. Another key feature of glioblastoma is its "cold" microenvironment, characterized by robust immunosuppression. Recent advances in single-cell RNA sequencing have uncovered new promising insights, revealing previously unrecognized aspects of this tumor. In this review, we consolidate current knowledge on glioblastoma cells and its microenvironment, with an emphasis on their biological properties and unique patterns of molecular communication through signaling pathways. The evidence underscores the critical need for personalized poly-immunotherapy and other approaches to overcome the plasticity of glioblastoma stem cells. Analyzing the tumor microenvironment of individual patients using single-cell transcriptomics and implementing a customized immunotherapeutic strategy could potentially improve survival outcomes for those facing this formidable disease.

Immune cells such as macrophages play a significant role in ocular inflammation by activating or inhibiting several cellular pathways. Systemic infections and autoimmune diseases could activate macrophages by releasing various pro-inflammatory cytokines, chemokines, and growth factors, which reach the eyes through the blood-retina barrier and cause immune and inflammatory responses. In addition, environmental pollutants, allergens, and eye injuries could also activate macrophages and cause an inflammatory response. Further, the inflammatory response generated by the macrophages could recruit additional immune cells and enhance the inflammatory response. The inflammatory response leads to ocular tissue damage and dysfunction and affects vision. Macrophages are generally implicated in the clearance of pathogens and debris, generate reactive oxygen species, and initiate immune response. However, uncontrolled immune and inflammatory responses could damage the ocular tissues, leading to various ocular inflammatory complications such as uveitis, scleritis, diabetic retinopathy, and retinitis. Recent studies describe the role of individual cytokines in the mediation of specific ocular inflammatory diseases. In this article, we discussed the potential impact of macrophages and their mediated inflammatory response on the development of various ocular inflammatory diseases and possible treatment strategies.

Diabetic wounds have a profound effect on both the physical and psychological health of patients, highlighting the urgent necessity for novel treatment strategies and materials. Macrophages are vital contributors to tissue repair mechanisms. Macrophage conditioned medium contains various proteins and cytokines related to wound healing, indicating its potential to improve recovery from diabetic wound. Engineering macrophages may enable a further improvement in their tissue repair capacity. Fibroblast growth factor 2 (FGF2) is a crucial growth factor that plays an integral role in wound healing process. And in this study, a stable macrophage cell line (engineered macrophages) overexpressing FGF2 was successfully established by engineering modification of macrophages. Proteomic analysis indicated that conditioned medium derived from FGF2 overexpressed macrophages may promote wound healing by enhancing the level of vascularization. Additionally, cellular assays demonstrated that this conditioned medium promotes endothelial cell migration in vitro. For the convenience of drug delivery and wound application, we prepared soluble hyaluronic acid microneedles to load the conditioned medium. These soluble microneedles exhibited excellent mechanical properties and biocompatibility while effectively releasing their contents in vivo. The microneedles significantly accelerated wound healing, leading to a marked increase in vascular proliferation and improved collagen deposition within a full thickness skin defect diabetic mouse model. In summary, we developed a type of hyaluronic acid microneedle loaded with conditioned medium of engineered macrophages. These microneedles have been demonstrated to enhance tissue vascularization and facilitate diabetic wound healing. This might potentially serve as a highly promising therapeutic approach for diabetic wounds.

Obstructive sleep apnea (OSA) is known to contribute to the occurrence and recurrence of atrial fibrillation (AF). However, the mechanism remains unknown.

Chronic OSA rat model was established to elucidate the role of macrophages in OSA-induced AF. Moreover, to reveal the mechanisms underlying the abnormal polarization of macrophages induced by chronic OSA, co-culture cell model of macrophages and atrial myocytes was created.

Chronic OSA altered the pathological phenotype of atrial myocardial tissues, rendering it more susceptible to AF. Furthermore, chronic OSA promoted the polarization of M1 macrophages in the atrial tissue, and the AF susceptibility induced by chronic OSA was reversed upon clearance of macrophages. Then, we found that macrophages induced an atrial fibrillation-like phenotype in atrial myocytes, while atrial myocytes promoted M1 polarization of macrophages, under hypoxia/reoxygenation treatment. Moreover, hypoxia/reoxygenation upregulated the expression of hypoxia-inducible factor 1-α (HIF1α) in atrial myocytes, which subsequently promoted the expression of macrophage migration inhibitory factor (MIF) by binding to the promoter region. The increased expression of MIF further activated the expression of nuclear factor-kappa B (NF-κB) through interaction with CD74, ultimately leading to M1 macrophages polarization.

Increased polarization of M1-type macrophages was involved in the increased susceptibility to AF induced by OSA. In mechanism, OSA increased MIF expression by HIF1α in atrial myocytes. Then, MIF activated NF-κB expression by CD74 in macrophages, consequently driving the polarization of M1-type macrophages. Finally, M1 macrophages exacerbated atrial remodeling through the secretion of inflammatory cytokines, which contributed to the increased susceptibility to AF.

Neutrophils play a crucial role in the innate immune response as a first line of defense in many diseases, including cancer. Tumor-associated neutrophils (TANs) can either promote or inhibit tumor growth in various steps of cancer progression via mutual interactions with cancer cells in a complex tumor microenvironment (TME). In this study, we developed and analyzed mathematical models to investigate the role of natural killer cells (NK cells) and the dynamic transition between N1 and N2 TAN phenotypes in killing cancer cells through key signaling networks and how adjuvant therapy with radiation can be used in combination to increase anti-tumor efficacy. We examined the complex immune-tumor dynamics among N1/N2 TANs, NK cells, and tumor cells, communicating through key extracellular mediators (Transforming growth factor (TGF-$ \beta $), Interferon gamma (IFN-$ \gamma $)) and intracellular regulation in the apoptosis signaling network. We developed several tumor prevention strategies to eradicate tumors, including combination (IFN-$ \gamma $, exogenous NK, TGF-$ \beta $ inhibitor) therapy and optimally-controlled ionizing radiation in a complex TME. Using this model, we investigated the fundamental mechanism of radiation-induced changes in the TME and the impact of internal and external immune composition on the tumor cell fate and their response to different treatment schedules.

Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood-brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.

Trimethylamine N-oxide (TMAO) is a gut microbial metabolite that promotes calcified aortic valve disease (CAVD), but the underlying mechanism remains obscure. Herein, we aim to test the hypothesis that TMAO regulated the inflammatory process in aortic valves via N6-methyladenosine (m6A) RNA methylation-mediated macrophage polarization.

In vitro, we stimulated macrophages (Phorbol-12-Myristate-13-Acetate-induced THP-1) with TMAO and assessed the expression of methyltransferase-like 3 (Mettl3), IL-1 receptor associated kinase M (IRAK-M) and polarization markers. The interaction between YTH domain family protein 2 (YTHDF2) and IRAK-M mRNA was explored by RNA-IP and RNA decay assay. Functionally, the effects of macrophages on human aortic valve interstitial cells (AVICs) were measured via macrophage adhesion assay and co-culture system. In vivo, the influence of IRAK-M on CAVD development was verified using Irak-m-/- mice.

Mettl3 was highly expressed while IRAK-M was decreased in human calcified aortic valves. In vitro, TMAO upregulated the expression of Mettl3, while the expression of IRAK-M, an important negative regulator of the NF-κB pathway, was remarkably decreased in macrophages. TMAO also induced classical macrophage activation (M1 polarization). Mechanistically, IRAK-M was identified as a target of Mettl3-mediated m6A modification, indicating the involvement of m6A methylation in the regulation of NF-κB activation. Moreover, RIP assay revealed the direct interaction between YTHDF2 and IRAK-M mRNA and this process was dependent on Mettl3. TMAO-treated macrophage conditioned medium induced inflammatory responses in human aortic valve interstitial cells (AVICs). In vivo experiments showed that the deletion of IRAK-M significantly accelerated the progression of aortic valve lesion in mice administrated with high-fat and choline diet (HFCD).

TMAO induces the expression of Mettl3 in macrophages. Mettl3 promotes M1 polarization of macrophages by inhibiting IRAK-M through a m6A/YTHDF2 pathway. TMAO-treated macrophages aggravate the inflammation of human AVICs.

Our previous study revealed that mesenchymal stem cells (MSCs) can secrete large amounts of the chemokine CCL2 under inflammatory conditions and alleviate idiopathic pneumonia syndrome (IPS) by promoting regulatory CCR2 + CD4 + T-cell formation through the CCL2‒CCR2 axis. Given the abundance of macrophages in lung tissue, how these macrophages are regulated by MSC-based prophylaxis via IPS and their interactions with T cells in lung tissue during allo-HSCT are still not fully understood.

An IPS mouse model was established, and MSC-based prophylaxis was administered. In vitro coculture systems and an IPS model were used to study the interactions among MSCs, macrophages and T cells.

Prophylactic administration of MSCs induced M2 polarization and alleviated acute graft-versus-host disease (aGVHD) and lung injury in an IPS mouse model. In vitro coculture studies revealed that M2 polarization was induced by MSC-released CCL2 and that these M2 macrophages promoted the formation of regulatory CCR2 + CD4 + T cells. Blocking the CCL2-CCR2 interaction in vitro reversed MSC-induced M2 polarization and abolished the induction of CCR2 + CD4 + T-cell formation. Additionally, in vivo administration of a CCL2 or CCR2 antagonist in the IPS mouse model exacerbated aGVHD and lung injury, accompanied by a reduction in M2 macrophages and reduced formation of regulatory CCR2 + CD4 + T cells in lung tissue.

MSCs alleviate IPS by facilitating M2 polarization via the CCL2‒CCR2 axis and further inducing the formation of regulatory CCR2 + CD4 + T cells.

Cardiac fibrosis is a physiological process that involves the formation of scar tissue in the heart in response to injury or damage. This process is initially a protective measure characterized by enhanced fibroblasts, which are responsible for producing extracellular matrix proteins that provide structural support to the heart. However, when fibrosis becomes excessive, it can lead to adverse outcomes, including increasing tissue stiffness and impaired cardiac function, which can ultimately result in heart failure with a poor prognosis. While fibroblasts are the primary cells involved in cardiac fibrosis, immune cells have also been found to play a vital role in its progression. Recent research has shown that immune cells exert multifaceted effects besides regulation of inflammatory response. Advanced research techniques such as single-cell sequencing and multiomics have provided insights into the specific subsets of immune cells involved in fibrosis and the complex regulation of the process. Targeted immunotherapy against fibrosis is gaining traction as a potential treatment option, but it is still unclear how immune cells achieve this regulation and whether distinct subsets are involved in different roles. To better understand the role of immune cells in cardiac fibrosis, it is essential to examine the classical signaling pathways that are closely related to fibrosis formation. We have also focused on the unique properties of diverse immune cells in cardiac fibrosis and their specific intercommunications. Therefore, this review will delve into the plasticity and heterogeneity of immune cells and their specific roles in cardiac fibrosis, which propose insights to facilitate the development of anti-fibrosis therapeutic strategies.

Cellular phenotypic transformation is a key process that occurs during the development and progression of atherosclerosis. Within the arterial wall, endothelial cells, vascular smooth muscle cells, and macrophages undergo phenotypic changes that contribute to the pathogenesis of atherosclerosis. miRNAs have emerged as potential biomarkers for cellular phenotypic changes during atherosclerosis. Monitoring miR-155-5p, miR-210-3p, and miR-126-3p or 5p levels could provide valuable insights into disease progression, risk of complications, and response to therapeutic interventions. Moreover, miR-92a-3p's elevated levels in atherosclerotic plaques present opportunities for predicting disease progression and related complications. Baseline levels of miR-33a/b hold the potential for predicting responses to cholesterol-lowering therapies, such as statins, and the likelihood of dyslipidemia-related complications. Additionally, the assessment of miR-122-5p levels may offer insights into the efficacy of low-density-lipoprotein-lowering therapies. Understanding the specific miRNA-mediated regulatory mechanisms involved in cellular phenotypic transformations can provide valuable insights into the pathogenesis of atherosclerosis and potentially identify novel therapeutic targets.

Orthobiologics, such as autologous nanofat, are emerging as a potential treatment option for osteoarthritis (OA), a common degenerative joint causing pain and disability in the elderly. Nanofat, a minimally processed human fat graft rich in stromal vascular fraction (SVF) secretory factors, has shown promise in relieving pain. This study aimed to elucidate the molecular mechanisms underlying nanofat treatment of OA-affected cells and compare two filtration systems used for nanofat preparation.

Chondrocytes and synoviocytes were isolated from articular cartilage and synovium of 22 OA-patients. Lipoaspirates from 13 OA-patients were emulsified using the Adinizer® or Lipocube™ Nano filter systems to generate nanofat. The fluid phase of SVF from both filtered and unfiltered lipoaspirates was applied to OA-affected cells. Luminex multiplex ELISA were performed with lipoaspirates and cell supernatants alongside functional assays evaluating cell migration, proliferation, metabolic activity, and senescence.

A total of 62 cytokines, chemokines, growth factors, neuropeptides, matrix-degrading enzymes, and complement components were identified in lipoaspirates. Among these, significant concentration differences were observed for TIMP-2, TGF-ß3, and complement component C3 between the filtered and unfiltered samples. Nanofat enhanced chondrocyte proliferation and migration, as well as synoviocyte migration and metabolic activity, while reducing chondrocyte metabolic activity. Pain-related factors like β-NGF, MCP-1, Substance P, VEGF, and αCGRP were reduced, while anti-inflammatory TGF-β1+3 increased and pro-inflammatory cytokines (IL-5, IL-7, IL-15, and IFN-γ) decreased. Nanofat also elevated secretion of complement components and TIMPs in both cell types. Notably, our results revealed no significant differences in cellular effects between sSVF filtered using the Adinizer® and Lipocube™ Nano systems, as well as compared to unfiltered sSVF.

Here, we provide first insights into how autologous nanofat therapy may ameliorate OA by enhancing chondrocyte proliferation and synoviocyte migration while modulating inflammatory and pain-related factors. However, further research is needed to determine its effects on cartilage regeneration.

The gut microbiota, a complex microbial ecosystem closely connected to the liver via the portal vein, has emerged as a critical regulator of liver health and disease. Numerous studies have underscored its role in the onset and progression of liver disorders, including alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). This review provides a comprehensive overview of current insights into the influence of the gut microbiota on HCC progression, particularly its effects on immune cells within the HCC tumor microenvironment (TME). Furthermore, we explore the potential of gut microbiota-targeted interventions, such as antibiotics, probiotics, prebiotics, and fecal microbiota transplantation (FMT), to modulate the immune response and improve outcomes of immunotherapy in HCC. By synthesizing insights from recent studies, this review aims to highlight microbiota-based strategies that may enhance immunotherapy outcomes, advancing personalized approaches in HCC treatment.