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Neutrophil extracellular traps (NETs) are crucial orchestrators in wound healing, exhibiting a dual nature by providing antimicrobial properties and mediating inflammation. The interactions between NETs and skin cells, such as fibroblasts, keratinocytes, and mesenchymal stem cells (MSCs), exhibit the multifaceted impact of NETs on wound healing. Imbalanced NET-related pathways, including NF-κB, PI3K-AKT, Hippo–YAP, and Wnt/β-catenin, may result in oxidative inflammation and hinder wound healing. Integrating immune markers like interleukin (IL)-1β, IL-6, and the NET-related biomarker citrullinated histone H3 (citH3) into predictive protocols can enhance the accuracy of wound healing prognosis. Therapeutic strategies targeting NETs through small molecule inhibitors, insulin, glycoproteins, MSCs, monoclonal antibodies, and gasotransmitters are effective in wound healing. Wound healing is a complex and orchestrated process that involves hemostasis, inflammation, proliferation, and tissue remodeling. Neutrophil extracellular traps (NETs) are intricate web-like structures released by neutrophils, comprising decondensed chromatin, myeloperoxidase (MPO), and neutrophil elastase (NE), which play vital roles in regulating neutrophil-mediated immune regulation. While NETs contribute to wound healing, excessive activation induced by dysregulated inflammation can hinder the healing process. Understanding the pivotal role of NETs in wound healing and tissue remodeling, as well as their intricate interactions within the wound microenvironment, presents opportunities for innovative wound healing strategies. In this review we discuss the process of NET formation, explore the interactions between NETs and skin cells, and examine therapeutic strategies targeting NETs and drug delivery platforms to accelerate wound healing. Additionally, we discuss current clinical investigations and research challenges towards advancing wound care practices. [ABSTRACT FROM AUTHOR]

The progression of ulcerative colitis (UC) is associated with immunologic derangement, intestinal hemorrhage, and microbiota imbalance. While traditional medications mainly focus on mitigating inflammation, it remains challenging to address multiple symptoms. Here, a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO 2 nanospheres with Cu 2 O nanoblocks. The resulting CaO 2 –Cu 2 O possessed a desirable diameter (291.3 nm) and a uniform size distribution. It could be efficiently internalized by colonic epithelial cells and macrophages, scavenge intracellular reactive oxygen/nitrogen species, and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype. This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles. Rectal administration of CaO 2 –Cu 2 O could stanch the bleeding, repair the disrupted colonic epithelial layer, and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation, anti-oxidation, wound healing, and anti-inflammation. Impressively, it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria (e.g. , Odoribacter and Bifidobacterium) and decreasing the abundances of harmful bacteria (e.g. , Prevotellaceae and Helicobacter). Our gas-driven CaO 2 –Cu 2 O offers a promising therapeutic platform for robust treatment of UC via the rectal route. A versatile gas-propelled nanomotor (CaO 2 –Cu 2 O) was facilely produced to overcome rectal drug delivery barriers and achieve effective synergistic treatment outcomes against ulcerative colitis. [Display omitted] [ABSTRACT FROM AUTHOR]

The epithelial lining of the respiratory tract and intestine provides a critical physical barrier to protect host tissues against environmental insults, including dietary antigens, allergens, chemicals, and microorganisms. In addition, specialized epithelial cells communicate directly with hematopoietic and neuronal cells. These epithelial-immune and epithelial-neuronal interactions control host immune responses and have important implications for inflammatory conditions associated with defects in the epithelial barrier, including asthma, allergy, and inflammatory bowel diseases. In this review, we discuss emerging research that identifies the mechanisms and impact of epithelial-immune and epithelial-neuronal cross talk in regulating immunity, inflammation, and tissue homeostasis at mucosal barrier surfaces. Understanding the regulation and impact of these pathways could provide new therapeutic targets for inflammatory diseases at mucosal sites. [ABSTRACT FROM AUTHOR]

[Display omitted] • The inflammatory factors and additional mediators contribute to systemic inflammation involved in cachexia. • Immune checkpoints exert a modulatory effect in the cachectic development through regulating adipocyte differentiation and systemic metabolic balance. • The multilayered insights including the immunometabolic axis, immune-gut axis and immune-nerve axis in cachexia are elaborated. Cancer-associated cachexia is a multi-organ disorder associated with progressive weight loss due to a variable combination of anorexia, systemic inflammation and excessive energy wasting. Considering the importance of immunoregulation in cachexia, it still lacks a complete understanding of the immunological mechanisms in cachectic progression. Our aim here is to describe the complex immunoregulatory system in cachexia. We summarize the effects and translational potential of the immune system on the development of cancer-associated cachexia and we attempt to conclude with thoughts on precise and integrated therapeutic strategies under the complex immunological context of cachexia. This review is focused on three main key concepts. First, we highlight the inflammatory factors and additional mediators that have been identified to modulate this syndrome. Second, we decipher the potential role of immune checkpoints in tissue wasting. Third, we discuss the multilayered insights in cachexia through the immunometabolic axis, immune-gut axis and immune-nerve axis. [ABSTRACT FROM AUTHOR]

Human amnion epithelial cells (hAEC) can be efficiently isolated from full-term amnion membrane and have been gaining recognition as advanced medical products. Such cells originate directly from the embryo during the early phase of development and exert a crucial function in the establishment of a tolerogenic environment, to avoid maternal immune rejection. Amnion cell immuno-modulation may be exploited, but additional efforts are required to establish the mechanisms underlying such capacity. The way to fully clarify such an issue is so far long. Here we overview current knowledge on the effects on innate or adaptive immune cells offered by intact hAEC or secreted mediators, pinpointing the mechanisms to date elucidated by our group and others. We move from the description of hAEC general features to molecular intermediaries generating effects directly or indirectly on immune cells. We focus on the role of non-canonical HLA class I molecules, with emphasis on HLA-G, but expand such analysis on adenosinergic mediators, cytokines, and hAEC-derived microvesicles. Finally, we report the ongoing clinical trials exploiting hAEC multipotency and immune modulation. [ABSTRACT FROM AUTHOR]

5-hydroxytryptamine (5-HT, serotonin) is a major mediator in allergic reactions. The number of tolerogenic dendritic cell (tolDC) and regulatory T cell is reduced in allergic disorders. The mechanism is unclear. The objective of this study is to elucidate the role of 5-HT in interfering with tolDC generation and regulatory Type 1 T cell (Tr1 cell). BALB/c mice were treated with 5-HT-containing nasal instillations. The frequency of tolDC and Tr1 cell was evaluated by flow cytometry. Following treatment with 5-HT nasal instillations for one week, the frequency of tolDC and Tr1 cell was significantly reduced in the respiratory tissues. Higher levels of SOS1 were detected in DCs isolated from the airway tissues of mice treated with 5-HT. A complex of SOS1 and c-Maf was detected in DCs in response to 5-HT stimulation. The expression of IL-10 was suppressed by the presence of 5-HT. The induction of Tr1 cell by DC was substantially compromised by 5-HT. 5-HT inhibits the expression of IL-10 in DCs. DCs primed with 5-HT lose the ability to induce Tr1 cells. • 5-HT inhibits the expression of IL-10 in DCs. • DCs primed with 5-HT lose the ability to induce Tr1 cells. • SOS1 mediates the effects of 5-HT on compromising DC's tolerogenic property. [ABSTRACT FROM AUTHOR]

The elevation of oxidative stress and inflammatory response after injury remains a substantial challenge that can deteriorate the wound microenvironment and compromise the success of wound healing. Herein, the assembly of naturally derived epigallocatechin-3-gallate (EGCG) and Cerium microscale complex (EGCG@Ce) was prepared as reactive oxygen species (ROS) scavenger, which was further loaded in antibacterial hydrogels as wound dressing. EGCG@Ce shows superior antioxidation capacity towards various ROS including free radical, O 2 − and H 2 O 2 through superoxide dismutase-like or catalase-mimicking catalytic activity. Importantly, EGCG@Ce could provide mitochondrial protective effect against oxidative stress damages, reverse the polarization of M1 macrophages and reduce the secretion of pro-inflammatory cytokines. Furtherly, EGCG@Ce was loaded into the PEG-chitosan hydrogel with dynamic, porous, injectable and antibacterial properties as wound dressing, which accelerated the regeneration of both epidermal layer and dermis, resulting in improved healing process of full-thickness skin wounds in vivo. Mechanistically, EGCG@Ce re-shaped the detrimental tissue microenvironment and augmented the pro-reparative response through reducing ROS accumulation, alleviating inflammatory response, enhancing the M2 macrophage polarization and angiogenesis. Collectively, antioxidative and immunomodulatory metal-organic complex-loaded hydrogel is a promising multifunctional dressing for the repair and regeneration of cutaneous wounds without additional drugs, exogenous cytokines, or cells. (1) We reported an effective antioxidant through self-assembly coordination of EGCG and Cerium for managing the inflammatory microenvironment at the wound site, which not only showed high catalytic capacity towards multiple ROS, but also could provide mitochondrial protective effect against oxidative stress damage, reverse the polarization of M1 macrophages and downregulate pro-inflammatory cytokines. EGCG@Ce was further loaded into porous and bactericidal PEG-chitosan (PEG-CS) hydrogel as a versatile wound dressing, which accelerated wound healing and angiogenesis. (2) The applicability of alleviating sustainable inflammation and regulating macrophage polarization through ROS scavenging is a promising strategy for tissue repair and regeneration without additional drugs, cytokines, or cells. [Display omitted] [ABSTRACT FROM AUTHOR]

• In-depth exploration of the role of the gut-skin axis in the treatment of eczema and psoriasis: We have thoroughly analyzed the key role of the gut microbiome in the pathogenesis of eczema and psoriasis, and explored the connection between the gut microbiome and these two skin diseases. • Comprehensive evaluation of the effects of drugs and natural products: We reviewed various drugs and natural products targeting eczema and psoriasis, and assessed their role in modulating the gut-skin axis, offering new perspectives for future treatment approaches. • Paving the way for personalized treatment: We proposed personalized treatment plans tailored to the individual characteristics of patients' microbiomes, which would enable doctors to formulate more accurate treatment strategies and improve treatment outcomes. • Leading future research directions: We call for future research to strengthen the understanding of the interactions between the gut microbiome and skin diseases, and to further evaluate the potential of drugs and natural products in regulating the gut-skin axis, to advance the treatment of skin diseases. • Integration of gut-skin axis insights into clinical practice: We advocate for the incorporation of gut microbiome assessments into routine clinical evaluations for eczema and psoriasis, aiming to enhance diagnostic accuracy and tailor treatment strategies based on individual microbiome profiles. Atopic dermatitis (AD) and psoriasis are chronic skin diseases with a global impact, posing significant challenges to public health systems and severely affecting patients' quality of life. This review delves into the key role of the gut microbiota in these diseases, emphasizing the importance of the gut-skin axis in inflammatory mediators and immune regulation and revealing a complex bidirectional communication system. We comprehensively assessed the pathogenesis, clinical manifestations, and treatment strategies for AD and psoriasis, with a particular focus on how the gut microbiota and their metabolites influence disease progression via the gut-skin axis. In addition, personalized treatment plans based on individual patient microbiome characteristics have been proposed, offering new perspectives for future treatment approaches. We call for enhanced interdisciplinary cooperation to further explore the interactions between gut microbiota and skin diseases and to assess the potential of drugs and natural products in modulating the gut-skin axis, aiming to advance the treatment of skin diseases. [ABSTRACT FROM AUTHOR]

Food allergy (FA) has increasingly attracted global attention in past decades. However, the mechanism and effect of FA are complex and varied, rendering it hard to prevention and management. Most of the allergens identified so far are macromolecular proteins in food and may have potential cross-reactions. Human milk oligosaccharides (HMOs) have been regarded as an ideal nutrient component for infants, as they can enhance the immunomodulatory capacity to inhibit the progress of FA. HMOs may intervene in the development of allergies by modifying gut microbiota and increasing specific short-chain fatty acids levels. Additionally, HMOs could improve the intestinal permeability and directly or indirectly regulate the balance of T helper cells and regulatory T cells by enhancing the inflammatory signaling pathways to combat FA. This review will discuss the influence factors of FA, key species of gut microbiota involved in FA, types of FA, and profiles of HMOs and provide evidence for future research trends to advance HMOs as potential therapeutic aids in preventing the progress of FA. [ABSTRACT FROM AUTHOR]

Due to the widespread and excessive use of antibiotics, bacterial resistance has become an increasingly serious problem affecting public health. Amphiphilic peptide hydrogels have good biological and mechanical properties, and can be used as ideal substitutes for antibiotics in the fields of infection control and wound healing. This review systematically summarized the design principles, assembly mechanism, and the latest progress of amphiphilic peptide hydrogels. Based on the molecular structure and function of peptides, the antibacterial mechanism of amphiphilic peptide hydrogels is further elaborated. Finally, we provide a perspective for the future development of antibacterial applications of amphiphilic peptide hydrogels. It is hoped that this review can provide inspiration for the design of amphiphilic peptide hydrogels and promote their clinical transformation against bacterial infections. This review summarized the assembly process and antibacterial mechanism of amphiphilic peptide hydrogels, and focused on the latest research progress in the antibacterial application of hydrogels. [Display omitted] [ABSTRACT FROM AUTHOR]

Norepinephrine (NE) is involved in regulating cytokine expression and phagocytosis of immune cells in the innate immunity of vertebrates. In the present study, the modulation mechanism of NE on the biosynthesis of TNFs in oyster granulocytes was explored. The transcripts of Cg TNF-1, Cg TNF-2 and Cg TNF-3 were highly expressed in granulocytes, and they were significantly up-regulated after LPS stimulation, while down-regulated after NE treatment. The phagocytic rate and apoptosis index of oyster granulocytes were also triggered by LPS stimulation and suppressed by NE treatment. The mRNA expressions of Cg MAPK14 and Cg Relish were significantly induced after NE treatment, and the translocation of Cg Relish from cytoplasm to nucleus was observed. The concentration of intracellular Ca2+ in granulocytes was significantly up-regulated upon NE incubation, and this trend reverted after the treatment with DOX (specific antagonist for NE receptor, Cg A1AR-1). No obvious significance was observed in intracellular cAMP concentrations in the PBS, NE and NE + DOX groups. Once Cg A1AR-1 was blocked by DOX, the mRNA expressions of Cg MAPK14 and Cg Relish were significantly inhibited, and the translocation of Cg Relish from cytoplasm to nucleus was also dramatically suppressed, while the mRNA expression of Cg TNF-1 and the apoptosis index increased significantly to the same level with those in LPS group, respectively. These results collectively suggested that NE modulated TNF expression in oyster granulocyte through A1AR-p38 MAPK-Relish signaling pathway. • Granulocytes were the main sub-population of haecmocytes to synthesize TNFs in response to LPS stimulation. • NE could regulate phagocytosis, apoptosis and TNFs expression in oyster granulocyte. • NE modulated phagocytosis, apoptosis and TNFs expression in granulocyte through A1AR-p38 MAPK-Relish signaling pathway. [ABSTRACT FROM AUTHOR]

Polysaccharides have garnered significant attention as potential nanoparticle carriers for targeted tumor therapy due to their excellent biodegradability and biocompatibility. Polyguluronic acid (PG) is a homogeneous acidic polysaccharide fragment derived from alginate, which is found in brown algae, possesses excellent bioactivities, unique properties. This study explored the immunomodulatory activity of PG and developed PG-based nanogels through modified disulfide bonds and Ca2+ dual crosslinking. We characterized their structure, assessed their drug-loading and release properties, and ultimately validated both the safety of the nanocarrier and the in vitro anti-tumor efficacy of the encapsulated drug. Results indicated that PG significantly enhanced the proliferative activity and phagocytosis of RAW264.7 cells while promoting reactive oxygen species (ROS) production and cytokine secretion. The study identified TLR4 as the primary receptor for PG recognition in RAW264.7 cells. Furthermore, PG-based drug-carrying nanogels were prepared, exhibiting uniform sizes of about 184 nm and demonstrating exceptional encapsulation efficiency (82.15 ± 0.82 %) and drug loading capacity (8.12 ± 0.08 %). In vitro release experiments showed that these nanogels could responsively release drugs under conditions of high glutathione (GSH) reduction, facilitating drug accumulation at tumor sites and enhancing therapeutic efficacy. This research not only expands the application of PG in drug delivery systems but also provides valuable insights into leveraging natural immunomodulatory polysaccharides as carriers for targeted drug delivery. [Display omitted] • Polyguluronic acid exhibits a significant immune-modulatory activity on RAW264.7 macrophages, with TLR4 as the primary receptor to recognize it. • Utilizing PG as a carrier, we developed doxorubicin (DOX) loaded nano hydrogel. • The PG-based nanogel demonstrates redox-responsive drug release characteristics, allowing for accumulation at the tumour site and rapid drug release. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells of the central nervous system (CNS) with roles in sensing, housekeeping, and defense. Exploring the role of microglia in the occurrence and development of Alzheimer's disease (AD) and the possible therapeutic mechanism of plant-derived natural compounds (PDNCs) that regulate microglia-associated neuroinflammation may potentially help in elucidating the pathogenesis of AD and provide novel insights for its treatment. This review explores the role of abnormal microglial activation and its dominant neuroinflammatory response, as well as the activation of their target receptors and signaling pathways in AD pathogenesis. Additionally, we report an update on the potential pharmacological mechanisms of multiple PDNCs in modulating microglia-associated neuroinflammation in AD treatment. Dysregulated activation of microglial receptors and their downstream pathways impaired immune homeostasis in animal models of AD. Multiple signaling pathways, such as mitogen-activated protein kinase (MAPK), nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and Toll-like receptors, play important roles in microglial activation and can exacerbate microglia-mediated neuroinflammation. PDNCs, such as magnolol, stigmasterol, matrine, naringenin, naringin, and resveratrol, can delay the progression of AD by inhibiting the proinflammatory receptors of microglia, activating its anti-inflammatory receptors, regulating the receptors related to β-amyloid (Aβ) clearance, reversing immune dysregulation, and maintaining the immune homeostasis of microglial downstream pathways. This review summarizes the mechanisms by which microglia cause chronic inflammation in AD and evaluates the beneficial effects of PDNCs on immune regulation in AD by regulating microglial receptors and their downstream pathways. [Display omitted] • The inflammatory response is a key factor in the pathogenesis of AD. • Improper regulation of microglial activity impairs immune homeostasis in AD. • PDNCs regulate the pathological process of AD by targeting microglia mediated neuroinflammation. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is labeled as an aggressive type of breast cancer and still has limited therapeutic targets despite the advanced development of cancer therapy. Neutrophils, representing the conventional inflammatory response, significantly influence the malignant phenotype of tumors, supported by abundant evidence. As a vital function of neutrophils, NETs are the extracellular fibrous networks including the depolymerized chromatin DNA frames with several antimicrobial proteins. They are produced by activated neutrophils and are involved in host defence or immunological reactions. This review focuses more on the interactions between neutrophils and TNBC, focusing on how neutrophils modulate the immune response within the tumor milieu. Specifically, we delve into the role of NETs, which are involved in promoting tumor growth and metastasis, inhibiting anti-tumor immunity, and promoting tumor-associated thrombosis. Furthermore, we discuss recent advancements in therapeutic strategies aimed at targeting NETs to enhance the efficacy of TNBC treatment. The advances in the knowledge of the dynamics between neutrophils and TNBC may lead to the opportunity to devise new immunotherapeutic strategies targeted to fight this hostile type of breast cancer. [Display omitted] • NETs participated in regulating the growth of TNBC. • NETs participated in regulating the metastatic cascade of TNBC. • NETs participated in thrombosis formation associated with TNBC. • NETs can regulate other immune cells in the TNBC immune microenvironment. [ABSTRACT FROM AUTHOR]

The regulation of T cell response depends on co-inhibitory pathways that serve to control immune-mediated tissue damage and resolve inflammation by modulating the magnitude and duration of immune response. In this process, the axis of T-cell-expressed programmed death-1 (PD-1) and its ligands (PD-L1 and PD-L2) play a key role. While the PD-1/PD-L pathway has received considerable attention for its role in the maintenance of T cell exhaustion in cancer and chronic infection, the PD-1/PD-L pathway also plays diverse roles in regulating host immunity beyond T cell exhaustion. In this review, we will discuss emerging concepts in co-stimulatory functions of PD-1/PD-L pathway on T cell- and B cell response and explore the potential underlying mechanisms. In addition, based on the elevated expression of PD-1 and its ligands in local inflamed tissues, we further discussed the role of PD-1/PD-L pathway in autoimmune diseases. [Display omitted] • The inhibitory or co-stimulatory function of PD-1/PD-L pathway is influenced by many factors. • PD-1/PD-L pathway also contributes to T cell and B cell development and activation. • The role of PD-1/PD-L pathway is involved in autoimmune diseases. [ABSTRACT FROM AUTHOR]

• CD8+Foxp3+ T cells are the counterpart to the better studies CD4+Foxp3+ Treg population. • CD8+Foxp3+ T cells share a common transcriptional profile and suppressive function with CD4+Foxp3+ Tregs. • CD8+Foxp3+ T cells have been reported to have a role in several disease states. • CD8+Foxp3+ T cells may have a unique function in regulating B cell responses. CD4+Foxp3+ Regulatory T cells (Tregs) are essential for maintaining self-tolerance and are increasingly recognised to have important roles in tissue homeostasis and repair. In the CD8 compartment an analogous Foxp3+ population is present, which shares phenotypic aspects with the more common CD4+Foxp3+Treg population. While oft neglected for their low frequency, there is increasing evidence that these CD8+Foxp3+ cells are bona fide regulatory cells, with both shared and distinct characteristics from their CD4+ analogue. Here we focus on the evidence for a regulatory function of CD8+Foxp3+ cells, and the potential unique role this neglected lineage may play in immune homeostasis and disease prevention. [ABSTRACT FROM AUTHOR]

NLRX1, an important member of regulatory Nod-like receptors (NLRs), exerts multifaceted roles in the regulation of mammalian innate immunity. However, the function and mechanism of fish NLRX1 in antibacterial immune regulation remain unclear. In this study, the zebrafish NLRX1 was cloned and characterized. Phylogenetic analysis demonstrated that zebrafish NLRX1 clustered closely with other NLRX1 homologs in fish and exhibited 84.6%–87.4% sequence identities to that of cyprinid fish. Subcellular localization analysis showed that zebrafish NLRX1 located both in the mitochondrial and cytoplasmic compartments of transfected cells. Functionally, zebrafish NLRX1 expression was dramatically induced upon Edwardsiella piscicida infection. Overexpression of NLRX1 promoted E. piscicida proliferation and impaired survival rate both in vitro and in vivo. Furthermore, the up-regulation of pro-inflammatory cytokines (IL8, IL6, TNFα, IL1β) and antibacterial gene defbl2 was reduced in E. piscicida infected larvae that were microinjected with NLRX1. Consistent with these observations, the antibacterial ability was significantly enhanced in NLRX1 knockdown cells. Mechanistically, zebrafish NLRX1 interacted with tumor necrosis factor receptor-associated factor 6 (TRAF6) through its NACHT domain, attenuating TRAF6-mediated antibacterial innate immunity. Our study sheds light on the negative regulatory role of fish NLRX1 in antibacterial immunity, offering potential applications in fish disease management and immune regulation. • Zebrafish NLRX1 was found in both the mitochondrial and cytoplasmic regions. • Overexpression of zebrafish NLRX1 led to the decreased antibacterial ability both in vitro and in vivo. • NLRX1 deficiency suppressed bacterial proliferation and improved cell viability. • Overexpression of zebrafish NLRX1 inhibited TRAF6 mediated antibacterial immune response. • Zebrafish NLRX1 interacted with TRAF6 through the NACHT domain. [ABSTRACT FROM AUTHOR]

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value. [ABSTRACT FROM AUTHOR]

• TREM2 is a key myeloid receptor influencing immune regulation and anti-inflammatory responses. • Research shows TREM2's role in diseases beyond neurology, including cancer and obesity, requiring further investigation. • TREM2 mutations in microglia raise the risk of Alzheimer's and frontotemporal dementia and contribute to obesity and cancer progression. • TREM2-targeting therapies (antibodies, scFv-CAR-T cells, sTREM2) enhance microglial function, modulating immunity, with potential applications beyond neurodegenerative diseases. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a transmembrane receptor initially linked to neurodegenerative diseases, has recently emerged as a key player in conditions such as obesity and cancer. This review explores the structure, function, and mechanisms of TREM2 across these diverse pathological contexts, with a particular focus on its critical roles in immune regulation and neuroprotection. TREM2 primarily modulates cellular activity by binding extracellular ligands, thereby activating downstream signaling pathways and exerting immunomodulatory effects. Additionally, the therapeutic potential of targeting TREM2 is discussed, emphasizing its promise as a future treatment strategy for various diseases. [ABSTRACT FROM AUTHOR]

• Phytoestrogens can regulate the activation and differentiation of specific immune cells including T cells and B cells. • Phytoestrogens affect the function of non-specific immune cells such as macrophages and NK cells. • The application of phytoestrogens in transplantation provides a new therapeutic avenue for preventing transplant rejection. Phytoestrogens are natural compounds found in plants and plant-based foods. When ingested, they can affect the human body in the same way as estrogen produced by the body. Phytoestrogens affect the regulation, differentiation, and production of immune cells. People who consume polyphenol and flavonoid-rich foods have lower incidences of inflammation, autoimmune diseases, and cancer. In organ transplantation, immune rejection is a lifelong problem for patients. In clinical practice, acute rejection is treated with hormonal shock or immunosuppressive drugs. However, effective reversal measures for chronic rejection, specifically for prevention, are still lacking. Recipients are also prone to post-transplant complications such as new tumors, diabetes, hyperlipidemia, hyperuricemia, and cardiovascular and cerebrovascular diseases, owing to the long-term use of immunosuppressive drugs. Phytoestrogens play a promising role in immune regulation and exert curative effects on cardiovascular diseases and cancer. In this study, we reviewed the use of phytoestrogens in the fields of immune regulation and organ transplantation. [ABSTRACT FROM AUTHOR]

• HRP obtained by hot-compressed steamed. • HRP exerted immunomodulatory effects by activating macrophage. • HRP acted as an immunopotentiator through the NF-κB signaling pathway. • HRP via alterations in gut microbiota to ameliorate CTX-induced immunocompromised mice. In this study, the immunomodulatory effects of polysaccharide obtained by hot-compressed steaming of Rehmannia glutinosa Libosch (HRP) were investigated using both in vitro and in vivo methods. It was found that HRP activated the TLR4/NF-κB signaling pathway, up-regulated the intracellular expression of TNF-α, IL-6 and IL-1β, and induced of innate immune memory in macrophages. We then investigated the effect of HRP on immunosuppressed mice induced by cyclophosphamide (CTX). Surprisingly, HRP improved CTX-induced weight loss and increased the splenic index, alleviated intestinal mucosal damage and hematopoietic insufficiency caused by CTX, as demonstrated by H&E staining. In addition, HRP promoted the expression of key proteins in the TLR4/NF-κB and autophagy pathways in intestinal tissues, thereby enhancing intestinal immune function. Bacterial 16S rRNA gene sequences of colon contents suggested that HRP may alleviate gut microbiota disruption by increasing the populations of Lachnospiraceae and Erysipelotrichaceae while inhibiting Lactobacillaceae. The results of this study show the potential use of HRP as an immunomodulator in functional foods or pharmaceuticals. [ABSTRACT FROM AUTHOR]

The intricate interplay among extracellular vesicles, cancer stemness properties, and the immune system significantly impacts hepatocellular carcinoma (HCC) progression, treatment response, and patient prognosis. Extracellular vesicles (EVs), which are membrane-bound structures, play a pivotal role in conveying proteins, lipids, and nucleic acids between cells, thereby serving as essential mediators of intercellular communication. Since a lot of current research focuses on small extracellular vesicles (sEVs), with diameters ranging from 30 nm to 200 nm, this review emphasizes the role of sEVs in the context of interactions between HCC stemness-bearing cells and the immune cells. sEVs offer promising opportunities for the clinical application of innovative diagnostic and prognostic biomarkers in HCC. By specifically targeting sEVs, novel therapeutics aimed at cancer stemness can be developed. Ongoing investigations into the roles of sEVs in cancer stemness and immune regulation in HCC will broaden our understanding and ultimately pave the way for groundbreaking therapeutic interventions. • Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths. • Small extracellular vesicles (sEVs) are key facilitators of cell-cell communication. • sEVs, cancer stemness and immunity interplay to influence HCC progression, therapy response, and patient outcomes. • sEVs have potential clinical use as novel diagnostic and prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Paecilomyces hepiali is a precious health-care edible medicinal fungus with rich polysaccharides and exhibits various biological activities. Polysaccharides from P. hepiali fermentation broth (PHP) exhibits good immunomodulatory activity; however, the mechanism underlying PHP-mediated regulation of immunity and gut microbiota remains unclear. To reveal the mechanisms, PHP of different doses were used to intervene cyclophosphamide (CTX)-induced immunosuppressive model mice. The results revealed that PHP facilitated the secretion of serum cytokines, increased the mRNA and protein expression of TLR4/NF-κB signaling pathway. Furthermore, it improved the physical barrier function of the intestine by upregulating the expression of tight junction proteins. PHP increased the proliferation of beneficial bacteria, including, Actinobacteriota, Alistipes , Candidatus_Saccharimonas and unclassified_Clostridia_vadinBB60_group , and reduced the abundance of Proteobacteria, Deferribacterota, Mucispirillum and Escherichia_Shigella , promoted the production of short-chain fatty acids, which were positively associated with immune traits. Thus, as an immune enhancer, PHP has the potential to regulate the intestinal immune response in immunosuppressed mice through modulating gut microbiota. [Display omitted] • Paecilomyces hepialid polysaccharides (PHP) showed immunomodulatory effects. • PHP improved the barrier function by upregulating tight junction expression. • PHP regulated gut microbiota and promoted the production of short-chain fatty acids. • TLR4/NF-κB pathway plays important roles in the immunomodulatory effects of PHP. • PHP has the potential to be developed as a novel functional ingredient. [ABSTRACT FROM AUTHOR]

[Display omitted] • BSSC can restore the regulation of the HPA axis, promote the differentiation of helper T cells into Th1 cells, thereby reducing the Th2/Th1 ratio, and improve eosinophil and basophil counts. • BSSC demonstrates a significant impact on maintaining gut barrier function, modulating the gut microbiota composition, promoting a balanced microbial community. • BSSC shows promise in alleviating inflammation and circadian rhythm disturbances induced by sleep deprivation. Circadian rhythm disruption induces oxidative stress in the brain and gut, causing chronic inflammation and immune imbalance. Using the Lafayette sleep fragmentation device to simulate sleep deprivation, sleep disruption was induced in 6-week-old male C57Bl/6J mice for a duration of 28 days. These results showed administration of BSSC crude extract could significantly differentiate helper T cells into Th1, reduce Th2/Th1 ratio, and improve eosinophil and basophil counts due to sleep deprivation. Furthermore, the crude extract notably improved reduced gut microbial abundance and enhanced gut barrier integrity caused by sleep deprivation. Gene expression analysis showed BSSC crude extract mitigated dysregulation in rhythmic and serotonin-related genes, reducing inflammatory gene expression in the brain. In conclusion, BSSC crude extract has the potential to address sleep disturbance-induced immune imbalance, reduced gut microbial abundance, altered gut microbiota, and brain gene disruption. [ABSTRACT FROM AUTHOR]

The impact of the Sema-3E/PlexinD1 axis on DC phenotype and function in DCs. [Display omitted] This comprehensive research review explores the complex interplay between the Sema-3E/PlexinD1 axis and dendritic cells (DCs), highlighting its critical role in immune modulation with implications for clinical application Critical regulators of immune responses Dendritic cells are central to adaptive immunity, and the Sema-3E /PlexinD1 axis emerges as a key modulator affecting their phenotypes and functions Review delineates the impact of this signaling axis on DC maturation, migration, antigen presentation, and cytokine production, unravels its multifaceted role in shaping the immune response. Recognizing the limitations and gaps in current knowledge, the study highlights the need for further studies to condition downstream signaling events and related information experienced by the Sema-3E/PlexinD1 axis emphasizes the clarity of the immune system. The review concludes by identifying opportunities for translation, focusing on therapeutic and diagnostic potential. It highlights the importance of collaborative, interdisciplinary efforts to address the challenges and harness the therapeutic and pathological potential of targeting the Sema-3E/PlexinD1 axis, thus opening the way for transformative advances in immunology and clinical medicine. [ABSTRACT FROM AUTHOR]

[Display omitted] • The immunosuppression mice model was established by subcutaneous injection of hydrocortisone (HC). • The effects of Edible bird's nest in low and high doses were investigated on the immunosuppression mice model. • Edible bird's nest plays an immune regulation role mainly by affecting the changes in the intestinal flora. This study aimed to investigate the immune regulation effect of edible bird's nest (EBN) in vivo and elucidate the influence of EBN on immune microbiome, which is the basis of the activity of EBN. The immunosuppression mice model was established by subcutaneous injection of hydrocortisone (HC). The optimal modeling dose of HC was screened by various immune indexes. Studies have found that the mice immunosuppression model can be constructed with a HC dose of 12.5 mg/kg. The effects of EBN in low (0.285 g/kg) and high doses (0.649 g/kg) were investigated on the immunosuppression mice model. EBN low-dose treatment significantly improved macrophage phagocytosis and NK cell activity in immunosuppression mice. EBN high-dose treatment significantly increased the serum TNF-α content phagocytosis ability of macrophages, NK cell activity and serum hemolysin content of immunosuppression mice. It was found that changes in the intestinal flora are usually accompanied by changes in immune cells and inflammatory factors, so it was hypothesized that there is a correlation between changes in intestinal flora and immune regulation, therefore the changes in the intestinal flora of mice were then investigated after EBN administration. The regulation of intestinal flora experiments showed that species richness decreased in the immunosuppression mice, and after EBN treatment the species richness in mice increased. Additionally, after continuous administration of EBN, the abundance of Bacteroides, Akkermansiaceae and other intestinal probiotics increased, while the abundance of Firmicutes decreased, indicating that EBN can regulate intestinal dysfunction, up-regulate beneficial bacteria. It is reported that the increase of Bacteroides and Akkermansiaceae and the decrease of Firmicutes in the intestinal flora caused an increase in the levels of TNF-α and improved immunity, which is consistent with our experimental results. Therefore, it is hypothesized that EBN plays an immune regulation role mainly by affecting the changes in the intestinal flora. The study provides a theoretical basis for the functional investigation of EBN. [ABSTRACT FROM AUTHOR]

Wound infections, posing a grave risk of severe physical consequences and even mortality, exact a substantial financial toll on society, rendering them among the most formidable challenges confronting our world today. A critical imperative is the development of hydrogel dressings endowed with immune-regulating and antibacterial properties. This study is founded upon the symbiotic physical and efficacious attributes of two small natural molecules. An injectable hydrogel is meticulously crafted by encapsulating puerarin (PUE) into tyramine-modified hyaluronic acid, subsequently introducing rhein (RHE), and catalyzing the formation of inter-phenol crosslinks with H 2 O 2 /horseradish peroxidase (HA-Tyr-R@P). Exhibiting a favorable microenvironmental impact the developed hydrogel attains an antibacterial efficacy exceeding 95 %, coupled with a wound closure rate twice that of the control group. HA-Tyr-R@P hydrogels not only inhibit bacterial growth but also mitigate inflammation, fostering wound healing, owing to their harmonized physicochemical characteristics and synergistic therapeutic effects. This work underscores the creation of a singular, versatile hydrogel platform, negating the complexities and side effects associated with pharmaceutical preparations. Furthermore, it offers new ideas for the formulation of RHE-based hydrogels for wound healing, emphasizing the pivotal role of natural small molecules in advancing biological materials. [ABSTRACT FROM AUTHOR]

• Macrophages occupy the major portion of immune cells collected from colon lavage fluid (CLF);. • The immune suppressive functions of CLF macrophage of UC patients are impaired;. • The inducibility of IL10 expression in CLF M0 cells is defective;. • Exposure to CpG can restore the inducibility of IL10 expression in UC CLF M0 cells to facilitate the M0 cells regain the potential to acquire the immune suppressive functions. Chronic inflammation is the pathological feature of inflammatory bowel diseases (IBD), but its etiology is unknown. Macrophages are one of the major immune cell fractions in the colon. The objectives of this study are to characterize the immune regulatory functions of macrophages in the colon of patients with ulcerative colitis (UC). UC patients (n = 30) were recruited into this study. Colon lavage fluid (CLF) was collected. Macrophages are isolated from the cellular components of CLF. The immune suppressive functions of macrophages were assessed using immunological approaches. We observed that macrophages occupied about half of the proportions of the cellular components in CLF. Lower amounts of IL10 mRNA and proteins were detected in macrophages of the UC group than the normal control (NC) group. The expression of IL10 in CLF macrophages was positively correlated with the UC-associated cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IFN-γ, eosinophil-derived mediators, in CLF. The immune suppressive functions of CLF macrophages in UC patients were impaired. The inducibility of IL10 expression of UC M0 cells was defective as compared with NC M0 cells. Exposure to CpG restored the inducibility of IL10 expression in UC M0 cells, and gain the potential to acquire the immune suppressive functions. To sum up, the immune suppressive functions of UC macrophages are impaired. The inducibility of IL10 expression of M0 cells is impaired, which can be restored by the treatment with CpG. [ABSTRACT FROM AUTHOR]

[Display omitted] • PS could improve the immunosuppressive effects caused by CTX on silkworm. • PS exhibited antioxidant activity by increasing the SOD, CAT, GSH-Px and decreasing ROS level. • PS could regulate the immunity of silkworm by reprogramming of lipid and amino acid metabolisms. The present study investigated the immune regulatory mechanisms of Poria cocos polysaccharides (PS) in a cyclophosphamide (CTX)-induced immunosuppression silkworm model. We found that PS increased the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, as well as reactive oxygen species (ROS) levels in the fat body or haemocytes of CTX-treated silkworms. PS also strongly stimulated the immunity of silkworms by increasing haemocyte counts and PO activity and upregulating the mRNA expression of immune-related genes. We further investigated the metabolic profile of the fat body after PS treatment using liquid chromatography–massspectrometry/mass spectrometry (LC–MS/MS) and identified 236 differentially expressed metabolites. Among them, nine metabolites related to amino acid metabolism were present at high levels in the PS-treated group, whereas the contents of metabolites involved in sphingolipid metabolism and alpha-linolenic acid metabolism were significantly decreased after PS treatment. The amino acid metabolism pathways and lipid metabolism pathways were found to be significantly altered in the PS-treated group, which indicates that PS may regulate the immune system of silkworms by reprogramming lipid and amino acid metabolism. This study provides new insight into the immune regulatory effect of PS in animals. [ABSTRACT FROM AUTHOR]

pBD2 is one of the porcine beta defensins with broad antimicrobial activity, and plays an important role in immune regulation. However, the activities and mechanisms of pBD2 regulating host resistance to Escherichia coli infection are unclear. In this study, the immunomodulatory activity and mechanisms of recombinant pBD2 against Escherichia coli infection were explored in IPEC-J2 cells. Recombinant pBD2 had no obvious effect on the growth of cells below 80 μg/mL, however, it reduced the number of E. coli adhering to cells. Furthermore, pBD2 restored the abnormal expression of ZO-1 and occludin in cells challenged with E. coli. pBD2 treatment also reduced cell apoptosis and decreased the expression of the apoptosis-related genes Cox-2 and Caspase-3, and decreased the expression of the pro-inflammatory IL-6, IL-8, IL-1α and TNF-α, and Cxcl2 and Ccl20. pBD2 also reduced the expression of TAK1, and inhibited the phosphorylation of NF-κB p65 following E. coli infection. In addition, pBD2 was localized in the cytoplasm. Collectively, pBD2 appeared to penetrate cells and alleviate inflammatory responses via the TAK1-NF-κB signaling pathway. Our results revealed the immunomodulatory activity of recombinant pBD2 against E. coli and provided insights into the molecular mechanisms that protected cells from E. coli infection. [ABSTRACT FROM AUTHOR]

The stem of Opuntia species, a traditional medicinal plant, is widely used as food and functional raw material because of its rich polysaccharide content. There have been many studies on the immune function of polysaccharides from Opuntia stem, but only few have examined this function with respect to intestinal microbes. In this study, the effects of different concentrations of Opuntia stem polysaccharides on the immunity and intestinal microflora of cyclophosphamide (CTX)-induced immunocompromised mice were explored. The results showed that Tibet Opuntia ficus-indica (Linn.) Mill. polysaccharides (ODPs) could effectively increase the white blood cells (WBC) count index of mice and improve their thymus and spleen indices, while effectively promoting the secretion of IL-4, IL-1β, TNF-α and IFN-γ, with these effects being dependent on the concentration of crude polysaccharides. The intake of ODPs significantly regulated the relative abundance of Lactobacillus, Bacteroides and Akkermansia, and the new dominant intestinal bacterial species were Deferribacteres, Actinomycetes, Firmicutes, Tenericutes, Actinomycetes and Pasteurella. In addition, the ODPs could effectively enhance the metabolic level of lysine synthesis and decomposition, regulate the gene expression level after immune disorders, and enhance the overall health of the immunodeficient mice. [Display omitted] • The Tibet Opuntia ficus-indica (Linn.) Mill. polysaccharides (ODPs) have unique properties and biological activity. • The Tibet ODPs have the effect of enhancing the overall health of immunodeficient mice. • The Tibet ODPs can be used as prebiotics. [ABSTRACT FROM AUTHOR]

RhoA (Ras homolog A) protein is a representative member of the Rho GTPase family and is involved in various cellular processes. The function of RhoA in sea cucumbers is unclear. In this study, we hypothesized that RhoA may regulate the innate immune response of Apostichopus japonicus. Our data showed that 1) the complete sequence of RhoA from A. japonicus (named AjRhoA) was 968 bp, with a high level sequence conservation across the echinoderms and other phyla; 2) tissue expression analysis showed that AjRhoA transcripts and protein exhibited higher abundance in coelomocytes, whereas the relative expression of miR-2012-5p was lower in coelomocytes; 3) interactive binding sites and a negative regulatory targeting relationship between AjRhoA and miR-2012-5p were confirmed through a dual-luciferase reporter assay and functional validation in vivo ; 4) the relative expression levels of AjRhoA transcripts and protein were upregulated in coelomocytes 4- and 72-hour post infection (hpi) with Vibrio splendidus , whereas miR-2012-5p was expressed in the opposite pattern; 5) both AjRhoA silencing and miR-2012-5p overexpression suppressed the phagocytic capacity of A. japonicus compared with the control at 4 and 72 hpi. Our observations suggest that AjRhoA can regulate the pathogen-induced immune response of A. japonicus through the " AjRhoA -miR-2012-5p" module during the early infection, while miR-2012-5p plays a direct immunomodulatory role as the infection progresses. [Display omitted] • A novel RhoA homolog gene (AjRhoA) in Apostichopus japonicus was cloned and characterized. • Phagocytosis of A. japonicus was repressed after AjRhoA silencing. • The targeting interaction relationship between AjRhoA and miR-2012-5p was verified. • " AjRhoA -miR-2012-5p" regulates the early innate immune response of A. japonicus via altering phagocytic capacity. [ABSTRACT FROM AUTHOR]

• Hemophilia A is a bleeding disorder related to the deficiency of coagulation FVIII. • FVIII deficiency is associated with osteoporosis. • A dysregulation of the inflammatory processes is observed in FVIII deficiency. • FVIII deficiency leads to the neoformation of abnormal blood vessels. • In addition to VWF, FVIII interacts with numerous cell membrane proteins. Hemophilia A is an X-linked hereditary disorder that results from deficient coagulation factor VIII (FVIII) activity, leading to spontaneous bleeding episodes, particularly in joints and muscles. FVIII deficiency has been associated with altered bone remodeling, dysregulated macrophage polarization, and inflammatory processes that are associated with the neoformation of abnormal blood vessels. Treatment based on FVIII replacement can lead to the development of inhibitors that render FVIII concentrate infusion ineffective. In this context, hemophilia has entered a new therapeutic era with the development of new drugs, such as emicizumab, that seek to restore the hemostatic balance by bypassing pathologically acquired antibodies. We discuss the potential extrahemostatic functions of FVIII that may be crucial for defining future therapies in hemophilia. [ABSTRACT FROM AUTHOR]

• Increased IL-10 production on PD-1+ NK, CTLA-4+ NK and LAG-3+ NK cells. • Impaired cytotoxic capacity on PD-1+ NK, CTLA-4+ NK and LAG-3+ NK cells. • PD-1+ NK, CTLA-4+ NK and LAG-3+ NK cells are resistant to K562 target cell stimulation. • TIGIT+ NK cells responded well to K562 target cell stimulation. • Perforin and granzyme a expressions remained unaffected in TIGIT+ NK cells. The roles of immune checkpoint receptors were defined in many cancers and autoimmune diseases, while there is limited information on their functional roles in the NK cells of healthy individuals. Immune checkpoint receptor expression of NK cell subsets and their association with NK cell functions (cytotoxic capacity and cytokine production) in healthy population were investigated. PD-1, CTLA-4, LAG-3 and TIGIT expression of peripheral blood NK cells, cytokine levels (TNF- α , IFN- γ , IL-10) and cytotoxic functions (granzyme A, perforin, CD107a; with/without K562 target cell stimulation) were evaluated by flow cytometry. CD56dimCD16dim NK cells had the highest expression of TIGIT, while CD56dimCD16− NK cells had highest expression of PD-1, CTLA-4 and LAG-3. PD-1+ NK cells, CTLA-4+ NK cells and LAG-3+ NK cells had increased amount of IL-10 however, reduced IFN- γ and TNF- α levels. Cytotoxic granule expressions (perforin and granzyme A) were reduced in PD-1+ NK cells, CTLA-4+ NK cells and LAG-3+ NK cells. However, TIGIT expression did not alter perforin and granzyme A expressions. Degranulation capacity was reduced in three groups of NK cells (PD-1+ or LAG-3+ or TIGIT+). TIGIT+ NK cells responded strongly to target cell stimulation, while NK cells in the other groups (PD-1+ or CTLA-4+ or LAG-3+) were resistant. PD-1+ NK cells, CTLA-4+ NK cells and LAG-3+ NK cells had a regulatory phenotype, impaired cytotoxic functions, and response to target cell stimulation. In contrast, TIGIT+ NK cells had strong baseline cytotoxic activity that further increased in response to target cell stimulation. [ABSTRACT FROM AUTHOR]

Inorganic polyphosphate (polyP) is produced by both bacteria and their eukaryotic hosts, and it appears to play multiple important roles in the interactions between those organisms. However, the detailed mechanisms of how polyP synthesis is regulated in bacteria, and how it influences both bacterial and host biology, remain largely unexplored. In this review, we examine recent developments in the understanding of how bacteria regulate the synthesis of polyP, what roles polyP plays in controlling virulence in pathogenic bacteria, and the effects of polyP on the mammalian immune system, as well as progress on developing drugs that may be able to target bacterial polyP synthesis as novel means of treating infectious disease. Inorganic polyphosphate (polyP) plays multiple roles in bacterial regulation, including controlling proteolysis by the Lon protease and regulating virulence factors, both positively and negatively. PolyP plays a major role in host repair by facilitating thrombin-driven coagulation and in defense mechanisms by recruiting neutrophils and driving M1 macrophage differentiation. Bacteria use polyP to manipulate host immune responses, impairing phagocytic cell functions, modulating inflammatory responses, and impairing antigen presentation. Dictyostelium discoideum is emerging as a powerful model system for investigating polyP biology. Multiple drugs influencing polyP levels in different organisms have recently been discovered. [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CTX) was used to establish the immunosuppressive mice model. The immune organ viscera index, phagocytes vitality, the levels of cytokines in serum, the oxidative stress resistance, proteomics and intestinal flora in mice were investigated to evaluate the effect of immune regulation of Nigella sativa seed polysaccharide (NSSP). The results showed that the high-dose NSSP group could significantly increase the thymus and spleen index. The levels of ACP, LDH, T-AOC, SOD, IL-2, IL-4 and IL-6 were significantly increased and the levels of TNF-α and MDA were reduced. All evidences indicated that NSSP could improve the immune effects of the immunosuppressed mice. Proteomics investigation showed that NSSP could improve the immune by regulating the differential proteins of PI3K and PTEN, and regulating the metabolism-related pathways such as autoimmune diseases and PI3K-Akt signaling pathway. of Gut microbes analysis showed that NSSP could exert immunomodulatory effects by improving the structure of the intestinal flora, increasing the diversity of the flora, and regulating metabolic pathways such as lipid metabolism, polysaccharide synthesis and signal transduction by the prediction of flora metabolic functions. In addition, NSSP could regulate intestinal environment by regulating the content of short chain fatty acids. [ABSTRACT FROM AUTHOR]

This comprehensive review delves into the intricate landscape of glycans and glycoconjugates, unraveling their multifaceted roles across diverse biological dimensions. From influencing fundamental cellular processes such as signaling, recognition, and adhesion to exerting profound effects at the molecular and genetic levels, these complex carbohydrate structures emerge as linchpins in cellular functions and interactions. The structural diversity of glycoconjugates, which can be specifically classified into glycoproteins, glycolipids, and proteoglycans, underscores their importance in shaping the architecture of cells. Beyond their structural roles, these molecules also play key functions in facilitating cellular communication and modulating recognition mechanisms. Further, glycans and glycoconjugates prove invaluable as biomarkers in disease diagnostics, particularly in cancer, where aberrant glycosylation patterns offer critical diagnostic cues. Furthermore, the review explores their promising therapeutic applications, ranging from the development of glycan-based nanomaterials for precise drug delivery to innovative interventions in cancer treatment. This review endeavors to comprehensively explore the intricate functions of glycans and glycoconjugates, with the primary goal of offering valuable insights into their extensive implications in both health and disease. Encompassing a broad spectrum of biological processes, the focus of the review aims to provide a comprehensive understanding of the significant roles played by glycans and glycoconjugates. [Display omitted] [ABSTRACT FROM AUTHOR]

• Highlights the critical role of the CXCR6/CXCL16 axis in fibrosis across various organs, including liver, kidney, lungs, cardiovascular system, skin, and intestines. • Discusses the mechanisms by which the CXCR6/CXCL16 axis modulates immune cell communication and fibroblast activity in fibrotic diseases. • Highlights the potential of targeting the CXCR6/CXCL16 axis as a therapeutic approach for treating fibrotic diseases. CXC chemokine receptor 6 (CXCR6), a seven-transmembrane domain G-protein-coupled receptor, plays a pivotal regulatory role in inflammation and tissue damage through its interaction with CXC chemokine ligand 16 (CXCL16). This axis is implicated in the pathogenesis of various fibrotic diseases and correlates with clinical parameters that indicate disease severity, activity, and prognosis in organ fibrosis, including afflictions of the liver, kidney, lung, cardiovascular system, skin, and intestines. Soluble CXCL16 (sCXCL16) serves as a chemokine, facilitating the migration and recruitment of CXCR6-expressing cells, while membrane-bound CXCL16 (mCXCL16) functions as a transmembrane protein with adhesion properties, facilitating intercellular interactions by binding to CXCR6. The CXCR6/CXCL16 axis is established to regulate the cycle of damage and repair during chronic inflammation, either through modulating immune cell-mediated intercellular communication or by independently influencing fibroblast homing, proliferation, and activation, with each pathway potentially culminating in the onset and progression of fibrotic diseases. However, clinically exploiting the targeting of the CXCR6/CXCL16 axis requires further elucidation of the intricate chemokine interactions within fibrosis pathogenesis. This review explores the biology of CXCR6/CXCL16, its multifaceted effects contributing to fibrosis in various organs, and the prospective clinical implications of these insights. [ABSTRACT FROM AUTHOR]

CpG oligodeoxynucleotide (CpG-ODN; CpG, in short) has been employed as an adjuvant in allergen specific immunotherapy (AIT) to treat allergic diseases. The underlying mechanism needs to be further explained. The aim of this study is to examine the mechanism by which CpG and dust mite extracts (DME, a specific antigen) alleviate experimental airway allergy. DME was used as the specific allergen to establish an airway allergy mouse model. The mice were directly exposed to DME and CpG through nasal instillations (the CpG.DME therapy). The response of DCs and allergic responses in the airways were assessed using immunological approaches. The airway allergy reaction was effectively suppressed by CpG.DME therapy. The administration of CpG or DME alone did not have any significant suppressive effects on the airway allergic response. Direct exposure to CpG.DME induced type 1 DCs (DC1s) and plasmacytoid DCs (pDCs), while CpG alone induced DC1s and DME alone induced DC2s in the airway tissues. Both DC1s and pDCs were required for the induction of type 1 regulatory T cells in the airway tissues by CpG.DME therapy. Depletion of either pDCs or DC1s abolished the induction of Tr1 cells, and abolished the suppressive effects on airway allergic response by the CpG.DME therapy. Direct exposure to CpG.DME induces DC1s and pDCs in the airway tissues. DC1s in synergy with pDCs induce type 1 regulatory T cells. The CpG.DME therapy is effective in suppressing allergic responses in mice with airway allergy. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a complex autoimmune inflammatory rheumatic disease characterized by an imbalance between immunological reactivity and immune tolerance. Regulatory T cells (Tregs), which play a crucial role in controlling ongoing autoimmunity and maintaining peripheral tolerance, have shown great potential for the treatment of autoimmune inflammatory rheumatic diseases such as RA. This review aims to provide an updated summary of the latest insights into Treg-targeting techniques in RA. We focus on current therapeutic strategies for targeting Tregs based on discussing their subsets, surface markers, suppressive function, and signaling pathways in RA. • Tregs can be split into tTregs, pTregs and iTregs, which suppress autoimmunity. • FoxP3 is considered to be the most specific marker of Tregs at present. • Tregs exert functions by cell-cell contact, cytokine meditation, markers, and TFs. • Upstream signaling pathways of Tregs trigger rheumatoid arthritis. • Treg targeted, based, and related therapies show potent in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Protein ubiquitination, one of the most significant post-translational modifications, plays an important role in controlling the proteins activity in diverse cellular processes. The reversible process of protein ubiquitination, known as deubiquitination, has emerged as a critical mechanism for maintaining cellular homeostasis. The deubiquitinases (DUBs), which participate in deubiquitination process are increasingly recognized as potential candidates for drug discovery. Among these DUBs, ubiquitin-specific protease 9× (USP9X), a highly conserved member of the USP family, exhibits versatile functions in various cellular processes, including the regulation of cell cycle, protein endocytosis, apoptosis, cell polarity, immunological microenvironment, and stem cell characteristics. The dysregulation and abnormal activities of USP9X are influenced by intricate cellular signaling pathway crosstalk and upstream non-coding RNAs. The complex expression patterns and controversial clinical significance of USP9X in cancers suggest its potential as a prognostic biomarker. Furthermore, USP9X inhibitors has shown promising antitumor activity and holds the potential to overcome therapeutic resistance in preclinical models. However, a comprehensive summary of the role and molecular functions of USP9X in cancer progression is currently lacking. In this review, we provide a comprehensive delineation of USP9X participation in numerous critical cellular processes, complicated signaling pathways within the tumor microenvironment, and its potential translational applications to combat therapeutic resistance. By systematically summarizing the updated molecular mechanisms of USP9X in cancer biology, this review aims to contribute to the advancement of cancer therapeutics and provide essential insights for specialists and clinicians in the development of improved cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) exhibits poor immune regulation and subnormal interferon (IFN-β) signaling. Secondary Progressive MS displays waning exacerbations, relentless neurodegeneration, and diminished benefit of therapy. We find dysregulated serum protein balance (Th1/Th2) and excessive gene expression in Relapsing-Remitting MS vs. healthy controls (8700 differentially-expressed genes, DEG) and intermediate levels in SPMS (3900 DEG). Olfactory receptor genes (chemosensing), and WNT/ß-catenin (anti-inflammatory, repair) and metallothionein (anti-oxidant) gene pathways, have less expression in SPMS than RRMS. IFN-β treatment decreased pro-inflammatory and increased metallothionein gene expression in SPMS. These gene expression biomarkers suggest new targets for immune regulation and brain repair in this neurodegenerative disease. [Display omitted] • 50% less abnormal gene and protein expression in therapy-naïve SPMS than in RRMS. • The balance of pro- and anti-inflammatory proteins is disrupted in RRMS but only intermediate in SPMS. • High olfactory receptor target-sensing and WNT/ß-catenin repair pathway expression in RRMS compared to SPMS. • IFN-β reverses low metallothionein gene expression, with a long-term priming/enhancing effect on this antioxidant pathway. • Disrupted SPMS neuroprotective pathways suggest novel disease mechanisms and therapeutic targets. [ABSTRACT FROM AUTHOR]

The Glu and GSH double-unlocked immunomodulatory tri-cascade nanoreactor was designed and developed for diabetic wounds therapy, which can release MACN nanoparticles through thermal ablation, thereby playing an important role in immune repair, angiogenesis, bacterial infection inhibition, and blood glucose regulation by further engaging with Glu and GSH substances to trigger multicascade. [Display omitted] • Glu and GSH dual-unlocked tri-cascade nanoreactor was developed for diabetic wounds. • MACNL NPs achieved light-free PDT in diabetic wounds for the first time. • Under NIR light irradiation, MACNL NPs enhanced the enzyme activity by 1.233-fold. The treatment of diabetic wounds remains a challenge due to the interaction between hyperglycemia, immune imbalance and bacterial infection. Herein, we developed a Glu and GSH double-unlocked immunomodulatory nanocascade reactor to accelerate diabetic wounds healing which dynamically manages the wound microenvironment by controlling blood glucose levels, restoring immune regulation and eliminating bacteria. On the one hand, ultra-small gold nanoparticles with GOx activity can catalyse glucose at the diabetic wound site, which can be further enhanced by photothermal effects, thus destroying bacterial biofilm structures, reversing wounds pH, and reducing bacterial reproduction. On the other hand, the sustained controlled release of NO at specific sites was achieved by depleting over-expressed GSH in the wounds to restore normal immune regulation, which not only promotes M2 macrophage polarisation and expressions of anti-inflammatory factors such as IL-10 and TGF-β1, but also produces VEGF and CD31 via the PI3K/AKT signalling pathway. Especially, the chemical resonance energy transfer (CRET) strategy was first applied to diabetic wounds treatment, achieving chemical photodynamic therapy (PDT) while reducing the secondary tissue damage caused by catalytically-generated H 2 O 2. In summary, the nanocascade reactor provides a new reference for bacterialy-infected diabetic wounds treatment mode by reducing blood glucose and restoring immune regulation in parallel. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic and multifactorial inflammatory oral disease that not only causes alveolar bone loss and tooth loosening but also amplifies systemic inflammation. Breakdown of periodontal host-microbe homeostasis creates dysbiotic microbial communities of keystone pathogens that trigger the host immune response creating a pro-inflammatory milieu in the periodontal region. Keystone pathogens damage the periodontal tissue and facilitate bacterial immune escape via direct infection in periodontal tissue or release of bacterial extracellular vesicles (EVs) and other virulence factors such as lipopolysaccharide (LPS) and endotoxins. Bacterial EVs are ̴ 100 nm diameter nanovesicles that carry LPS, endotoxins, catalytic enzymes, and bacterial nucleic acids and can easily internalize in host cells. Keystone pathogen EVs have been reported to disrupt the survival and function of various cells in the periodontal region. In contrast, probiotic EVs have been reported to alleviate the progression of various inflammatory diseases including colitis and atopic dermatitis. Based on these facts, this review aimed to discuss the pathogenic bacterial EVs as possible targets and probiotic EVs as nano-drugs or nanocarriers for immune modulation, inflammation regulation, and periodontitis treatment in clinics. We also elaborated challenges and prospects of the development of bacterial EVs-based diagnostic and therapeutic approaches for periodontitis. [Display omitted] • EVs from pathogenic bacteria exacerbate host-immune response, inflammation, and periodontitis pathogenicity. • EVs from probiotics alleviate host immune response, inflammation, and microbiome dysbiosis. • Pathogenic bacterial EVs could be used as diagnostic and prognostic markers of periodontitis. • Novel approaches inhibiting pathogenic bacterial EVs' production could treat inflammatory diseases including periodontitis. • Probiotic EVs have tremendous potential to be used as therapeutic agents for immune regulation and periodontitis treatment. [ABSTRACT FROM AUTHOR]

Brain metastasis (BrM) is a common malignancy, predominantly originating from lung, melanoma, and breast cancers. The vasculature is a key component of the BrM tumor microenvironment with critical roles in regulating metastatic seeding and progression. However, the heterogeneity of the major BrM vascular components, namely endothelial and mural cells, is still poorly understood. We perform single-cell and bulk RNA-sequencing of sorted vascular cell types and detect multiple subtypes enriched specifically in BrM compared to non-tumor brain, including previously unrecognized immune regulatory subtypes. We integrate the human data with mouse models, creating a platform to interrogate vascular targets for the treatment of BrM. We find that the CD276 immune checkpoint molecule is significantly upregulated in the BrM vasculature, and anti-CD276 blocking antibodies prolonged survival in preclinical trials. This study provides important insights into the complex interactions between the vasculature, immune cells, and cancer cells, with translational relevance for designing therapeutic interventions. [Display omitted] • We performed single-cell and bulk RNA-seq of human BrM and healthy brain vascular cells • BrMs are defined by pathological endothelial and mural cell subtypes • We created a preclinical platform by integrating human data with mouse BrM models • This interspecies analysis revealed CD276 as a potential therapeutic target for BrM The brain tumor-associated vasculature is a key component of the tumor microenvironment in brain metastasis, protecting cancer cells from immune attack and interfering with the delivery of therapeutic agents into the brain. In this study, Bejarano et al. unravel the vascular heterogeneity in human BrM and further construct a preclinical platform to design novel vascular-targeted therapeutic strategies for the treatment of these aggressive tumors. [ABSTRACT FROM AUTHOR]

Melanoma is one of the most lethal cutaneous malignancies. Despite great advances in radiotherapy, chemotherapy, and immunotherapy, the survival rate and prognosis of patients with melanoma remain poor. The abundant and sophisticated reciprocal communication network between melanoma cells and non-tumor cells contributes to the high heterogeneity of the melanoma microenvironment and is intimately related to varying treatment responses and clinical courses. Extracellular vesicles (EVs) are membrane structures generated by nearly all cell types. EVs contain biologically active molecules, mainly comprising proteins, lipids, and RNAs, and undoubtedly play multifaceted roles in numerous diseases, represented by melanoma. Non-coding RNAs (ncRNAs) mainly encompass long non-coding RNAs, microRNAs, and circular RNAs and constitute the majority of the human transcriptome. Multiple ncRNAs encapsulated in EVs coordinate various pathophysiological processes in melanoma. This review summarizes the mechanisms by which EV-ncRNAs modulate biological behaviors and immunity, and their potential diagnostic and therapeutic applications in melanoma. Undoubtedly, further insight into EV-ncRNAs and their functions in melanoma will contribute to the clinical treatment of melanoma and the implementation of precision medicine. [Display omitted] • EV-ncRNAs mediate melanoma resistance to drugs including Vemurafenib and the pharmacology for metformin with cisplatin. • EV-ncRNAs are pivotal in reconfiguring the biological behavior of melanoma and participating in melanoma diagnosis. • Multiple EV-ncRNAs derived from melanoma microenvironment participate in melanoma growth, metastasis, and Warburg effects. • EV-ncRNAs can regulate the immune responses of melanoma by remodeling recipient immune cells. • EV-ncRNAs in serum are promising biomarkers for liquid biopsy and possible therapeutic targets for melanoma. [ABSTRACT FROM AUTHOR]

Protein phosphorylation modifications are post-translational modifications (PTMs) that play important roles in signal transduction and immune regulation. Implanting a spherical nucleus into a recipient shellfish is critical in marine pearl aquaculture. Protein phosphorylation may be important in the immune responses of Pinctada fucata martensii after nucleus implantation, but their involvement in regulation remains unclear. Here, phosphoproteomics of P. f. martensii gill tissues was conducted 12 h after nuclear implantation using label-free data-independent acquisition (DIA) with LC-MS/MS. Among the 4024 phosphorylated peptides with quantitative information, 181 were up-regulated and 148 were down-regulated. Functional enrichment analysis of these differentially expressed phosphorylated proteins (DEPPs) revealed significant enrichment in functions related to membrane trafficking, exosomes, cytoskeleton, and signal transduction mechanisms. Further, 16 conserved motifs were identified among the DEPPs, including the RSphP, SphP, RSphA, RSphE, PTphP, and ATphP motifs that were significantly conserved, and which may be related to specific kinase recognition. Parallel response monitoring (PRM) analysis validated the abundances of 12 DEPPs from the proteomics, indicating that the phosphoproteomics analyses were robust. 12 DEPPs were selected from the proteomics results through Quantitative real-time PCR (qPCR) technology, and verification analysis was conducted at the gene level. The study suggests that kinases such as MAPKs, Akt, and CK2 may regulate the phosphorylation of related proteins following nuclear implantation. Furthermore, the important signaling pathways of Rap 1, IL-17A, and NF-κB, which are influenced by phosphorylated or dephosphorylated proteins, are found to be involved in this response. Overall, this study revealed the protein phosphorylation responses after nucleus implantation in P. f. martensii , helping to elucidate the characteristics and mechanisms of immune regulation responses in P. f. martensii, in addition to promoting a further understanding of protein phosphorylation modification functions in P. f. martensii. [Display omitted] • Allograft-induced phosphorylomic changes in Pinctada fucata martensii were studied for the first time. • Differentially expressed phosphorylated proteins (DEPPs) were responsive to nucleus implantation. • DEPPs were associated with functions related to inflammatory mediator regulation. • DEPPs were enriched in cAMP signaling pathways and the Rap1 signaling pathway. [ABSTRACT FROM AUTHOR]

Summary: Gut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is the most common sexually transmitted virus worldwide. More than 99% of cervical cancer cases are associated with certain types of HPVs, termed high-risk types. In addition to the well-known transformative properties, HPVs-infected cells actively instruct the local milieu and create a supportive post-infection microenvironment (PIM), which is becoming recognized as a key factor for the viral persistence, propagation, and malignant progression. The PIM is initiated and established via a complex interplay among virus-infected cells, immune cells, and host stroma, as well as their derived components including chemokines, cytokines, extracellular vesicles, and metabolites. In this review, we summarize the current understanding of these key components, characteristics, and effects of the PIM, and highlights the prospect of targeting the PIM as a potential strategy to improve therapeutic outcomes for cervical cancer. [ABSTRACT FROM AUTHOR]