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This study explored the anti-pruritic and immunomodulatory effects of Coix sprouts extract, focusing on histamine release and IL-31 cytokine production in HMC-1 cells. The extract significantly inhibited both factors, indicating its potential for pruritus relief. In a pruritus induction mouse model, Coix sprouts extract outperformed prednisolone in anti-pruritus effectiveness, also improving skin lesions and inhibiting mast cell infiltration. The extract suppressed tryptase expression, reduced release, inhibited mast cell proliferation, and lowered nitric oxide production, suggesting anti-inflammatory properties. Coix sprouts extract shows promise in suppressing inflammation and pruritus, making it a valuable candidate for clinical use. Additionally, the analysis of coixol content in Coix sprouts revealed variations in growth time, indicating their potential as functional materials with anti-pruritus and immune-enhancing applications.

Pateamines act as inhibitors of the RNA helicase eIF4A and exhibit antiviral and anticancer properties. Recently, we observed that inhibition of eIF4A by rocaglates affects the immune response. To investigate whether the observed immunomodulatory effects are specific to rocaglates or the inhibition of eIF4A, a comprehensive study was conducted on the influence of pateamines that exhibit the same inhibitory mode of action as rocaglates on various immune cells. The effects of pateamine A (PatA) and des-methyl des-amino pateamine A (DMDA) on the expression of surface markers, release of cytokines, cell proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdM), T cells and B cells were assessed. Additionally, safety and bioavailability profiles were determined. DMDA revealed almost no immunomodulatory effects within the tested concentration range of 0.5-5 nM. PatA reduced B cell activation, as shown by reduced immune globulin release and decreased chemokine release from macrophages, while T cell function remained unaffected. Both DMDA and PatA showed low permeability in Caco-2 and Calu-3 cell barrier assays and no mutagenic potential. However, 10 nM PatA exhibited genotoxic potential, as shown by the micronucleus assay. In conclusion, DMDA had a good safety profile but exhibited low permeability, whereas PatA had a poor safety profile and also low permeability. The observed immunomodulatory effects of elF4A inhibitors on B cells appear to be target-specific.

Curcumin (Cur), the primary curcuminoid found in Curcuma longa L., has garnered significant attention for its potential anti-inflammatory and antibacterial properties. However, its hydrophobic nature significantly limits its bioavailability. Additionally, adipose-derived stem cells (ADSCs) possess immunomodulatory properties, making them useful for treating inflammatory and autoimmune conditions. This study aims to verify the efficacy of poly(ε-caprolactone) nanocapsules (NCs) in improving Cur's bioavailability, antibacterial, and immunomodulatory activities. The Cur-loaded nanocapsules (Cur-NCs) were characterized for their physicochemical properties (particle size, polydispersity index, Zeta potential, and encapsulation efficiency) and stability over time. A digestion test simulated the behavior of Cur-NCs in the gastrointestinal tract. Micellar phase analyses evaluated the Cur-NCs' bioaccessibility. The antibacterial activity of free Cur, NCs, and Cur-NCs against various Gram-positive and Gram-negative strains was determined using the microdilution method. ADSC viability, treated with Cur-NCs and Cur-NCs in the presence or absence of lipopolysaccharide, was analyzed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay. Additionally, ADSC survival was assessed through the Muse apoptotic assay. The expression of both pro-inflammatory (interleukin-1β and tumor necrosis factor-α) and anti-inflammatory (IL-10 and transforming growth factor-β) cytokines on ADSCs was evaluated by real-time polymerase chain reaction. The results demonstrated high stability post-gastric digestion of Cur-NCs and elevated bioaccessibility of Cur post-intestinal digestion. Moreover, Cur-NCs exhibited antibacterial activity against Escherichia coli without affecting Lactobacillus growth. No significant changes in the viability and survival of ADSCs were observed under the experimental conditions. Finally, Cur-NCs modulated the expression of both pro- and anti-inflammatory cytokines in ADSCs exposed to inflammatory stimuli. Collectively, these findings highlight the potential of Cur-NCs to enhance Cur's bioavailability and therapeutic efficacy, particularly in cell-based treatments for inflammatory diseases and intestinal dysbiosis.

In the postantibiotic era, the pathogenicity and resistance of pathogens have increased, leading to an increase in intestinal inflammatory disease. Bacterial infections remain the leading cause of animal mortality. With increasing resistance to antibiotics, there has been a significant decrease in resistance to both inflammation and disease in animals, thus decreasing production efficiency and increasing production costs. These side effects have serious consequences and have detracted from the development of China's pig industry. Microcin C7 (McC7) demonstrates potent antibacterial activity against a broad spectrum of pathogens, stable physicochemical properties, and low toxicity, reducing the likelihood of resistance development. Thus, McC7 has received increasing attention as a potential clinical antibacterial and immunomodulatory agent. McC7 has the potential to serve as a new generation of antibiotic substitutes; however, its commercial applications in the livestock and poultry industry have been limited. In this review, we summarize and discuss the biosynthesis, biochemical properties, structural characteristics, mechanism of action, and immune strategies of McC7. We also describe the ability of McC7 to improve intestinal health. Our aim in this study was to provide a theoretical basis for the application of McC7 as a new feed additive or new veterinary drug in the livestock and poultry breeding industry, thus providing a new strategy for alleviating resistance through feed and mitigating drug resistance. Furthermore, this review provides insight into the new functions and anti-infection mechanisms of bacteriocin peptides and proposes crucial ideas for the research, product development, and application of bacteriocin peptides in different fields, such as the food and medical industries.

Metformin, a medication known for its anti-glycemic properties, also demonstrates potent immune system activation. In our study, using a 4T1 breast cancer model in BALB/C WT mice, we examined metformin's impact on the functional phenotype of multiple immune cells, with a specific emphasis on natural killer T (NKT) cells due to their understudied role in this context. Metformin administration delayed the appearance and growth of carcinoma. Furthermore, metformin increased the percentage of IFN-γ + NKT cells, and enhanced CD107a expression, as measured by MFI, while decreasing PD-1 + , FoxP3 + , and IL-10 + NKT cells in spleens of metformin-treated mice. In primary tumors, metformin increased the percentage of NKp46 + NKT cells and increased FasL expression, while lowering the percentages of FoxP3 + , PD-1 + , and IL-10-producing NKT cells and KLRG1 expression. Activation markers increased, and immunosuppressive markers declined in T cells from both the spleen and tumors. Furthermore, metformin decreased IL-10 + and FoxP3 + Tregs, along with Gr-1 + myeloid-derived suppressor cells (MDSCs) in spleens, and in tumor tissue, it decreased IL-10 + and FoxP3 + Tregs, Gr-1 + , NF-κB + , and iNOS + MDSCs, and iNOS + dendritic cells (DCs), while increasing the DCs quantity. Additionally, increased expression levels of MIP1a, STAT4, and NFAT in splenocytes were found. These comprehensive findings illustrate metformin's broad immunomodulatory impact across a variety of immune cells, including stimulating NKT cells and T cells, while inhibiting Tregs and MDSCs. This dynamic modulation may potentiate its use in cancer immunotherapy, highlighting its potential to modulate the tumor microenvironment across a spectrum of immune cell types.

Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4 + and CD8 + T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant 'low' dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID 50 ) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.

Mulberry is a rapidly growing plant that thrives in diverse climatic, topographical, and soil types, spanning temperature and temperate countries. Mulberry plants are valued as functional foods for their abundant chemical composition, serving as a significant reservoir of bioactive compounds like proteins, polysaccharides, phenolics, and flavonoids. Moreover, these compounds displayed potent antioxidant activity by scavenging free radicals, inhibiting reactive oxygen species generation, and restoring elevated nitric oxide production induced by LPS stimulation through the downregulation of inducible NO synthase expression. Active components like oxyresveratrol found in Morus demonstrated anti-inflammatory effects by inhibiting leukocyte migration through the MEK/ERK signaling pathway. Gallic and chlorogenic acids in mulberry leaves (ML) powder-modulated TNF, IL-6, and IRS1 proteins, improving various inflammatory conditions by immune system modulation. As we delve deeper into understanding its anti-inflammatory potential and how it works therapeutically, it is crucial to refine the extraction process to enhance the effectiveness of its bioactive elements. Recent advancements in extraction techniques, such as solid-liquid extraction, pressurized liquid extraction, superficial fluid extraction, microwave-assisted extraction, and ultrasonic-assisted extraction, are being explored. Among the extraction methods tested, including Soxhlet extraction, maceration, and ultrasound-assisted extraction (UAE), UAE demonstrated superior efficiency in extracting bioactive compounds from mulberry leaves. Overall, this comprehensive review sheds light on the potential of mulberry as a natural immunomodulatory agent and provides insights into its mechanisms of action for future research and therapeutic applications.

Cancer immunotherapy relies on the insight that the immune system can be used to defend against malignant cells. The aim of cancer immunotherapy is to utilize, modulate, activate, and train the immune system to amplify antitumor T-cell immunity. In parallel, the immune system response to damaged tissue is also crucial in determining the success or failure of an implant. Due to their extracellular matrix mimetics and tunable chemical or physical performance, hydrogels are promising platforms for building immunomodulatory microenvironments for realizing cancer therapy and tissue regeneration. However, submicron or nanosized pore structures within hydrogels are not favorable for modulating immune cell function, such as cell invasion, migration, and immunophenotype. In contrast, hydrogels with a porous structure not only allow for nutrient transportation and metabolite discharge but also offer more space for realizing cell function. In this review, the design strategies and influencing factors of porous hydrogels for cancer therapy and tissue regeneration are first discussed. Second, the immunomodulatory effects and therapeutic outcomes of different porous hydrogels for cancer immunotherapy and tissue regeneration are highlighted. Beyond that, this review highlights the effects of pore size on immune function and potential signal transduction. Finally, the remaining challenges and perspectives of immunomodulatory porous hydrogels are discussed.

The use of deer antlers dates back thousands of years in Chinese history. Deer antlers have antitumor, anti-inflammatory, and immunomodulatory properties and can be used in treating neurological diseases. However, only a few studies have reported the immunomodulatory mechanism of deer antler active compounds. Using network pharmacology, molecular docking, and molecular dynamics simulation techniques, we analyzed the underlying mechanism by which deer antlers regulate the immune response. We identified 4 substances and 130 core targets that may play immunomodulatory roles, and the beneficial and non-beneficial effects in the process of immune regulation were analyzed. The targets were enriched in pathways related to cancer, human cytomegalovirus infection, the PI3K-Akt signaling pathway, human T cell leukemia virus 1 infection, and lipids and atherosclerosis. Molecular docking showed that AKT1, MAPK3, and SRC have good binding activity with 17 beta estradiol and estrone. Additionally, the molecular dynamics simulation of the molecular docking result using GROMACS software (version: 2021.2) was performed and we found that the AKT1-estrone complex, 17 beta estradiol-AKT1 complex, estrone-MAPK3 complex, and 17 beta estradiol-MAPK3 complex had relatively good binding stability. Our research sheds light on the immunomodulatory mechanism of deer antlers and provides a theoretical foundation for further exploration of their active compounds.

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.

The blue-green alga Spirulina platensis is rich in phycocyanins, that exhibit a wide range of pharmacological actions. C-phycocyanin (C-PC), in particular, possesses hepatoprotective, nephroprotective, antioxidant, and anticancer effects. Furthermore, several studies have reported both anti- and proinflammatory properties of this pigment. However, the precise mechanism(s) of action of C-PC in these processes remain largely unknown. Therefore, here we explored the C-PC effect in in vitro microglia activation. The effect of C-PC on the expression and release of IL-1β and TNF-α and the activation of NF-κB was examined in primary microglia by real-time PCR, ELISA, and immunofluorescence. Treatment with C-PC up-regulated the expression and release of IL-1β and TNF-α. C-PC also promoted the nuclear translocation of the NF-κB transcription factor. Then, to elucidate the molecular mechanisms for the immunoregulatory function of C-PC, we focused on investigating the role of Toll-like receptor 4 (TLR4). Accordingly, several TLR4 inhibitors have been used. Curcumin, ciprofloxacin, L48H37, and CLI-095 that suppresses specifically TLR4 signaling, blocked IL-1β and TNF-α. Overall, these results indicate the immunomodulatory effect of C-PC in microglia cultures and show for the first time that the molecular mechanism implicated in this effect may involve TLR4 activation.

Oral melatonin supplement has been shown to improve dermatitis severity in children with AD, but the mechanism of the effect is unclear, and it is uncertain whether melatonin has a direct immunomodulatory effect on the dermatitis. Topical melatonin treatment was applied to DNCB-stimulated Balb/c mice, and gross and pathological skin findings, serum IgE, and cytokine levels in superficial lymph nodes were analyzed. Secretion of chemokines and cell proliferative response after melatonin treatment in human keratinocyte HaCaT cells were also studied. We found that in DNCB-stimulated Balb/c mice, topical melatonin treatment improved gross dermatitis severity, reduced epidermal hyperplasia and lymphocyte infiltration in the skin, and decreased IP-10, CCL27, IL-4, and IL-17 levels in superficial skin-draining lymph nodes. Melatonin also reduced cytokine-induced secretion of AD-related chemokines IP-10 and MCP-1 and decreased IL-4-induced cell proliferation in HaCaT cells. Melatonin seems to have an immunomodulatory effect on AD, with IP-10 as a possible target, and topical melatonin treatment is a potentially useful treatment for patients with AD.

The white-rot fungi Ceriporia lacerata is used in bioremediation, such as lignocellulose degradation, in nature. Submerged cultures and extracts of C. lacerata mycelia (CLM) have been reported to contain various active ingredients, including β-glucan and extracellular polysaccharides, and to exert anti-diabetogenic properties in mice and cell lines. However, the immunostimulatory effects have not yet been reported. This study aimed to identify the immunomodulatory effects, and underlying mechanisms thereof, of submerged cultures of CLM using RAW264.7 macrophages and cyclophosphamide (CTX)-induced immunosuppression in mice. Compared to CTX-induced immunosuppressed mice, the spleen and thymus indexes in mice orally administered CLM were significantly increased; body weight loss was alleviated; and natural killer (NK) cytotoxicity, lymphocyte proliferation, and cytokine (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, and interleukin [IL]-2) production were elevated in the serum. In RAW264.7 macrophages, treatment with CLM induced phagocytic activity, increased the production of nitric oxide (NO), and promoted mRNA expression of the immunomodulatory cytokines TNF-α, IFN-γ, IL-1β, IL-6, IL-10, and IL-12. In addition, CLM increased the inducible NO synthase (iNOS) concentration in macrophages, similar to lipopolysaccharide (LPS) stimulation. Mechanistic studies showed that CLM induced the activation of the NF-κB, PI3k/Akt, ERK1/2, and JNK1/2 pathways. Moreover, the phosphorylation of NF-κB and IκB induced by CLM in RAW264.7 cells was suppressed by specific MAPKs and PI3K inhibitors. Further experiments with a TLR4 inhibitor demonstrated that the production of TNF-α, IL-1β, and IL-6 induced by CLM was decreased after TLR4 was blocked. Overall, CLM protected against CTX-induced adverse reactions by enhancing humoral and cellular immune functions, and has potential as an immunomodulatory agent.

The rapid rise of multidrug-resistant (MDR) bacteria has once again caused bacterial infections to become a global health concern. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), offer a viable solution to these pathogens due to their diverse mechanisms of actions, which include direct killing as well as immunomodulatory properties (e.g., anti-inflammatory activity). HDPs may hence provide a more robust treatment of bacterial infections. In this review, the advent of and the mechanisms that lead to antibiotic resistance will be described. HDP mechanisms of antibacterial and immunomodulatory action will be presented, with specific examples of how the HDP aurein 2.2 and a few of its derivatives, namely peptide 73 and cG4L73, function. Finally, resistance that may arise from a broader use of HDPs in a clinical setting and methods to improve biocompatibility will be briefly discussed.

Paracrine factors of human mesenchymal stem cells (hMSCs) have the potential of preventing adverse cardiac remodeling after myocardial infarction (MI). S100A8 and S100A9 are calcium-binding proteins playing essential roles in the regulation of inflammation and fibrous tissue formation, and they might modulate the paracrine effect of hMSCs. We isolated human amniotic mesenchymal stem cells (hAMSCs) and examined the changes in the expression level of regulatory genes of inflammation and fibrosis after hAMSCs were treated with S100A8/A9. The anti-inflammatory and anti-fibrotic effects of hAMSCs pretreated with S100A8/A9 were shown to be superior to those of hAMSCs without S100A8/A9 pretreatment in the cardiomyocyte hypoxia/reoxygenation experiment. We established a murine myocardial ischemia/reperfusion model to compare the therapeutic effects of the conditioned medium of hAMSCs with or without S100A8/A9 pretreatment. We found the hearts administered with a conditioned medium of hAMSCs with S100A8/A9 pretreatment had better left ventricular systolic function on day 7, 14, and 28 after MI. These results suggest S100A8/A9 enhances the paracrine therapeutic effects of hAMSCs in aspects of anti-inflammation, anti-fibrosis, and cardiac function preservation after MI.