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Background: Tomato (Solanum lycopersicum L.) production is severely threatened by bacterial wilt, caused by the phytopathogenic bacterium Ralstonia solanacearum. Recently, nano-enabled strategies have shown tremendous potential in crop disease management., Objectives: This study investigates the efficacy of biogenic nanoformulations (BNFs), comprising biogenic silica nanoparticles (SiNPs) and melatonin (MT), in controlling bacterial wilt in tomato., Methods: SiNPs were synthesized using Zizania latifolia leaves extract. Further, MT containing BNFs were synthesized through the one-pot approach. Nanomaterials were characterized using standard characterization techniques. Greenhouse disease assays were conducted to assess the impact of SiNPs and BNFs on tomato plant immunity and resistance to bacterial wilt., Results: The SiNPs and BNFs exhibited a spherical morphology, with particle sizes ranging from 13.02 nm to 22.33 nm for the SiNPs and 17.63 nm to 21.79 nm for the BNFs, indicating a relatively uniform size distribution and consistent shape across both materials. Greenhouse experiments revealed that soil application of BNFs outperformed SiNPs, significantly enhancing plant immunity and reducing bacterial wilt incidence by 78.29% in tomato plants by maintaining oxidative stress homeostasis via increasing the activities of antioxidant enzymes such as superoxide dismutase (31.81%), peroxidase (32.9%), catalase (32.65%), and ascorbate peroxidase (47.37%) compared to untreated infected plants. Additionally, BNFs induced disease resistance by enhancing the production of salicylic acid and activating defense-related genes (e.g., SlPAL1, SlICS1, SlNPR1, SlEDS, SlPD4, and SlSARD1) involved in phytohormones signaling in infected tomato plants. High-throughput 16 S rRNA sequencing revealed that BNFs promoted growth of beneficial rhizosphere bacteria (Gemmatimonadaceae, Ramlibacter, Microscillaceae, Anaerolineaceae, Chloroplast and Phormidium) in both healthy and diseased plants, while suppressing R. solanacearum abundance in infected plants., Conclusion: Overall, these findings suggest that BNFs offer a more promising and sustainable approach for managing bacterial wilt disease in tomato plants., (© 2024. The Author(s).)

Otitis media (OM), a condition stemming from the proliferation of various bacteria within the tympanic cavity (TC), is commonly addressed through the administration of ofloxacin (OFL), a fluoroquinolone antibiotic. Nevertheless, the escalating issue of antibiotic resistance and the challenge of drug leakage underscore the exploration of an alternative, more effective treatment modality in clinical practice. Here, we introduce a simple and easily implementable fluid-regulated strategy aimed at delivering immunomodulatory hydrogels into the TC, ensuring conformal contact with the irregular anatomical surfaces of the middle ear cavity to more effectively eliminate bacteria and treat OM. This innovative strategy exhibits expedited therapeutic process of antibiotic-resistant, acute and chronic OM rats, and significant reductions in the severity of tympanic membrane (TM) inflammation, residual bacteria within the TC (0.12 *10 5 CFU), and the thickness of TM/TC mucosa (17.63/32.43 μm), as compared to conventional OFL treatment (3.6, 0.76 *10 5 CFU, 48.70/151.26 μm). The broad-spectrum antibacterial and antibiofilm properties of this strategy against a spectrum of OM pathogens are demonstrated. The strategy is validated to bolster the host's innate immune response through the stimulation of antibacterial protein synthesis, macrophage proliferation and activation, thereby accelerating bacterial eradication and inflammation resolution within the TC. This facile, cost-effective and in vivo degradable technology exhibits promising prospects for future clinical implementation., (© 2024. The Author(s).)

Background: Astragali radix (AR) is one of the most widely used traditional Chinese herbal medicines. It exhibits diverse biological activities, including immunomodulatory and anti-inflammatory properties; however, some of its activities have only been demonstrated in vitro., Objective: To examine the effects of orally administered AR extract on immune cells and the intestine under physiological conditions, which bridges the gap between previously observed in vitro outcomes and in vivo results., Methods: AR extract was prepared by hot water extraction. Three separate animal experiments were conducted to isolate macrophages, splenocytes, and the small intestine epithelium. For the macrophage preparation experiment, an intraperitoneal injection of sterile thioglycolate was administered. The mice received oral AR extract at doses of 0.1, 0.5, or 2.5 g/kg for ten days. At the end of each experiment, cells or tissues were isolated. A portion of macrophages and splenocytes were analyzed for the phenotypic changes. The remaining cells were cultured and stimulated with lipopolysaccharide (LPS) or mitogen ex vivo to assess activation status, proliferation, and cytokine production. Samples of the intestine were subjected to real-time RT-PCR., Results: Peritoneal macrophages from AR-treated mice exhibited increased expression of scavenger receptors, including SRA and CD36. Stimulation of these macrophages ex vivo with LPS selectively modulated the inflammatory response, including reduced expression of the costimulatory molecules CD40 and CD86, which are important for T cell responses, without affecting TNF-α and IL-6 production. Splenocytes from AR-treated mice exhibited a dose-dependent increase in CD4 and CD8 T cells; however, stimulation with mitogen decreased T cell proliferation and reduced IFN-γ production, which is essential for macrophage activation. An analysis of the small intestinal epithelium revealed an attenuated antimicrobial response, including reduced IgA content in the lumen and decreased expression of mucin-2 and polymeric Ig receptor genes., Conclusion: The response of immune cells following oral treatment with AR extract did not replicate the previously documented in vitro findings. Immune cells and intestinal epithelium from mice administered oral AR extract exhibited a selective anti-inflammatory phenotype. The overall findings indicate that the systemic effects after oral administration of AR extract include reduced sensitivity to inflammatory insults., (© 2024. The Author(s).)

Background: This meta-analysis aimed to summarize the immunomodulatory effect of Huaier (Trametes robiniophila Murr) granule as adjuvant therapy in patients with cancer. MATERIALS AND METHODS: Two authors conducted a search for literature indexed on various databases including PubMed, Embase, Cochrane Library, CNKI, Sinomed, VIP, and WanFang. Randomized controlled trials (RCTs) that investigated the immunomodulatory effect of Huaier granule as adjuvant therapy in cancer patients were included. The outcome of interest included T-lymphocyte subsets (CD3 + , CD4 + , CD8 + and CD4 + /CD8 + ), immunoglobulin (IgA, IgG, IgM), and natural killer (NK) cells., Results: We identified 29 RCTs involving a total of 2206 cancer (including hepatocellular, breast, gastric, colorectal, lung, or nasopharyngeal carcinoma) patients. Compared with conventional treatment alone, Huaier combined conventional treatment significantly improved CD3 + (mean difference [MD] 6.95; 95% confidence intervals [CI] 4.42-9.48), CD4 + (MD 5.53; 95%CI 4.22-6.83), CD4 + /CD8 + (MD 0.35; 95%CI 0.25-0.45), IgA (standardized mean difference [SMD] 1.18; 95%CI 0.44-1.93), IgG(SMD 1.71; 95%CI 1.11-2.30), IgM (SMD 0.83; 95%CI 0.59-1.07), and NK cells (MD 5.01; 95%CI 3.61-6.40). However, the effect of Huaier on CD8 + (MD - 1.35; 95%CI - 2.80 to 0.11) was not statistically significant between the groups., Conclusions: Huaier granule as adjuvant therapy may significantly improve immune function in patients with cancers. However, additional well-designed RCTs are needed to validate the current findings considering the methodological flaws of the analyzed trials., (© 2024. The Author(s).)

Background: Cancer remains a major global health concern, with conventional treatments often limited by side effects and resistance. Bojungikki-tang (BJIKT), a traditional herbal formula, has shown promise in alleviating cancer-related symptoms and enhancing anti-cancer effects when combined with conventional treatments. As immune checkpoint inhibitors (ICIs) have become the standard for cancer treatment, a combination of BJIKT and ICIs may exhibit immune-mediated anti-cancer effects. This review aims to summarize the recent evidence on BJIKT use in cancer treatment, investigate its immunomodulatory effects, and identify research gaps., Methods: This review was conducted and reported following the Arksey and O'Malley framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Scoping Review. A comprehensive search of six electronic databases was conducted, and studies published between 2013 and 2022 were identified. Reports on oral administration of BJIKT to patients with cancer were included and analyzed by two reviewers. The extracted data were synthesized using descriptive reporting and meta-analysis., Results: Overall, 56 studies met the inclusion criteria: 36 human studies, 14 experimental studies, and 6 reviews on clinical and preclinical investigations. The use of BJIKT in restoring immune function and improving fatigue, cancer-related fever, and quality of life after chemotherapy has been reported in clinical studies. The different medication forms of BJIKT included decoction, extract granules, pills, and water extract. The meta-analysis revealed a significantly higher Karnofsky Performance Scale score in the BJIKT plus chemotherapy group than in the chemotherapy alone group. Preclinical studies have demonstrated that BJIKT has anti-cancer effects, enhances gastrointestinal function and immunomodulatory effects, and supports favorable chemotherapy outcomes., Conclusion: In recent clinical research on BJIKT, its impact on fatigue, quality of life, and alleviating cancer-related fever has mostly been examined. The direct anti-cancer activities and immunomodulatory mechanisms of BJIKT have been reported in preclinical studies; however, clinical research on BJIKT-induced enhancement of immune function is lacking. Further research on the efficacy and safety of ICI combined with BJIKT and the association of immunomarker changes with clinical outcomes is required to precisely identify the effect of BJIKT on immune system modulation., (© 2024. The Author(s).)

Ovine contagious pustular dermatitis (ORF) is one of the main diseases of sheep and is a zoonotic disease caused by Ovine contagious pustular dermatitis virus (ORFV) infection, posing a significant constraint on sheep breeding industry and human health. The Tibetan medical formulation composed of Polygonum leucoides, Polygonum xanthoxylum and Acanthophora rotunda significantly regulated lymphocyte immune function following ORFV stimulation, although the mechanism remains unclear. In order to study the immunomodulatory effects and mechanism of three Tibetan medicinal extracts (Polygonum leucoides, Polygonum xanthoxylum, and Acanthophora rotunda) against ORFV in vitro, sheep peripheral blood lymphocytes were isolated in vitro and treated with different concentrations of Tibetan medicine compound extract solution after ORFV infection. The cytokine expression levels in lymphocytes were measured at 4 h, 8 h and 12 h. Additionally endogenous metabolites in lymphocytes at 0 h, 4 h, 8 h and 12 h were quantified by untargeted metabolomics method. The results showed that, the extracts could regulate the lymphocyte immune factors altered by ORFV, and regulate the lymphocyte immune function through cysteine and methionine metabolic pathways as well as the pyrimidine metabolic pathways, potentially alleviating the immune evasion induced by ORFV., (© 2024. The Author(s).)

Osteoarthritis (OA) is a degenerative illness that greatly impacts the life quality of patients. Currently, the therapeutic approaches for OA are very limited in clinical. The extracellular vesicles (EVs) derived from different mesenchymal stem cells displayed a prominent therapeutic effect on OA. But most EVs have limited resources and the risks of host rejection, immunological response, and etc. Human umbilical cord mesenchymal stem cells (hUCMSCs) hold the advantages of easy availability, minimal immune rejection, and excellent immunomodulatory effects, although hUCMSCs-EVs have seldom been applied in OA. Herein, we investigated the potential immunomodulatory and anti-inflammatory effects of hUCMSCs-EVs on the treatment of OA. In our results, the treatment of hUCMSCs-EVs promoted the polarization of M2-type macrophages and the expression of anti-inflammation-related cytokines (IL-10). Notably, the supernate of M2 macrophages induced by hUCMSCs-EVs inhibited the level of inflammation-associated factors in OA chondrocytes caused by IL-1β. Further, injection of hUCMSCs-EVs in the articular lumen ameliorated progression of OA and exerted chondroprotective potential based on the OA joint model created by the surgical transection of the anterior cruciate ligament (ACLT). In addition, we found five highly enriched miRNAs in hUCMSCs-EVs, including has-miR-122-5p, has-miR-148a-3p, has-miR-486-5p, has-miR-let-7a-5p, and has-miR-100-5p by High-throughput sequencing of miRNAs, with targeted genes mainly enriched in the PI3K-Akt signaling pathway. Furthermore, we also detected the protein abundance of hUCMSCs-EVs using liquidation chromatography with tandem quadrupole mass spectrometry (LC-MS/MS) analysis. Thus, our study indicates that hUCMSCs-EVs can alleviate cartilage degradation during the OA progression, mechanically may through delivering key proteins and modulating the PI3K-Akt signaling pathway mediated by miRNAs to promote polarization of M2 macrophage, exhibiting potent immunomodulatory potential. The current findings suggest that hUCMSCs-EVs might serve as a new reagent for the therapy of OA., (© 2022. The Author(s).)

Background: The present study extensively aimed to evaluate the underlying mechanism of the immunomodulatory and anti-inflammatory effects of Phellinus linteus mycelium (PLM)., Methods: To assess whether PLM influences the production of markers related to inflammation, Lipopolysaccharide (LPS)-stimulated RAW264.7 cells were treated with PLM (50, 100, 200, and 500 μg/mL). Splenocyte, thymus, peritoneal exudate cells (PEC), and peripheral blood mononuclear cells (PBMC) were isolated from the Balb/c mice treated with Korean red ginseng or PLM once a day for 5 weeks. Moreover, all mice except normal mice were stimulated with 10% proteose peptone (PP) treated 3 days before the sacrifice and 2% starch treated 2 days before the sacrifice. Subsequently, the cytotropic substance was evaluated by using flow cytometry analysis and ELISA assay., Results: PLM200 treatment significantly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and inhibited the release of proinflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α dose-dependently in the LPS-stimulated RAW264.7 cells. PLM200 supplementation showed a significant increase in IL-2, IL-12, and interferon (IFN)-γ production and upregulated the ratio of IFN-γ (T-helper type 1, Th1) to IL-4 (T-helper type 2, Th2) in splenocytes. After PLM200 treatment, the significant elevation of CD4 + CD25 + , CD4 + &CD8 + , and CD4 + CD69 + treatment were detected in thymus. Moreover, CD4 + and CD4 + CD69 + in PBMC and CD69 + in PEC were also shown in a significant increase., Conclusions: Taken together, these results showed an immunomodulatory effect of PLM about an elevated INF-γ/IL4 ratio, as an index of Th1/Th2, as well as the anti-inflammatory effect in the LPS-stimulated RAW264.7 cells. Therefore, our findings demonstrate that PLM possesses immunostimulatory and anti-inflammatory effects., (© 2021. The Author(s).)

Background: Fungal cell wall polysaccharides maintain the integrity of fungi and interact with host immune cells. The immunomodulation of fungal polysaccharides has been demonstrated in previous studies. However, the effect of chitin-rich heteroglycan extracted from Sporothrix schenckii sensu stricto on the immune response has not been investigated., Results: In this study, chitin-rich heteroglycan was extracted from S. schenckii sensu stricto, and immunomodulation was investigated via histopathological analysis of skin lesions in a mouse model of sporotrichosis and evaluation of the phagocytic function and cytokine secretion of macrophages in vitro. The results showed that the skin lesions regressed and granulomatous inflammation was reduced in infected mice within 5 weeks. Moreover, heteroglycan promoted the fungal phagocytosis by macrophages and modulated the cytokine secretion. Heteroglycan upregulated TNF-α expression early at 24 h and IL-12 expression late at 72 h after incubation, which might result from moderate activation of macrophages and contribute to the subsequent adaptive immune response., Conclusions: Chitin-rich heteroglycan extracted from S. schenckii sensu stricto potentiated fungal clearance in a mouse model of sporotrichosis. Moreover, chitin-rich heteroglycan promoted fungus phagocytosis by macrophages and modulated cytokines secretion. These results might indicate that chitin-rich heteroglycan could be considered as an immunomodulator used in the treatment of sporotrichosis.

Background: Taurochenodeoxycholic acid (TCDCA) is one of the major active components in bile acid. It was proven to have inhibitory activities on inflammation and also participate in host immuno-regulation. TCDCA exerts anti-inflammatory and immuno-regulatory effects through the glucocorticoid receptor (GR) mediated genomic signaling pathway and the G protein-coupled bile acid receptor 5 (TGR5) mediated AC-cAMP-PKA signaling pathway. However, it is unclear whether GR or TGR5 plays an important role in the regulatory effects of TCDCA. In order to further investigate this effects mechanism of TCDCA, the research use the transcriptome to identify the major genes and pathway in the anti-inflammatory and immuno-regulatory effects., Methods: After the Fibroblast-like synoviocytes (FLS) being treated by different concentrations (10 - 5 , 10 - 6 and 10 - 7  M) of TCDCA for 12 h, the resulting mRNA was analyzed by RNA-seq. The differentially expressed genes were screened from sequencing results using bioinformatics techniques. In the next step, other published literature were referred in order to find out whether those genes mentioned above are related to inflammation. The final selected differentially expressed genes associated with inflammation were then validated by q-PCR and western blot assays., Results: Five genes associated with anti-inflammatory and immuno-regulatory effects, include Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Glutathione peroxidase 3 (GPX3), Serine/arginine-rich splicing factor-9 (SRSF9), Connective tissue growth factor (CTGF) and Cystatin B (CSTB) were identified. TCDCA at the concentrations of 10 - 5 , 10 - 6 and 10 - 7  M significantly (p < 0.05) up-regulate the mRNA and protein expression of SRSF9 and GPX3 and also up-regulate the mRNA expression of CSTB, CTGF and GAPDH. RNA-seq results of GPX3 and SRSF9 expression were consistent with q-PCR results, while q-PCR results of CTGF, GAPDH showed inconsistent with their RNA-seq results. Q-PCR result of CSTB expression also showed inconsistent with the RNA-seq result., Conclusions: The anti-inflammatory and immuno-regulatory activities of TCDCA are proven to be related to the up-regulation expression of GPX3, SRSF9 and CSTB.