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In our research, a novel polysaccharide (named SSP-3a) with uniform molecular weight was extracted from Scutellaria baicalensis stem-leaf. The structural analysis revealed that SSP-3a was an acidic polysaccharide with a heavy average molecular weight of 1.83 × 10 5  Da. By HPLC, the primary constituents of SSP-3a were mannose (11.60 %), glucuronic acid (42.99 %), glucose (23.43 %), and xylose (22.04 %). According to FT-IR and 1 H NMR analysis, it was confirmed to be a β-configuration pyranose with a CO stretching vibrational peak. The immunomodulation results also showed that SSP-3a not only significantly promoted RAW264.7 cell proliferation and phagocytosis, but also stimulated the release of NO and cytokines. Furthermore, mechanistic studies suggested that SSP-3a had the ability to trigger MAPKs and NF-κB immunological signaling pathways via TLR4 receptors. The findings suggested that SSP-3a might be a beneficial active component for the food and pharmaceutical industries., Competing Interests: Declaration of competing interest The authors state that they have no known conflicting financial interests or personal ties that might have influenced the work presented in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ficus carica (F. carica), commonly referred to as the fig tree, has received considerable attention due to its delectable and nutritious fruits. F. carica polysaccharides (FPs) are one of the key bioactive constituents of F. carica, demonstrating various biological activities such as antioxidative, immunomodulatory, anti-inflammatory, and antitumor effects, among others. Nevertheless, the extraction and purification techniques for FPs still require innovations to address their structural characteristics in order to elucidate the intricate mechanisms affecting their biological activities. Given this, the current review systematically summarizes the recent advancements in FPs, covering extraction, purification, structural characteristics, bioactivities, structure-activity relationships (SARs), current applications, challenges and future prospects. The composition of FPs predominantly includes Glu, Gal, and Rha, with a broad molecular weight distribution (ranging from 21.9 kDa to 6890 kDa). The SARs analysis suggests that the bioactivities of FPs are closely linked to their monosaccharide composition, molecular weight, uronic acid content, and configuration characteristics, underscoring the significant role of FPs in driving the development of novel bioactive compounds in the health, food, and medical sectors. In conclusion, this review would contribute the valuable research insights and provide the updated information to foster the advancement of FPs for diverse therapeutic and industrial applications., Competing Interests: Declaration of competing interest The authors declared that there were no competing financial interests or personal relationships., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mycelium polysaccharide (MPP) from Monascus pilosus with the compositions of glucose, galactose, mannose, glucosamine hydrochloride, rhamnose and arabinose, was obtained using alkaline extracting, and subsequently three purified components (MPP-0, MPP-0.1 and MPP-0.3) were separated. The purity and extraction volume of the MPP-0.1 fraction surpassed those of the other two groups, thus warranting its selection for subsequent experimental investigations. The sample MPP-0.1, with an average molecular weight of 3.7776 × 10 4  Da, exhibited exceptional thermal stability up to 170 °C. The main glycosidic linkage pattern of MPP-0.1 was structured as→[4)-α-D-Glcp-(1] 6  → 4)-α-D-Glcp-(1 → [2)-α-D-Manp-(1] 5  → 2)-α-D-Manp-(1 → 5)-β-D-Galf-(1 → 3)-β-D-Galf (1 → 3)-β-D-Galf-(1 → 3)-β-D-Galf-(1→, and branched Glcp, Manp, Galf fragments were connected with the main chain through →4, 6)-α-D-Glcp-(1→, →2, 6)-α-D-Manp-(1 → and →3, 6)-β-D-Galf-(1→. Besides, the up-regulated levels of Nitric oxide (NO), Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and other pro-inflammatory cytokines along with increased phagocytic activity revealed that MPP-0.1 has significant immunomodulatory effect, and can significantly enhance the proliferation and activation of RAW264.7 cells. Finally, the gene UGE (UDP-glucose 4-epimerase) was overexpressed in M. pilosus to increase the MPP production. Results showed that the biomass of the recombinant strain exhibited a remarkable increase of approximately 62.56 ± 1.50 % compared to that of the parental strain, and the extraction yield of MPP increased significantly by 83.19 ± 4.56 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fu brick tea (FBT), a post-fermented dark tea, is highly esteemed for its abundant nutritional and medicinal values. Fu brick polysaccharides (FBTPs) are acidic heteropolysaccharides primarily composed of galactose and galacturonic acid, which are crucial components of FBT. FBTPs exhibit multiple bioactivities, including immunomodulatory, antioxidant, anti-inflammatory, regulatory effects on intestinal microbiota, anti-obesity, among others. Owing to their significant marketing potential and promising development prospects, FBTPs have attracted considerable attention from researchers worldwide. However, the specific mechanisms and underlying structure-function relationships of FBTPs are not well understood. Consequently, this review aims to provide comprehensive and cutting-edge information on the extraction, purification, structural characteristics, and biological activities of FBTPs, with an emphasis on exploring how their structural characteristics influence biological activities and therapeutic potential. We found that different materials and extraction techniques could result in differences in the structure-activity relationship of FBTPs. Furthermore, monosaccharide composition and molecular weight could also significantly impact the bioactivities of FBTPs, such as lipid-lowering effects and immunomodulatory activity. This review would further facilitate the applications of FBTPs as therapeutic agents and functional foods, thereby laying a solid foundation for their further development and utilization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Under the guidance of MS/MS-based molecular networking, five new clerodane diterpenoid glucosides, tinosinesides R-V (1-5), along with 15 known diterpenoids (6-20), were isolated from the stems of Tinospora sinensis. Compound 1 represents the first example of diterpenoid bearing a thio sugar and compound 5 is the first 18,19-dinor-clerodane with cis-fused A/B ring. The structures of the new compounds were elucidated by spectroscopic means, and their absolute configurations were established on the basis of time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculation and chemical methods. Selected compounds were evaluated for their immunomodulatory effect and several compounds could enhance the proliferation of B lymphocytes. Preliminary mechanistic studies disclosed that 3 could promote B cell generation and inhibit B cell differentiation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Saussurea laniceps is a traditional medicinal herb. In our previous study, a pectin polysaccharide, SLP-4, was isolated from the petals of S. laniceps. In this study, the immunomodulatory activity of SLP-4 was studied by analyzing its effects on macrophage (RAW 264.7 cells) polarization. The immunomodulatory activity assays indicated that SLP-4 could significantly enhance the pinocytic and phagocytic capacity and promote the expression and secretion of cytotoxic molecules (nitric oxide, increased by 6.4 times when the SLP-4 concentration was 800 μg/mL) and cytokines (tumor necrosis factor-α and interleukin-6 increased by 7.7 and 11.9 times, respectively) in original macrophage. The possible mechanism could be attributed to the activation of the mitogen-activated protein kinase and nuclear factor-κB signaling pathways through Toll-like receptors 2 and 4. Moreover, SLP-4 significantly induced M1 polarization of original macrophages and transferred macrophages from M2 to M1, but had little effect on the conversion of M1 macrophages into M2 phenotype. Overall, these results demonstrate the potential of SLP-4 as an attractive immunomodulating functional supplement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Autoimmune diseases (AIDs) affect 5 to 10% of the population. There are more than ∼100 different autoimmune diseases. The AIDs are one of the top 10 causes of death in women under 65; 2nd highest cause of chronic illness; top cause of morbidity in women in the US. The NIH estimates annual direct healthcare costs for autoimmune diseases about $100 billion, in comparison, with cancers investment of $57 billion, heart and stroke cost of $200 billion. The current treatments for autoimmune diseases encompasses: steroids, chemotherapy, immunosuppressants, biological drugs, disease specific drugs (like acethylcholine-estherase for myasthenia gravis). The treatments for autooimmune diseases supress the patient immune network, which leads the patients to be more susceptible to infections. Hence, there is a need to develop immunomodulatory small molecules with minimal side effects to treat autoimmune diseases. The helminths developed secreting compounds which modulate the human defense pathways in order to develop tolerance and survive in the host environment. We have imitated the immunomodulatory activity of the helminth by using a derivative of the helminth secretory molecule. A bi-functional small molecule -tuftsin (T)-phosphorylcholine (PC), coined as TPC, was constructed. This chimeric molecule showed its immunomodulatory activity in 4 murine models of autoimmune diseases, attenuating the clinical score and the inflammatory response by immunomodutating the host immune system. Ex-vivo in human peripheral blood mononuclear cells (PBMCs) and biopsies originated from arteries of patients with giant cell arteritis. This paper decipher the mode of action of TPC immunomodulatory activity. Our data propose the potential for this small molecule to be a novel therapy for patients with autoimmune diseases., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Lactarius deliciosus, a widely appreciated mushroom with delightful tastes and texture, has exhibited immunomodulatory activity in vitro, while the effects on intestinal flora metabolisms in vivo are ambiguous. In this study, a L. deliciosus polysaccharide (LDP) was extracted and purified, and the structural characteristics were evaluated, as well as the immunological enhancement on tumor-bearing mice through regulating intestinal flora metabolisms. Results showed that LDP was a heteropolysaccharide (average molecular weight of 1.44 × 10 7  Da) with a backbone of α-(1 → 6)-Manp and branches of α-(1 → 6)-Galp, α-(1 → 3)-Fucp, α-(1 → 6)-Glcp, α-(1 → 4)-Glcp. Animal experiments indicated that LDP could significantly protect immune organs of tumor-beraing mice and suppress solid tumors growth with inhibitory rate of 51.61 % (high-dose, 100 mg/kg), and improve the intestinal lactobacillus contents, promote adenine mediated zeatin biosynthesis, then competitively antagonize A2A receptor and enhance the activities of CD4 + T cells and CD8 + T cells, finally effectively facilitate the apoptosis and elimination of tumor cells. These results would provide powerful data supports for the further antitumor mechanisms development and practical applications of L. deliciosus polysaccharide in food and drug industries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study investigated the impact of high-intensity ultrasound (HIU) treatment on the physiochemical, conformational, and immunomodulatory activity of the OVT-CA complex, emphasizing the structure-function relationship. HIU treatment reduced particle size, improved dispersion, and increased electronegativity of the complex. It facilitated binding between OVT and CA, achieving a maximum degree of 45.22 mg/g CA grafting and reducing interaction time from 2 h to 15 min. HIU-induced cavitation and shear promoted the exposure of -SH and unfolding of OVT, leading to increased surface hydrophobicity of the complex and transformation of its structure from β-sheet to α-helix. Additionally, CA binds to OVT in the C-lobe region, and HIU treatment modulates the intermolecular forces governing the complex formation, particularly by reinforcing hydrogen bonding, hydrophobic interactions, and introducing electrostatic interactions. Furthermore, HIU treatment increased the immunomodulatory activity of the complex, which was attributed to complex structural changes facilitating enhanced cell membrane affinity, antigen recognition, and B-cell epitope availability. Hierarchical cluster and Pearson correlation analysis confirmed that HIU treatment duration had a greater impact than power on both the structure and activity of the complex, and an optimal HIU treatment duration within 30 min was found to be crucial for activity enhancement. Moreover, structural changes, including ζ-potential, particle size/turbidity, and surface hydrophobicity, were closely correlated with immunomodulatory activity. This study highlights the potential application of HIU in developing protein-polyphenol immunomodulatory agents for public health and food nutrition., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, the immunomodulatory efficacy of Dendrobium officinale leaf polysaccharide (DOLP) has attracted much attention, but its potential immunomodulatory mechanism remains unclear. Therefore, we investigated the molecular mechanism of DOLP to ameliorate cyclophosphamide-induced immunosuppressed mice based on transcriptome profiling technology. The results indicated that DOLP significantly mitigated damage to immune organs, regulated the expression levels of inflammatory factors and immunoglobulins, and restored the balance of gut microbiota. Furthermore, it modulated metabolic pathways associated with the immune system, including antigen processing and presentation, hematopoietic cell line development, and natural killer cell-mediated cytotoxicity. DOLP might promote host hematopoietic function to enhance immune cell proliferation and differentiation by up-regulating Cd19, Cr2 and Il7r but down-regulating Dntt. DOLP also up-regulated the expression of MHC-1 (Gm11127, H2-K1, H2-Q10, H2-Q6, and H2-Q7), thus promoting antigen recognition by NK cells to enhance the innate immunity and helping T cells to deliver antigen and secrete immune factors so that enhancing the adaptive immunity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Herbal polysaccharides are extensively studied as vaccine adjuvants due to their safety and potent immunoenhancing activity. This study aimed to analyze the structure of Lagenaria siceraria (Molina) Standl polysaccharide (LSP50) and investigate its adjuvant activity for the H9N2 vaccine in broiler chickens. Structural analysis revealed that LSP50 primarily consisted of rhamnose, arabinose, xylose, mannose, glucose, and galactose with molar ratios of 23.12: 12.28: 10.87: 8.26: 2.64: 22.82 respectively. The adjuvant activity of LSP50 was evaluated, which showing significant enhancements compared to the H9N2 group. Parameters including the immune organ index, H9N2 specific IgG level, cytokines contents (IFN-γ, IL-2, IL-4, and IL-5), and the proportion of CD3e + CD8aT + cells were significantly increased in the LSP50 group (P < 0.05). Additionally, sequencing results showed that LSP50 modulates the immune response by regulating PLA2G12B and PTGDS genes involved in the arachidonic acid pathway. These findings were further validated through qPCR analysis to affirm the reliability of the sequencing data. In conclusion, our results demonstrate that LSP50 exhibits potent adjuvant activity, enhancing both cellular and humoral immunity., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunomodulatory therapies are beneficial strategies for the improvement of immune system function. Today, due to the increasing prevalence of immune disorders, cancer, and new viral diseases, there is a greater need to introduce immunomodulatory compounds with more efficiency and fewer side effects. Microbial derivatives are fertile and attractive grounds for discovering lots of novel compounds with various medical properties. The discovery of many natural compounds derived from bacterial sources, such as secondary metabolites with promising immunomodulating activities, represents the importance of this topic in drug discovery and emphasizes the necessity for a coherent source of study in this area. Considering this need, in this review, we aim to focus on the current information about the immunomodulatory effects of bacterial secondary metabolites and natural immunomodulators derived from microorganisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to optimize the extraction of Hericium erinaceus polysaccharides (HEP) using ultrasound-assisted enzymatic extraction combined with Plackett-Burman design (PBD) and response surface methodology (RSM). The optimal extraction conditions were identified as: 33 min extraction time, 30:1 liquid to material ratio, 38 °C extraction temperature, 9 g/kg cellulase amount, pH 4, and 20 % ethanol concentration. Under these conditions, the extraction yield of HEP was 5.87 ± 0.16 %, consistent with the predicted results. Additionally, the potential immunomodulatory activity of HEP on RAW 264.7 macrophage was evaluated. The results revealed that HEP improved the immunostimulatory activity of RAW264.7 cells, evident from increased production of IL-6 and TNF-α. These findings suggest that HEP is capable of enhancing the immune activity of RAW 264.7 macrophage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

sCAP was obtained by the nitrate‑sodium selenite method. SEM, molecular weight evaluation, monosaccharide composition, FT-IR and NMR of sCAP were carried out. Compared with CAP, sCAP had a relatively smooth and lamellar sheet morphology with edge folds on the surface, presented molecular weights in range of 0.90-97.08 KDa, and was mainly composed of GalA, Ara and Gal. sCAP had both α and β configurations of the pyranose ring, the characteristic vibrational peak of Se-O-C and the signal of galacturonic acid residue. The phagocytic activity of immature BMDCs, the expression of CD40, CD80, CD86, and MHCII on BMDCs were detected by flow cytometry, the ability of sCAP-treated BMDCs to stimulate the proliferation of allogeneic lymphocytes, presentation of antigens, cytokines in the supernatants and the protein in MyD88/NF-κB signaling pathway were detected. The results showed that the phagocytic activity of immature BMDCs was significantly enhanced when sCAP was at 3.92-1.96 μg·mL -1 . The levels of IL-6, TGF-β1, INF-γ, and TNF-α were significantly elevated, IL-1β and MIP-1α were significantly reduced. These results indicate that sCAP could be as a new immunopotentiator by increasing MyD88/NF-κB signaling pathway. This study provides a reference for the research and development of new dosage forms of polysaccharide., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

A new polysaccharide, named SP40015A01, was obtained from Saposhnikoviae Radix by water extraction, isolation and purification. SP40015A01 (9.7 × 10 5  Da) is composed of Rhamnose (Rha), Galacturonic acid (GalA), Galactose (Gal), and Arabinose (Ara) with the proportion of 1.6:85.6:5.8:7.6. The backbone of SP40015A01 is composed of 3-α-GalAp, 2-α-GalAp, 2,3-β-GalAp and 2,3-β-Galp, and branched at C3 of 2,3-β-GalAp, C3 of 2,3-β-Galp. Zebrafish experiments were used to explore the immunomodulatory activity of SP40015A01. Results showed that SP40015A01 could significantly improve the neutrophils density of immunocompromised zebrafish and reduce the content of nitric oxide (NO) and interleukin-1β (IL-1β). This study demonstrated that SP40015A01 has significant immunomodulatory activity, which can improve the neutrophils density and reduce inflammatory factor content, suggesting SP40015A01 may be a potential immunomodulator in Saposhnikoviae Radix (SR) for treatment of hypoimmunity related disease. This study supplemented the research on the polysaccharide components in traditional Chinese medicine and provided a scientific explanation for the development and clinical applications of SR., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LIU BIN reports financial support was provided by National Natural Science Foundation of China (82074283). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Fungi-derived exosome-like nanovesicles (ENs) are emerging as a highly promising class of nanoparticles, particularly noted for their cost-effective production. However, their impact on immune regulation and their potential as anti-tumor agents need further exploration. Our study specifically focused on the investigation of the immunomodulatory and anti-tumor properties of ENs derived from Cordyceps militaris, an edible fungus that had achieved large-scale commercial production, referred to as CMDENs., Main Methods: The ENs of C. militaris were collected through ultra-high-speed centrifugation, followed by characterization of their physicochemical properties and contents. Subsequently, the biological distribution of these vesicles was investigated using in vivo fluorescence imaging experiments. Finally, the immune activation and polarization of macrophages were examined through both in vitro and in vivo experiments., Key Findings: Herein, we presented the discovery of CMDENs that were rich in proteins, lipids, flavonoids and alkaloids. Immunomodulatory experiments conducted in vivo demonstrated that CMDENs exhibited protective effects against cyclophosphamide-induced immunosuppression in mice by significantly enhancing macrophage phagocytosis and peripheral blood immune cell counts. Moreover, CMDENs effectively induced the polarization of M0- and M2-like macrophages toward M1-like phenotype by activating MAPKs signaling pathway. Notably, CMDENs exhibited remarkable capabilities in inhibiting tumor growth by reprogramming tumor-associated macrophages and activating tumor-infiltrating T lymphocytes, without any observed toxicity in mice bearing tumors., Significance: Our research suggested that CMDENs possessed the potential to be explored as a nano-immunomodulatory agent for cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Eubiotics are water and/or feed additives used in poultry to promote gut health and control enteric burden of pathogens, including Clostridium perfringens. While several eubiotic compounds (ECs) are being introduced commercially, it is essential to devise an in vitro model to screen these compounds to assess their immunomodulatory and antimicrobial properties prior to their testing in vivo. A chicken macrophage cell-line (MQ-NCSU) was used to develop an in vitro model to screen the immunological and anti-C. perfringens properties of 10 ECs: monobutyrin, monolaurin, calcium butyrate, tributyrin, carvacrol, curcumin, green tea extract, rosemary extract, monomyristate, and tartaric acid. An optimal concentration for each EC was selected by measuring the effect on viability of MQ-NCSU cells. Cells were then treated with ECs for 6, 12, and 24 h. and expression of interferon-gamma (IFNγ), interleukin (IL)-1β, IL-6, IL-10, transforming growth factor-beta (TGFβ) and cluster of differentiation (CD40) genes, as well as major histocompatibility complex (MHC)-II protein were evaluated. At 6 h post-stimulation, monobutyrin, calcium butyrate, and green tea extract treatments induced a significant downregulation of IFNγ, IL-6, or IL-1β gene transcription and MHC-II expression, while the IL-10 or TGFβ gene expression in these treatments as well as those receiving rosemary extract and tartaric acid was significantly upregulated, when compared to control, suggesting immunomodulatory properties of these ECs. Finally, pretreatment of macrophages with these selected 5 ECs for 24 h followed by C. perfringens infection showed that monobutyrin, green tea extract, rosemary extract, and calcium butyrate treatments can inhibit bacterial growth significantly at 12 and/or 24 h post-infection, when compared to the control. Collectively, our findings show that ECs possessing immunomodulatory and anti-C. perfringens properties can be selected using an in vitro avian macrophage cell-based model so that such ECs can further be tested in vivo for their disease prevention efficacy., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Vaccine adjuvants, such as liposome-based cationic adjuvant formulations (CAFs), are able to boost immune responses and, by incorporation of distinct immunomodulators, steer immunity towards a desired direction in mice, non-human primates and humans, while less studied in pigs. Here we used commercial pigs to investigate polarizing adjuvant effects of CAFs with immunomodulators: C-type lectin receptor ligands trehalose-6,6'-dibehenate and monomycolyl glycerol, toll-like receptor 3 ligand Poly(I:C) or retinoic acid. Vaccines were formulated with a recombinant Chlamydia model protein antigen and administered via three injection routes. All adjuvants significantly increased antigen-specific IgG in serum, compared to non-adjuvanted antigen. Administering the vaccines through intramuscular and intraperitoneal routes induced significantly higher antigen-specific IgG and IgA serum antibodies, than the perirectal route. Although immunizations triggered cell-mediated immunity, no significant differences between adjuvants or injection sites were detected. Genes depicting T cell subtypes revealed only minor differences. Our findings suggest that specific signatures of the tested adjuvant immunomodulation do not translate well from mice to pigs in standard two-dose immunizations. This study provides new insights into immune responses to CAFs in pigs, and highlights that adjuvant development should ideally be carried out in the intended species of interest or in models with high predictive validity/translational value., Competing Interests: Declaration of competing interest EŠ, GE, JTJ, GJ and GKP are employed by Statens Serum Institut, which is a non-profit government research facility, holding patents on the cationic adjuvant formulations (CAF®)., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Traditional medicinal plants have been used for centuries for their immunomodulatory properties and therapeutic potentials. The present study aims to investigate the immunomodulatory constituents from traditional medicinal plant, Tinospora cordifolia (willd.). Our study resulted in the isolation of new compound, 27-hydroxy octacosyl ferulate (1) along with eleven known compounds (2-12). The structures of the isolated compounds were characterized by combination of NMR (1D and 2D) and Mass spectroscopic methods. The hemisynthesis of compound 12 (ferulic acid) yielded (12a-12d and 12e-12 m) derivatives. Further, the isolated compounds and synthesized derivatives were assessed for their immunomodulatory potentials by evaluating their cytotoxicity and pro-inflammatory effects against macrophage cells (IL-6) and DC activation markers (CD 11c and 86). The biological results indicated that crude extract displayed potent immunomodulatory activity while isolated compounds and synthetic analogues showed moderate activity. Among the tested compounds, new compound (1), quercetin (10) and derivatives 12b, 12c found to be non-cytotoxic and displayed immunomodulatory potentials. Therefore, these compounds can be studied for autoimmunity and other immune suppressing conditions., Competing Interests: Declaration of competing interest Authors declare that no conflict of interest for this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The crude polysaccharide of Bletilla striata in this study was extracted by water extraction and alcohol precipitation and further purified by gel column to yield the purified component Bletilla striata polysaccharide (BSP). Its structure and innate immune regulation activity were studied. BSP mainly comprises mannose and glucose, with a monosaccharide molar ratio of 2.9:1 and a weight-average molecular weight of 28,365 Da. It is a new low-molecular-weight water-soluble neutral glucomannan. BSP contains a → 6)-β-Manp-(1→, →4)-β-Glcp-(1→, →4)-β-Manp-(1 → and →3)-α-Manp-(1 → linear main chain, containing β-Glcp-(1 → and β-Manp-(1 → two branched chain fragments were connected to the Man residue at position 4. BSP can enhance the anti-infection ability of Caenorhabditis elegans against Pseudomonas aeruginosa, significantly improve the phagocytic ability of RAW264.7 macrophages, stimulate the secretion of NO and TNF-α, and have good innate immune regulation activity. These findings guide the use of Bletilla striata polysaccharides with immunomodulatory action., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fungal polysaccharides have been explored by many for both structural studies and biological activities, but few studies have been done on the extracellular polysaccharides of Dictyophora rubrovalvata, so a new exopolysaccharide was isolated from Dictyophora rubrovalvata and its structure and its immunological activity were investigated. The crude exopolysaccharide (EPS) was purified by DEAE52 cellulose and Sephadex G-200 to obtain a new acidic polysaccharide (DR-EPS). DR-EPS (2.66 × 10 3  kDa) was consisted mainly of mannose, glucose, galactose and glucuronic acid with a molar ratio of 1: 0.86: 0.20: 0.01. In addition, DR-EPS increased the phagocytic activity of RAW264.7 cells up to 2.67 times of the blank control group. DR-EPS improved intracellular nucleic acid and glycogen metabolism as observed by AO and PAS staining. DR-EPS(40 μg/mL) promoted NO production up to 30.66 μmol, enhanced acid phosphatase (ACP) and superoxide dismutase (SOD) activities, with activity maxima of 660 U/gprot and 96.27 U/mgprot, respectively, and DR-EPS (160 μg / mL) significantly increased the lysozyme content as 2.73 times of the control group. The good immunological activity of extracellular polysaccharides of Dictyophora rubrovalvata provides directions for the use of fermentation broths., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To alleviate the adverse effects of chemotherapy and bolster immune function, a novel polysaccharide derived from Sargassum fusiforme named as SFP-αII. The structural composition of SFP-αII predominantly consisted of guluronic and mannuronic acids in a molar ratio of 33.8:66.2, with an average molecular weight of 16.5 kDa. Its structure was primarily characterized by →4)-α-GulA-(1 → and →4)-β-ManA-(1 → linkages confirmed by FT-IR, methylation, and NMR analyses. The absence of a triple-helix structure was in SFP-αII was confirmed using circular dichroism and Congo red dye assays. The dimensions varied with lengths ranging from 20 nm up to 3 μm revealed by atomic force microscopy (AFM). SFP-αII has been found to enhance immunomodulatory activity in cyclophosphamide (CTX)-induced immunosuppressed mice. This was evidenced by improvements in immune organ indices, cytokine levels, and the release of nitric oxide (NO). Specifically, SFP-αII mitigated immunosuppression by upregulating the secretion of IL-1β (167.3 %) and TNF-α (227.1 %) at a dose of 400 mg/kg, compared with the CTX group in macrophages. Ultimately, SFP-αII may serve as a mechanism for immune enhancement through modulation of TLR4-mediated NF-κB and MAPK signaling pathways. This integration of traditional Chinese and Western medicine, leveraging SFP-αII as a potential functional food could be pivotal in alleviating immunosuppressive side effects in CTX treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent research has demonstrated the immunomodulatory potential of Panax notoginseng in the treatment of chronic inflammatory diseases and cerebral hemorrhage, suggesting its significance in clinical practice. Nevertheless, the complex immune activity of various components has hindered a comprehensive understanding of the immune-regulating properties of Panax notoginseng, impeding its broader utilization. This review evaluates the effect of Panax notoginseng to various types of white blood cells, elucidates the underlying mechanisms, and compares the immunomodulatory effects of different Panax notoginseng active fractions, aiming to provide the theory basis for future immunomodulatory investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases., (Copyright © 2021. Published by Elsevier B.V.)

The platinum drugs belong to prevailing chemotherapeutics used in the treatment of cancer. At present, however, the search for new anticancer metal-based drugs that operate by the mechanisms distinct from those of the conventional chemotherapeutics is very active. Furthermore, it has been demonstrated that cytotoxic chemotherapy and immunotherapy may exert a highly synergistic anticancer activity. Thus, the development of antitumor platinum and other metal-based drugs that exhibit cytostatic effects and concurrently elicit immunogenic cell death (ICD) has shown promise for cancer treatment. Notably, conventional platinum drug oxaliplatin ([Pt(1R,2R-DACH)(oxalate)], DACH = diaminocyclohexane) is a well-known agent that displays both cytostatic and immune responses. Moreover, it was also demonstrated that even minor derivatization of the unleaving cycloalkyl moiety in oxaliplatin might have a pronounced effect on its immunomodulatory activity. Here, we investigated how replacing the 1R,2R- diaminocyclohexane ring by 1,3-diaminocycloalkane (alkane = butane, pentane, or hexane) affects the ability to evoke secretion of damage-associated molecular patterns characteristic of ICD in model murine colorectal carcinoma cell line CT26. The results indicate that among the investigated [Pt(cis-1,3-diaminocycloalkane)Cl 2 ] complexes, the complex containing the cyclobutyl moiety exhibits the hallmarks typical of ICD inducers. Thus, [Pt(cis-1,3-diaminocyclobutane)Cl 2 ] may expand the spectrum of anticancer chemotherapeutics capable of inducing ICD in cancer cells and might be of interest for further (pre)clinical development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Lactarius volemus Fr. is an edible mushroom widely consumed in China. Polysaccharide is an important nutritional component of L. volemus. This research aimed to isolate the polysaccharide from L. volemus and study its structure and bioactivities. A purified polysaccharide was identified and named as LVF-I whose primary structure was proposed considering the comprehensive results of monosaccharide composition, periodate oxidation-smith degradation, methylation analysis, FT-IR and 1D/2D NMR spectroscopy. Then the immunomodulation of LVF-I and its inhibition effect on H1299 and MCF-7 cells were investigated. Results showed that LVF-I (12,894 Da) contained fucose, mannose, glucose and galactose. It had a backbone consisting of →4)-α-D-Glcp-(1→, →6)-β-D-Manp-(1→, →6)-α-D-Galp-(1 → and →4)-β-D-Manp-(1→. And its side chains were branched at C2 of →4)-β-D-Manp-(1 → by →6)-α-D-Galp-(1→, α-D-Glcp-(1→, α-D-Galp-(1 → and α-L-Fucp-(1→. LVF-I (250-1000 μg/mL) could inhibit the proliferation of H1299 and MCF-7 cells, while enhance the proliferative response of splenocyte and the phagocytic ability of RAW264.7. Furthermore, LVF-I (250-1000 μg/mL) significantly induced the secretion of nitric oxide, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) by up-regulating their mRNA expression in macrophages. These results suggested that LVF-I had the potential to be developed as antitumor or immunomodulatory agents by inhibiting the proliferation of tumor cells and stimulating macrophages-mediated immune responses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there's no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The in vitro and in vivo immunoregulatory activity of a water-soluble sulfated fucan AL1-1 from the sea cucumber A. leucoprocta was elucidated. In vitro experiments showed that AL1-1 up-regulated immunostimulatory activities in RAW264.7 cells and that it could successfully promote ROS production and phagocytic activity, increase secretion levels of iNOS, and induce the production of considerable amounts of cytokines (TNF-α, IL-6, IL-1β and IL-12). We found that toll-like receptor 4 (TLR4) was mainly involved in AL1-1 mediated macrophage activation. AL1-1's in vivo immunomodulatory activity on cyclophosphamide (CY)-treated mice was investigated and it was shown that it could strongly enhance Sig A levels, promote the total antioxidant capacity (T-AOC), and reduce malondialdehyde (MDA) level in the intestine. It could also increase activities of superoxidase dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). These results demonstrate that AL1-1 has a significant effect on enhancing in vivo and in vitro immune response., (Copyright © 2021. Published by Elsevier B.V.)

The aim of this study was to explore the indirect immunomodulatory activities and its mechanism of enzymatic hydrolysis of Hericium erinaceus polysaccharides (EHEP) in the MODE-K/DCs co-culture model. According to the TEER value, transmission of phenol red and AKP activity of MODE-K cells, single model was established in order to evaluate the eligibility of MODE-K cells monolayer. Then the MODE-K/DCs co-culture model was set up and HEP and EHEP were added into the apical chamber, DCs were obtained for the expression of key surface markers, the ability of phagocytosis, the morphology, the secretion of cytokines and the production of target proteins. We found that after 21 d of culture, the MODE-K cells monolayer became intact and dense, which can be used for the MODE-K/DCs co-culture model. Under the treatment of HEP and EHEP, immature DCs become into mature DCs with the high expression of CD86 and MHCII, the low antigens up-taking, the typical morphology, the more content of IL-12 and TNF-α and the high level of TLR4, MyD88 and NF-κB proteins. However, compared with HEP, EHEP showed the better immunomodulatory activities. These findings indicated that EHEP could indirectly affect the immune function of DCs in the MODE-K/DCs co-culture model., (Copyright © 2021. Published by Elsevier B.V.)

Ganoderma lucidum (G. lucidum) polysaccharides and triterpenoids are the major bioactive compounds and have been used as traditional medicine for ancient times. Massive demands of G. lucidum have fascinated the researchers towards its application as functional food, nutraceutical and modern medicine owing to wide range of application in various diseases include immunomodulators, anticancer, antiviral, antioxidant, cardioprotective, hepatoprotective. G. lucidum polysaccharides exhibit immunomodulatory properties through boosting the action of antigen-presenting cells, mononuclear phagocyte system, along with humoral and cellular immunity. β-Glucans isolated from G. lucidum are anticipated to produce an immune response through pathogen associated molecular patterns (PAMPs). β-Glucans after binding with dectin-1 receptor present on different cells include macrophages, monocytes, dendritic cells and neutrophils produce signal transduction that lead to trigger the mitogen-activated protein kinases (MAPKs), T cells and Nuclear factor-κB (NF-κB) that refer to cytokines production and contributing to immune response. While triterpenoids produce antiviral effects through inhibiting various enzymes like neuraminidase, HIV-protease, DENV2 NS2B-NS3 protease and HSV multiplication. Polysaccharides and triterpenoids adjunct to other drugs exhibit potential action in prevention and treatment of various diseases. Immunomodulators and antiviral properties of this mushroom could be a potential source to overcome this current pandemic outbreak., (Copyright © 2021. Published by Elsevier B.V.)

The structures and immunomodulatory activities of two polysaccharides (SDH-WA and SDH-0.2A) from Rehmanniae Radix Praeparata (RRP) were investigated. RRP crude polysaccharide was obtained by water extraction and purified. Ion chromatography, high-performance gel permeation chromatography, Fourier-transform infrared spectroscopy, methylation analysis, gas chromatography-mass spectrometry, and nuclear magnetic resonance were used to characterize the polysaccharides. The main chain of SDH-WA was →6)-α-D-Galp-(1→6)-α-D-Galp-(1→5)-α-L-Araf-(1→3,5)-α-L-Araf-(1→, terminal sugar residue α-L-Araf-(1→ linked to residue →3,5)-α-L-Araf-(1→ on the main chain by an O-3 bond. The other two terminal sugar residues α-D-Galp-(1→ and →6)-β-D-Galp were linked to the end of the main chain. The main chain of SDH-0.2A was →2,4)-α-L-Rhap-(1→4)-α-D-GalpA-(1→. Three branched chains α-D-Galp-(1→6)-α-D-Galp-(1→5)-α-L-Araf-(1→3,5)-α-L-Araf-(1→, →3,6)-β-D-Galp-(1→5)-α-L-Araf-(1→, and →4)-β-D-Galp-(1→5)-α-L-Araf-(1→ were linked to the main chain residue →2,4)-α-L-Rhap-(1→ by an O-2 bond. Three terminal sugar residues α-D-Galp-(1→, α-L-Araf-(1→, and →6)-β-D-Galp were linked to the end of the chain. Both polysaccharides showed no cytotoxic effects on and significantly promoted the phagocytic activity of RAW264.7 cells. They dose-dependently improved lysozyme activity and stimulated the production of TNF-α and IL-6 by RAW264.7 cells, but attenuated the secretion of lysozymes, TNF-α, IL-6, IL-1β, and nitric oxide by lipopolysaccharide-induced RAW264.7 cells. The present studies suggest that PRR polysaccharide is a valuable source with immunomodulating., (Copyright © 2021. Published by Elsevier B.V.)

Docosahexaenoyl ethanolamide (DHEA), the ethanolamine conjugate of the n-3 long chain polyunsaturated fatty acid docosahexaenoic acid, is endogenously present in the human circulation and in tissues. Its immunomodulating properties have been (partly) attributed to an interaction with the cyclooxygenase-2 (COX-2) enzyme. Recently, we discovered that COX-2 converts DHEA into two oxygenated metabolites, 13- and 16-hydroxylated-DHEA (13- and 16-HDHEA, respectively). It remained unclear whether these oxygenated metabolites also display immunomodulating properties like their parent DHEA. In the current study we investigated the immunomodulating properties of 13- and 16-HDHEA in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The compounds reduced production of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β and IL-1Ra, but did not affect nitric oxide (NO) and IL-6 release. Transcriptome analysis showed that the compounds inhibited the LPS-mediated induction of pro-inflammatory genes (InhbA, Ifit1) and suggested potential inhibition of regulators such as toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 3 (IRF3), whereas anti-inflammatory genes (SerpinB2) and potential regulators IL-10, sirtuin 1 (Sirt-1), fluticasone propionate were induced. Additionally, transcriptome analysis of 13-HDHEA suggests a potential anti-angiogenic role. In contrast to the known oxylipin-lowering effects of DHEA, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses revealed that 13- and 16-HDHEA did not affect oxylipin formation. Overall, the anti-inflammatory effects of 13-HDHEA and 16-HDHEA are less pronounced compared to their parent molecule DHEA. Therefore, we propose that COX-2 metabolism of DHEA acts as a regulatory mechanism to limit the anti-inflammatory properties of DHEA., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Chloroquine (CQ) and hydroxychloroquine (HCQ) are the most common drugs used to relieve acute and chronic inflammatory diseases. In this article, we present a review about the use of CQ and HCQ in antitumor therapies based on autophagy mechanisms. These molecules break/discontinue autophagosome-lysosome fusions in initial phases and enhance antiproliferative action of chemotherapeutics. Their sensitizing effects of chemotherapy when used as an adjuvant option in clinical trials against cancer. However, human related-MDR genes are also under risk to develop chemo or radioresistance because cancer cells have ability to throw 4-aminoquinolines out from digestive vacuoles well. Additionally, they also have antitumor mechanism unrelated to autophagy, including cell death from apoptosis and necroptosis and immunomodulatory/anti-inflammatory properties. However, the link between some anticancer mechanisms, clinical efficacy and pharmacological safety has not yet been fully defined., (Copyright © 2021 Elsevier Ltd. All rights reserved.)