Potent Immunomodulatory Activity Research Articles

Application of Antioxidant Compounds in Bone Defect Repair

Bone defects caused by trauma, tumor resection, and infections are significant clinical challenges. Excessive reactive oxygen species (ROS) usually accumulate in the defect area, which may impair the function of cells involved in bone formation, posing a serious challenge for bone repair. Due to the potent ROS scavenging ability, as well as potential anti-inflammatory and immunomodulatory activities, antioxidants play an indispensable role in the maintenance and protection of bone health and have gained increasing attention in recent years. This narrative review aims to give an overview of the main research directions on the application of antioxidant compounds in bone defect repair over the past decade. In addition, the positive effects of various antioxidants and their biomaterial delivery systems in bone repair are summarized to provide new insights for exploring antioxidant-based strategies for bone defect repair.

Pap12-6: A host defense peptide with potent immunomodulatory activity in a chicken hepatic cell culture.

In the fight against antimicrobial resistance, host defense peptides (HDPs) are increasingly referred to as promising molecules for the design of new antimicrobial agents. In terms of their future clinical use, particularly small, synthetic HDPs offer several advantages, based on which their application as feed additives has aroused great interest in the poultry sector. However, given their complex mechanism of action and the limited data about the cellular effects in production animals, their investigation is of great importance in these species. The present study aimed to examine the immunomodulatory activity of the synthetic HDP Pap12-6 (PAP) solely and in inflammatory environments evoked by lipoteichoic acid (LTA) and polyinosinic-polycytidylic acid (Poly I:C), in a primary chicken hepatocyte-non-parenchymal cell co-culture. Based on the investigation of the extracellular lactate dehydrogenase (LDH) activity, PAP seemed to exert no cytotoxicity on hepatic cells, suggesting its safe application. Moreover, PAP was able to influence the immune response, reflected by the decreased production of interleukin (IL)-6, IL-8, and "regulated on activation, normal T cell expressed and secreted"(RANTES), as well as the reduced IL-6/IL-10 ratio in Poly I:C-induced inflammation. PAP also diminished the levels of extracellular H2O2 and nuclear factor erythroid 2-related factor 2 (Nrf2) when applied together with Poly I:C and in both inflammatory conditions, respectively. Consequently, PAP appeared to display potent immunomodulatory activity, preferring to act towards the cellular anti-inflammatory and antioxidant processes. These findings confirm that PAP might be a promising alternative for designing novel antimicrobial immunomodulatory agents for chickens, thereby contributing to the reduction of the use of conventional antibiotics.

Thymoquinone: An Effective Natural Compound for Kidney Protection.

Kidney disease is a common health problem worldwide. Acute or chronic injuries may interfere with kidney functions, eventually resulting in irreversible kidney damage. A number of recent studies have shown that the plant-derived natural products have an extensive potential for renal protection. Thymoquinone (TQ) is an essential compound derived from Nigella Sativa (NS), which is widely applied in the Middle East as a folk medicine. Previous experiments have demonstrated that TQ has a variety of potential pharmacological effects, including anti-oxidant, antibacterial, antitumor, immunomodulatory, and neuroprotective activities. In particular, the prominent renal protective efficacy of TQ has been demonstrated in both in vivo and in vitro experiments. TQ can prevent acute kidney injuries from various xenobiotics through anti-oxidation, anti-inflammatory, and anti-apoptosis effects. In addition, TQ exhibited significant pharmacological effects on renal cell carcinoma, renal fibrosis, and urinary calculi. The essential mechanisms involve scavenging ROS and increasing anti-oxidant activity, decreasing inflammatory mediators, inducing apoptosis, and inhibiting migration and invasion. The purpose of this review is to conclude the pharmacological effects and the potential mechanisms of TQ in renal protection, shedding new light on the exploration of medicinal phyto-protective agents targeting kidneys.

Bioactive constituents from Tinospora cordifolia (willd.): Isolation, synthesis and their immunomodulatory activity

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.

Molecular docking of gingerol and shogaol for immunomodulatory effect in lupus disease

Background: One of the autoimmune diseases associated with high mortality is lupus or Systemic Lupus Erythematosus (SLE). In addition to symptomatic therapy, the treatment management of this condition includes immunomodulatory therapy. Various studies have been carried out on immunomodulators from natural products. Ginger rhizome (Zingiber officinale Roxb.) is a plant with potential immunomodulatory activity. Shogaol, which gives a spicy taste, is a metabolite of gingerol, a marker compound in ginger. Both of these compounds become important components of pharmacological activity. Objective: This study aimed to determine the in silico immunomodulatory activity of gingerol and shogaol compounds contained in ginger against S100A9, CTLA-4, SRSF1, JAK3, and MYD88 receptors. Method: In silico, a test was carried out using Pymol and PyRx applications, and receptors were involved in developing the immune system and SLE disease. Result: Docking results showed negative binding affinity and an RMSD of 2˚Angstroms. The shogaol, gingerol, and tofacitinib had several amino acid residues in common. Conclusion: In-silico analysis suggests that shogaol and gingerol could modulate the immune response against lupus. The resulting protein residues were similar between shogaol, gingerol, and the control, supporting their potential for immunomodulatory activity against lupus disease.

PD-L1 targeted peptide demonstrates potent antitumor and immunomodulatory activity in cancer immunotherapy.

In recent years, immunotherapy has been emerging as a promising alternative therapeutic method for cancer patients, offering potential benefits. The expression of PD-L1 by tumors can inhibit the T-cell response to the tumor and allow the tumor to evade immune surveillance. To address this issue, cancer immunotherapy has shown promise in disrupting the interaction between PD-L1 and its ligand PD-1. We used mirror-image phage display technology in our experiment to screen and determine PD-L1 specific affinity peptides (PPL-C). Using CT26 cells, we established a transplanted mouse tumor model to evaluate the inhibitory effects of PPL-C on tumor growth in vivo. We also demonstrated that PPL-C inhibited the differentiation of T regulatory cells (Tregs) and regulated the production of cytokines. In vitro, PPL-C has a strong affinity for PD-L1, with a binding rate of 0.75 μM. An activation assay using T cells and mixed lymphocytes demonstrated that PPL-C inhibits the interaction between PD-1 and PD-L1. PPL-C or an anti-PD-L1 antibody significantly reduced the rate of tumor mass development in mice compared to those given a control peptide (78% versus 77%, respectively). The results of this study demonstrate that PPL-C prevents or retards tumor growth. Further, immunotherapy with PPL-C enhances lymphocyte cytotoxicity and promotes proliferation in CT26-bearing mice. PPL-C exhibited antitumor and immunoregulatory properties in the colon cancer. Therefore, PPL-C peptides of low molecular weight could serve as effective cancer immunotherapy.

The structures of two polysaccharides from Lepidium meyenii and their immunomodulatory effects via activating NF-κB signaling pathway

Lepidium meyenii Walp., also known as the “Peruvian national treasure”, is a popular functional food in the daily lives of Peruvian people due to its bioactive with main polysaccharides. However, studies on polysaccharides isolated from Lepidium meyenii were few. Two new highly heterogeneous polysaccharides, MCP-1a and MCP-2b, were isolated and purified from the tuber of Lepidium meyenii. The structure characterization revealed that MCP-1a primarily consisted of D-Glc and had a molecular weight of 6.6 kDa. Its backbone was composed of 1,4,6-α-D-Glc, while branches feature T-α-L-Ara, 1,5-α-L-Ara, and T-α-D-Glc attached to the O-6 positions. MCP-2b was a rare arabinogalactan with a molecular weight of 49.4 kDa. Interestingly, the backbone of MCP-2b was composed of 1,6-β-D-Gal, 1,3,6-β-D-Gal with a few 1,3-β-D-GlcpA-4-OMe units inserted. Side chains of MCP-2b were mainly composed of 1,3-β-D-Gal, T-β-D-Gal, T-α-L-Ara, 1,5-α-L-Ara, with trace amounts of 1,4-β-D-Glc and T-β-D-Glc. The bioactivity assay results revealed that MCP-1a and MCP-2b increased the release of NO, IL-1β, TNF-α, and IL-6 from RAW 264.7 cells at concentrations ranging from 50 μg/mL to 400 μg/mL. Furthermore, MCP-1a and MCP-2b could promote the expression of key transcription factors (IκB-α, p-IκB-α, p65, and p-p65) in the NF-κB pathway, indicating that MCP-1a and MCP-2b had potential immunomodulatory activities.

Ameliorative effects of topical ramelteon on imiquimod-induced psoriasiform inflammation in mice.

Psoriasis is a long-lasting, immune-related inflammatory skin disease that affects 2-3% of the global population. It is distinguished by erythematous, silvery, and scaly patches. Ramelteon is a type of melatonin agonist that is used to treat insomnia. It has enhanced non-classical immunomodulatory and anti-inflammatory activities. The aim of the study is to assess the ameliorative effects of topical ramelteon on imiquimod (IMQ)-aggravated psoriasiform-like dermatosis in mice. The 32 albino mouse males were placed into six groups of eight animals, all of them. With the exception of the control group, all groups gained a once-a-day regimen of topical imiquimod 5% cream at a dose of 62.5mg for eight uninterrupted days, while mice in the control group gained vaseline-based ointment alternately. Immediately after an 8-day induction period in the imiquimod group, mice in the clobetasol and ramelteon treatment groups obtained a twice-daily regimen of topical clobetasol propionate 0.05% ointment and 0.1% ointment, respectively, for a further 8days. This extends the total duration of the experimental study to 16 continuous days. The findings of our study found that ramelteon significantly mitigated the concentrations of inflammatory cytokines in the skin tissue, including interleukin (IL)-6, IL-17A, IL-23, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF), as well as the scores associated with psoriatic lesions, including erythema, scaling, skin thickening, ear thickness, and overall cumulative PASI scores. Additionally, the anti-inflammatory impact of ramelteon was achieved by markedly increasing IL-10 levels in the skin tissue and correcting cutaneous histopathological alterations. Ramelteon ointment (0.1%) was comparable to that of clobetasol (0.05%) ointment in alleviating a mouse model of imiquimod-induced psoriasiform inflammation; this is probably due to its potential anti-inflammatory and immunomodulatory activities. Therefore, ramelteon could be a good additive option for therapeutic management of immune-triggered inflammatory conditions such as psoriasis.

Extracellular matrix-mimetic immunomodulatory fibrous scaffold based on a peony stamens polysaccharide for accelerated wound healing

Re-establishment of the extracellular matrix (ECM) in wound tissue is critical for activating endogenous tissue repair. In this study, we designed an ECM-like scaffold material using plant polysaccharides and assessed its efficacy through in vitro and in vivo experiments. The scaffold accelerates wound healing by regulating inflammatory responses and accelerating tissue regeneration. Briefly, we isolated two polysaccharides of varying molecular weights from peony stamens. One of the polysaccharides exhibits potent immunomodulatory and tissue regeneration activities. We further prepared electrospinning materials containing this polysaccharide. In vitro investigations have demonstrated the polysaccharide's ability to modulate immune responses by targeting TLR receptors. In vivo experiments utilizing a scaffold composed of this polysaccharide showed accelerated healing of full-thickness skin wounds in mice, promoting rapid tissue regeneration. In conclusion, our study shows that this scaffold can mobilize the endogenous regenerative capacity of tissues to accelerate repair by mimicking the characteristics of ECM. The overall study has implications for the design of new, effective, and safer tissue regeneration strategies.

Carboxymethylated Abrus cantoniensis polysaccharide prevents CTX-induced immunosuppression and intestinal damage by regulating intestinal flora and butyric acid content

As a Chinese folk health product, Abrus cantoniensis exhibits good immunomodulatory activity because of its polysaccharide components (ACP), and carboxymethylation of polysaccharides can often further improve the biological activity of polysaccharides. In this study, we explored the impact of prophylactic administration of carboxymethylated Abrus cantoniensis polysaccharide (CM-ACP) on immunosuppression and intestinal damage induced by cyclophosphamide (CTX) in mice. Our findings demonstrated that CM-ACP exhibited a more potent immunomodulatory activity compared to ACP. Additionally, CM-ACP effectively enhanced the abundance of short-chain fatty acid (SCFA)-producing bacteria in immunosuppressed mice and regulated the gene expression of STAT6 and STAT3 mediated pathway signals. In order to further explore the relationship among polysaccharides, intestinal immunity and intestinal flora, we performed a pseudo-sterile mouse validation experiment and fecal microbiota transplantation (FMT) experiment. The findings suggest that CM-FMT and butyrate attenuate CTX-induced immunosuppression and intestinal injury. CM-FMT and butyrate show superior immunomodulatory ability, and may effectively regulate intestinal cell metabolism and repair the damaged intestine by activating STAT6 and STAT3-mediated pathways. These findings offer new insights into the mechanisms by which CM-ACP functions as functional food or drug, facilitating immune response regulation and maintaining intestinal health.

Dissection of the potential immunomodulatory activity materials and mechanism of Wu Shen Wan (a classical traditional Chinese medicine prescription) based on in vivo substances profiling and network pharmacology

AbstractIn the present study, a comprehensive strategy based on substances profiling in vivo and network pharmacology method was applied to screen out the potential immunomodulatory activity substances and mechanism of Wu Shen Wan. As a result, a total of 121 constituents were identified or tentatively characterized, including 26 flavonoids, 16 alkaloids, 10 tanshinones, four diterpenes, seven iridoid glycosides, eight coumarin, 18 phenolic acids, 29 ginsenosides, and three others. Moreover, 57 prototypes were clearly screened out in rat plasma and urine after ingestion of Wu Shen Wan. The Wu Shen Wan exhibited immunomodulatory effects via significantly increasing the phagocytic activity of macrophages and inducing the release of nitric oxide, tumor necrosis factor‐α, and interleukin 6 in RAW264.7 cells. In addition, the network pharmacology results showed that the top 20 Kyoto Encyclopedia of Genes and Genomes clusters were enriched, such as mitogen‐activated protein kinases pathway. This is the first systematic study on the chemical constituents of Wu Shen Wan. The analytical method features a quick and comprehensive dissection of the chemical composition and provides a basis for exploring its immunomodulatory effects.

Edible insects as a source of biopeptides and their role in immunonutrition.

Many edible insect species are attracting the attention of the food industry and consumers in Western societies due to their high content and quality of protein, and consequently, the potential to be used as a more environmentally friendly dietary source could be beneficial for humans. On the other hand, prevention of inflammatory diseases using nutritional interventions is currently being proposed as a sustainable and cost-effective strategy to improve people's health. In this regard, finding bioactive compounds such as peptides with anti-inflammatory properties from sustainable sources (e.g., edible insects) is one area of particular interest, which might have a relevant role in immunonutrition. This review aims to summarize the recent literature on the discovery of immunomodulatory peptides through in vitro studies from edible insects, as well as to describe cell-based assays aiming to prove their bioactivity. On top of that, in vivo studies (i.e., animal and human), although scarce, have been mentioned in relation to the topic. In addition, the challenges and future perspectives related to edible-insect peptides and their role in immunonutrition are discussed. The amount of literature aiming to demonstrate the potential immunomodulatory activity of edible-insect peptides is scarce but promising. Different approaches have been employed, especially cell assays and animal studies employing insect meal as supplementation in the diet. Insects such as Tenebrio molitor or Gryllodes sigillatus are some of the most studied and have demonstrated to contain bioactive peptides. Further investigations, mostly with humans, are needed in order to clearly state that peptides from edible insects may contribute to the modulation of the immune system.

Immunomodulatory effect of fermented Benincasa hispida cong. extracts on BALB/c mice

Recently, interest in functional foods that enhance immunity has increased owing to social and environmental changes. In this study, we investigated the immunomodulatory effects of fermented Benincasa hispida extract (FBE) in normal BALB/c mice. FBE enhanced nitric oxide (NO) production and natural killer (NK) cell activity. In addition, FBE increased perforin 1 and granzyme B production, demonstrating increased CD8+ cytotoxic T cell activity. CD4+ helper T cell activity was analyzed by measuring Th1 and Th2 cell-related cytokines. FBE enhanced the activity of Th1 and Th2 cells while maintaining their balance. Furthermore, FBE increased the mRNA expression of regulatory T cell-related genes (foxp3, IL-10, and TGF-β) that control excessive immune response, and upregulated the production of IgA and short-chain fatty acids (SCFA) that improve the immune environment in the intestine. Taken together, our results indicate that FBE represents a functional food ingredient with potential immunomodulatory activities.

In vitro evaluation of the immunomodulatory activity of the nutraceutical formulation AminoDefence

Immune system (IS) functionality is warranted by inter-dependent processes that balance body defences without exceeding in inflammation. An ideal nutraceutical approach should sustain the protective IS activity while controlling inflammation. The potential immunomodulatory activity of the food supplement (FS) AminoDefence was studied in resting macrophages RAW264.7 and following stimulation of bacterial- and viral-associated inflammation trough LPS and PolyI:C treatments, respectively. In unstimulated macrophages, the formulation exerted a dose-dependent immunostimulant activity by up-regulating NO, IL-6, TNF-α and MCP-1 release, while it dampened the aberrant release of these factors induced by pro-inflammatory stimuli. Exploring the contribution of single components Echinacea purpurea (E. purpurea) extract and quercetin, used at proportional concentrations than in whole formulation, a more pronounced immunostimulant effect was observed for E. purpurea, and an anti-inflammatory activity for quercetin. Hence, AminoDefence exerts an immunomodulatory activity in macrophages by effectively stimulating a protective inflammatory response and limiting it in cases of excessive inflammation.

Design, synthesis and biological evaluation of newly triazolo-quinoxaline based potential immunomodulatory anticancer molecules

It is evident that cancer is a serious disease with a growing incidence and high mortality rate. Based on the CRBN binding properties of glutarimide moiety of thalidomide molecule, and triazolo-quinoxaline cytotoxic activity, we decided to innovate new triazolo-quinoxaline based molecules hybridized with glutarimide moiety for potential immunomodulatory anticancer activity. The biological data revealed that 4-oxotriazoloquinoxaline based candidate (15) was of particular antiproliferative significance compared to doxorubicin. It showed IC50 of 9.81 ± 0.7, 15.49 ± 1.2, and 10.09 ± 0.9 μM against hepatocellular (HepG2), prostate cancer (PC3), and breast cancer (MCF-7), respectively. Meanwhile, doxorubicin revealed IC50 of 14.61 ± 1.1, 16.32 ± 1.1, and 12.41 ± 0.74 μM, respectively. Moreover, compound 15 was comparable to thalidomide in elevating the levels of caspase-8 by about 8 folds in HepG-2 cells. Similarly, it showed almost the same effect as thalidomide in reducing VEGF levels in HepG-2 cells. Whereas it was superior to thalidomide in decreasing the levels of NF-κB P65 in HepG-2 cells from 278.1 pg/mL to 82.4 pg/mL compared to 110.5 pg/mL reported for thalidomide. At the same time, 15 and thalidomide were comparable in their significant reduction of TNF-α levels in HepG-2 cells by about one third. Furthermore, molecular docking studies demonstrated the binding properties of the new candidates to CRBN. Accordingly, this work suggests the significance of the triazolo-quinoxaline derivatives carrying glutarimide moiety, in particular compound 15, that showed considerable data for further consideration in order to develop new effective anticancer drugs.

The extracellular polysaccharide inhibit porcine epidemic diarrhea virus with extract and gene editing Lacticaseibacillus

Lacticaseibacillus is one of the predominant microorganisms in gut from human and animal, and the lacticaseibacillus have effective applications against the viral diarrhea of piglets in the farm. However, the function and the concrete cell single pathways of the active ingredient from lacticaseibacillus was not clear within anti-infection in the postbiotics research. Here, we compared the biological function of extracellular polysaccharides (EPS) purified from lacticaseibacillus casei (L. casei) and gene editing lacticaseibacillus casei with the CRISPER-Cas9 technology, which were with the ability of antioxidation and anti-inflammation, and the EPS could also inhibit the ROS production within the Porcine Small Intestinal Epithelial Cells-J2 (IPEC-J2). Interestingly, we found that both of EPS and genome editing lacticaseibacillus casei could specifically target the IFN-λ expression in the IPEC-J2, which was beneficial against the PEDV infection in the virus replication and production with the qRT-PCR and indirect immunofluorescence methods. Finally, the STAT3 cell single pathway was stimulated to transcribe IFN-λ with the EPS to elucidate the detailed mechanism of activating type III IFN signals receptor of IL-10R2, which play the function between anti-inflammation and anti-virus in the PEDV infection. Taken together, our research linked a postbiotics of EPS with the antiviral infection of PEDV, which suggest that the lacticaseibacillus itself still have displayed the potential immunomodulatory activities, and highlight the immunomodulatory potential of EPS-producing microbes.Graphical

Four new triterpene saponins from Cephalaria speciosa and their potent cytotoxic and immunomodulatory activities

Four new triterpene saponins, namely speciosides A-D (1–4) along with six known saponins were isolated from the n-butanol extract of Cephalaria speciosa. In addition to these, three new prosapogenins (2a–4a) were obtained after alkaline hydrolysis. Elucidation of the structures of the isolated compounds was carried out by 1D, 2D NMR, HR-ESI/MS and GC–MS analyses. Cytotoxic activity was investigated on A549, CCD34-Lu, MDA-MB-231, PC-3, U-87MG, HeLa, HepG-2 cells by MTT method. Additionally, the immunomodulatory effect of compounds was evaluated for macrophage polarization with/without inactivated IBV D274 antigen treatment on THP-1 cells originated macrophage cells in terms of M1 or M2. According to the cytotoxicity results, compound 1 and prosapogenin 2a exhibit significant cytotoxicity than doxorubicin by comparison. The results demonstrated that saponin molecules treated THP-1 originated macrophages were induced M1 and/or M2 polarization. Additionally, macrophage cells treated with/without IBV D274 antigen contained saponin compounds were triggered significantly M2 polarization relative to M1. Notably, monodesmosidic saponins (1 and 2a–4a) in comparison with bisdesmosidic ones (2–4) demonstrated the most effect on M2 polarization. In conclusion, the results showed that all the isolated new saponins and their prosapogenins have immunomodulatory potential on macrophage cells increasing immune response without significant cytotoxic effect on THP-1 originated macrophages.

SAT039 Chronic Glucocorticoid Exposure Induced A S1PR2-Rorc Axis To Enhance Hepatic Gluconeogenesis

Abstract Disclosure: R.A. Lee: None. M. Chang: None. A. Tsay: None. Y. Lee: None. D. Li: None. N. Yiv: None. S. Tian: None. J. Wang: None. Glucocorticoids are steroid hormones whose circulating levels are elevated in response to stress to maintain metabolic homeostasis. Glucocorticoids are also used to treat inflammatory and autoimmune diseases due to their potent anti-inflammatory and immunomodulatory activities. However, chronic glucocorticoid treatment causes various metabolic disorders, such as hyperglycemia and insulin resistance. Glucocorticoids convey their functions through an intracellular glucocorticoid receptor (GR) which is a transcriptional regulator. While GR stimulates hepatic gluconeogenic gene transcription, additional mechanisms activated specifically by chronic glucocorticoid exposure can further enhance hyperglycemia. We found that chronic glucocorticoid exposure elevated hepatic production of sphingosine-1-phosphate (S1P) and hepatic knockdown of sphingosine-1-phosphate receptor 2 (S1PR2) attenuated chronic glucocorticoid-induced glucose intolerance and hepatic gluconeogenesis while having no effect on insulin signaling. Hepatic S1PR2 knockdown reduced GR occupancy on glucocorticoid response elements (GREs) of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (Pck1) and the catalytic subunit of glucose 6 phosphatase (G6pc), thus reducing their expressions. Interestingly, RAR-related orphan receptor C (Rorc) expression was reduced in the liver of glucocorticoid treated hepatic S1PR2 knockdown mice. We found that Rorc was also recruited to the promoter of Pck1 upon glucocorticoid treatment and reducing Rorc activity decreased the GR occupancy at the GRE of Pck1. In contrast, overexpressing Rorc in the liver of hepatic S1PR2 knockdown mice restored glucocorticoid-induced glucose intolerance, GR recruitment to GREs of gluconeogenic genes, and gluconeogenic gene expression. Overall, we propose that chronic glucocorticoid exposure induces a novel S1PR2-Rorc axis to promote the transcription of gluconeogenic genes to enhance hyperglycemia. Presentation: Saturday, June 17, 2023

Multi-Faceted Bioactivity Assessment of an Exopolysaccharide from Limosilactobacillus fermentum NCDC400: Antioxidant, Antibacterial, and Immunomodulatory Proficiencies.

Exopolysaccharides (EPS) are acknowledged for their diverse functional and technological properties. This study presents the characterization of EPS400, an acidic exopolysaccharide sourced from the native probiotic Limosilactobacillus fermentum NCDC400. Notably, this strain has demonstrated previous capabilities in enhancing dairy food texture and displaying in vivo hypocholesterolemic activity. Our investigation aimed to unveil EPS400's potential biological roles, encompassing antioxidant, antibacterial, and immunomodulatory activities. The results underscore EPS400's prowess in scavenging radicals, including the 2,2-diphenyl-1-picrylhydrazyl radical, 2,2'-azino-di-(3-ethylbenzthiazoline sulfonic acid) radical, superoxide radical, hydroxyl radical, and chelating activity targeting the ferrous ion. Furthermore, EPS400 displayed substantial antibacterial effectiveness against prevalent food spoilage bacteria such as Pseudomonas aeruginosa NCDC105 and Micrococcus luteus. Remarkably, EPS400 exhibited the ability to modulate cytokine production, downregulating pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and nitric oxide, while concurrently promoting the release of anti-inflammatory cytokine IL-10 within lipopolysaccharide-activated murine primary macrophages. Additionally, EPS400 significantly (p ≤ 0.05) enhanced the phagocytic potential of macrophages. Collectively, our findings spotlight EPS400 as a promising contender endowed with significant antioxidant, antibacterial, and immunomodulatory attributes. These characteristics propose EPS400 as a potential pharmaceutical or bioactive component, with potential applications in the realm of functional food development.

Immunomodulatory Activity of Polysaccharides Isolated from Saussurea salicifolia L. and Saussurea frolovii Ledeb.

The genus Saussurea has been used in the preparation of therapies for a number of medical problems, yet not much is known about the therapeutic high-molecular-weight compounds present in extracts from these plants. Since polysaccharides are important in immune modulation, we investigated the chemical composition and immunomodulatory activity of Saussurea salicifolia L. and Saussurea frolovii Ledeb polysaccharides. Water-soluble polysaccharides from the aerial parts of these plants were extracted using water at pHs of 2 and 6 and subsequently precipitated in ethanol to obtain fractions SSP2 and SSP6 from S. salicifolia and fractions SSF2 and SSF6 from S. frolovii. The molecular weights of fractions SSP2, SSP6, SFP2, and SFP6 were estimated to be 143.7, 113.2, 75.3, and 64.3 kDa, respectively. The polysaccharides from S. frolovii contained xylose (67.1-71.7%) and glucose (28.3-32.9%), whereas the polysaccharides from S. frolovii contained xylose (63.1-76.7%), glucose (11.8-19.2%), galactose (4.7-8.3%), and rhamnose (6.8-9.4%). Fractions SSP2, SSP6, and SFP2 stimulated nitric oxide (NO) production by murine macrophages, and NO production induced by SSP2, SSP6, and SFP2 was not inhibited by polymyxin B treatment of the fractions, whereaspolymyxin B treatment diminished the effects of SFP6, suggesting that SFP6 could contain lipopolysaccharide (LPS). The LPS-free fractions SSP2, SSP6, and SFP2 had potent immunomodulatory activity, induced NO production, and activated transcription factors NF-κB/AP-1 in human monocytic THP-1 cells and cytokine production by human MonoMac-6 monocytic cells, including interleukin (IL)-1α, IL-1β, IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-γ, monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor (TNF). These data suggest that at least part of the beneficial therapeutic effects reported for water extracts of the Saussurea species are due to the modulation of leukocyte functions by polysaccharides.