Article

Activation of murine macrophages by G1-4A, a polysaccharide from Tinospora cordifolia , in TLR4/MyD88 dependent manner

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Abstract

Macrophages are centrally placed in the innate immune system and their activation is crucial to the generation of appropriate immune response in the event of any pathogenic invasion, tumorigenesis or other human diseases. Many plant derived polysaccharides are known to activate macrophages. In the present study, effects of G1-4A, a polysaccharide derived from Tinospora cordifolia, on the activation of macrophages were investigated. Our data demonstrated the up regulation of expression of TNF-α, IL-β, IL-6, IL-12, IL-10 and IFN-γ in RAW 264.7 cell line and peritoneal macrophages after G-14A treatment. Nitric oxide levels were also enhanced along with up-regulation of NOS2 expression in murine macrophages post G1-4A treatment. Further, G1-4A treatment up-regulated the surface expression of MHC-II and CD-86 in macrophages. Using siRNA against TLR4, MyD88 and anti-TLR4 blocking antibodies, we established that G1-4A activated macrophages by classical pathway in TLR4-MyD88 dependent manner. Additionally, G1-4A treatment activated p38, ERK and JNK MAPKs in macrophages. Using pharmaceutical inhibitors of above MAPKs we concluded that G1-4A activates the macrophages by activation of p38, ERK and JNK MAPKs in RAW264.7 macrophages. Thus our data suggests the activation of macrophages by classical pathway after treatment of G1-4A.

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... G1-4A a polysaccharide of Tinospora cordifolia effectively activated macrophages via TLR4-MyD88 dependent pathway and plays an important role in innate immunity (Gupta et al., 2017). ...
... One of the studies depicted that silver nano-particles of Piper longum fruit extract has potential antibacterial activity and cytotoxicity activity against MCF-7 (breast cancer cell lines) cell lines (Reddy, Vali, Rani, & Rani, 2014) while Tinospora cordifolia has promising antiviral, immunomodulatory, and thrombolytic properties (Alrumaihi et al., 2019;Gupta et al., 2017;Mary et al., 2003;Velazquez et al., 2009). ...
... Ocimum tenuiflorum can affect the neutrophil and lymphocyte population (Mukherjee et al., 2005), whereas Psoralea corylifolia induced the NK-cell activity and antibodies-dependent cytotoxicity in cancer cells (Latha et al., 2000). Tinospora cordifolia activated the innate immune response via TLR4-MY88 axis (Gupta et al., 2017) and ameliorated cyclophosphamide-induced immunosuppression in rats (Alrumaihi et al., 2019). Viscum album regulated immune indices in radioactive exposed children (Chernyshov et al., 2000) while Withania somnifera has a beneficial role in humoral immunity (Davis & Kuttan, 2000). ...
Article
Traditional Indian medical practices (Ayurveda, Siddha, Unani, and homeopathy) are a vast reservoir of knowledge about medicinal plants. The promising pharmacological properties of these plants have paved the way for developing therapy against novel Coronavirus (CoV) infection. The current review will summarize published works of literature on the effects of traditional Indian medicinal plants against acute respiratory infection (COVID‐19, SARS, Influenza, and Respiratory syncytial virus infection) and registered clinical trials of traditional Indian herbal medicines in COVID‐19. The current study aims to comprehensively evaluate the data of traditional Indian medicinal plants to warrant their use in COVID‐19 management. PubMed, Embase, and Cochrane databases were searched along with different clinical trial databases. A total of 22 relevant traditional Indian medicinal plants (35 relevant studies) were included in the current study having potential antiviral properties against virus‐induced respiratory illness along with promising immunomodulatory and thrombolytic properties. Further, 36 randomized and nonrandomized registered clinical trials were also included that were aimed at evaluating the efficacy of herbal plants or their formulations in COVID‐19 management. The antiviral, immunomodulatory, and thrombolytic activities of the traditional Indian medicinal plants laid down a strong rationale for their use in developing therapies against SARS‐CoV‐2 infection. The study identified some important potential traditional Indian medicinal herbs such as Ocimum tenuiflorum, Tinospora cordifolia, Achyranthes bidentata, Cinnamomum cassia, Cydonia oblonga, Embelin ribes, Justicia adhatoda, Momordica charantia, Withania somnifera, Zingiber officinale, Camphor, and Kabusura kudineer, which could be used in therapeutic strategies against SARS‐CoV‐2 infection.
... In conditions such as infectious diseases, e.g., From medicinal plants, 86 molecules were isolated, 80 molecules were evaluated for their immunomodulatory proprieties (Table 1), and 56 had their structures represented (Figures 3-7). (51), N-methyl-2-pyrrolidone (52), N-formylannonaine (2) Cordifolioside (53), Tinocordiside (54) Syringin (50) [ [18][19][20] Piper longum Linn. Piperaceae Fruits Methanol Alkaloids Piperine (6) Anti-inflammatory, anti-infectious, antitumor, analgesic [21] Echinacea purpura, Echinaceae Whole plant, Root ...
... Flavonoids, glycosides, phenolic compounds, terpenoids Ellagic acid, Hyperin (29), Isoquercitin (27), Guajaverin (31), Avicularin (32), Asiatic acid (21), Maslinic acid (20), Corosolic acid (9), Oleanolic acid (7), Ursolic acid (8) Antiallergic, antitumoral, anti-inflammatory, analgesic, antimicrobial [45,46] ...
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A robust, well-functioning immune system is the cornerstone of good health. Various factors may influence the immune system’s effectiveness, potentially leading to immune system failure. This review aims to provide an overview of the structure and action of immunomodulators isolated from African medicinal plants. The research was conducted according to PRISMA guidelines. Full-text access research articles published in English up to December 2023, including plant characteristics, isolated phytochemicals, and immuno-modulatory activities, were screened. The chemical structures of the isolated compounds were generated using ChemDraw® (version 12.0.1076), and convergent and distinctive signaling pathways were highlighted. These phytochemicals with demonstrated immunostimulatory activity include alkaloids (berberine, piperine, magnoflorine), polysaccharides (pectin, glucan, acemannan, CALB-4, GMP90-1), glycosides (syringin, cordifolioside, tinocordiside, aucubin), phenolic compounds (ferulic acid, vanillic acid, eupalitin), flavonoids (curcumin, centaurein, kaempferin, luteolin, guajaverin, etc.), terpenoids (oleanolic acid, ursolic acid, betulinic acid, boswellic acids, corosolic acid, nimbidin, andrographolides). These discussed compounds exert their effects through various mechanisms, targeting the modulation of MAPKs, PI3K-Akt, and NF-kB. These mechanisms can support the traditional use of medicinal plants to treat immune-related diseases. The outcomes of this overview are to provoke structural action optimization, to orient research on particular natural chemicals for managing inflammatory, infectious diseases and cancers, or to boost vaccine immunogenicity.
... 56/Bom/98 [7]. Using this method Gupta et al. [40] and Raveendran Nair et al. [8] reported immune modulatory activity, whereas Subramanian et al. [26] and Desai et al. [45] reported antioxidant activity of T. cordifolia polysaccharide. Furthermore, Mohan and Koul [46] extracted T. cordifolia polysaccharide through aqueous extraction and it was found to be effective modulator of tumorigenesis in mice and in vitro antioxidant activity. ...
... It is obvious that PRE and G1-4A modulated the host innate immune response in RAW 264.7 cells in order to decrease MTB's intracellular survival. Gupta et al. [40] studied the impact of G1-4A on macrophage (RAW264.7 cells) activation. There was a significant (P < 0.05) increase in the secretion of cytokines such as IL-6, IL-10, IL-12, IL-1β, NO and IFN-γ, when G1-4A (1 mg/mL) was added. ...
Article
Human awareness of the need for health and wellness practices that enhance disease resilience has increased as a result of recent health risks. Plant-derived polysaccharides with biological activity are good candidates to fight diseases because of their low toxicity. Tinospora cordifolia (Willd.) Hook.f. & Thomson polysaccharides extract from different plant parts have been reported to possess significant biological activity such as anti-oxidant, anti-cancer, immunomodulatory, anti-diabetic, radioprotective and hepatoprotective. Several extraction and purification techniques have been used to isolate and characterize T. cordifolia polysaccharides. Along with hot-water extraction (HWE), other novel techniques like microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), pulsed electric field (PEF), supercritical-fluid extraction (SFE), and enzyme-assisted extraction (EAE) are used to extract T cordifolia polysaccharides. SFE is a revolutionary technology that gives the best yield and purity of low-molecular-weight polysaccharides. According to the findings, polysaccharides extracted and purified from T. cordifolia have a significant impact on their structure and biological activity. As a result, the methods of extraction, structural characterization, and biological activity of T. cordifolia polysaccharides are covered in this review. Research on T. cordifolia polysaccharides and their potential applications will benefit greatly from the findings presented in this review.
... It established that G1-4A as a TLR4 agonist is having the potential to cause M1-activation of macrophages like Interferon gamma (IFN-γ) and lipopolysaccharide (LPS). 28 In the human subject also, it is considered as an immune stimulator by increasing the killing capacities of neutrophils and phagocytosis activities. 29 Different extracts of Tinospora cordifolia also exhibit immunemodulatory activity by splenocyte proliferation. ...
... Hematological and serum chemistry parameters were within the normal limits and there were no treatment related gross or histopathological findings14,15,16 Some pilot studies conducted on efficacy and safety evaluation ofAshwagandha showed normal hepatic functions and renal functions when given for 7 weeks.17 A study on healthy volunteers (12 Male &6Female, age: 18-30 years, and BMI:[19][20][21][22][23][24][25][26][27][28][29][30] had shown normal organ function tests before and after the intervention. After baseline investigations, they received WS capsules (Rx) (aqueous extract, 8:1) daily in two divided doses with increase in daily dosage every 10 days for 30 days (750 mg/day ×10 days, 1000 mg/day × 10 days, 1250 mg/day × 10 days). ...
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This booklet covers easily available medicinal plant products that have been used in Ayurvedic system of medicine for various indications and have useful properties in respiratory infections and have been also shown to have antiviral, anti-inflammatory, immunomodulatory ands other properties which can be beneficial in such infections.
... The results indicated significant up-regulation of these cytokine genes in PBMCs isolated from supplemented birds, compared with the control. These results are in accordance with the study where polysaccharide (G1-4A arabinogalactan polysaccharide) derived from T. cordifolia was found to stimulate murine macrophages leading to up-regulation of IL-2, IFN-γ, IL-4, and IL-1β in vitro [40]. Therefore, these results are indicative of the immunomodulatory potential of this herb in chickens, through alteration of the expressions of immune response cytokines. ...
... It has been found that G1-4A, an arabinogalactan polysaccharide from the stem of T. cordifolia, responsible for its immunomodulatory potential, acts by activating the B cells polyclonally, via an increase in CD69 expression in lymphocytes. TLR4 on B lymphocytes and macrophages acts as a receptor for G1-4A polysaccharide, activating these immune cells via TLR4/MyD88 dependent manner [40,43]. Similarly, G1-4A leads to enhanced antigen presentation from dendritic cells, and further activation of cytotoxic T cells [44]. ...
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Infectious bursal disease (IBD), caused by infectious bursal disease virus (IBDV), is characterized by severe immunosuppression in young chicks of 3 to 6 week age group. Although vaccines are available to prevent IBD, outbreaks of disease are still noticed in the field among vaccinated flocks. Further, the birds surviving IBD become susceptible to secondary infections caused by various viral and bacterial agents. This study assessed the immunoprophylactic potential of Cytosine-guanosinedeoxynucleotide (CpG) oligodeoxynucleotides (ODN) and Tinospora cordifolia stem aqueous extract in the specific pathogen free (SPF) chicks, experimentally infected with very virulent IBDV (vvIBDV). Both of these agents (CpG ODN and herbal extract) showed significant increase in the IFN-γ, IL-2, IL-4, and IL-1 levels in the peripheral blood mononuclear cells (PBMCs) (p < 0.05) of chickens in the treatment groups following IBD infection.Further we found significant reduction in mortality rate in vvIBDV infected chicks treated with either, or in combination, compared with the birds of control group. Additionally, the adjuvant or immune enhancing potential of these two immunomodulatory agents with the commercially available IBDV vaccine was determined in chicks. The augmentation of vaccine response in terms of an enhanced antibody titer after vaccination, along with either or a combination of the two agents was noticed. The findings provide a way forward to counter the menace of IBDV in the poultry sector through use of these herbal or synthetic immunomodulatory supplements.
... Polysaccharides have been confirmed to promote the body's immune system by stimulating macrophages [7,8], triggering various cellular events, and enhancing immune response, mainly by promoting macrophage proliferation, boosting macrophage phagocytic activity, increasing the production of NO and ROS, and related cytokines and chemokines [9][10][11]. The molecular weight of polysaccharides is also one of the important elements affecting their biological efficacy [12]. ...
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In the current study, a novel crude polysaccharide (cNCEP) was extracted from N. commune Vaucher utilizing ultrasonic-assisted extraction (UAE) with 60 % ethanol, employing response surface methodology. The optimal yield of cNCEP was determined to be 8.07 ± 0.08 mg/g, achieved through ultrasonic-assisted extraction under the conditions of a material-to-liquid ratio of 1:22, temperature of 56 °C, power of 570 W, and duration of 147 min. Subsequent purification of NCEP via Sephadex G75 resulted in a novel polysaccharide with a molecular weight of 20.466 kDa. NCEP exhibited significant scavenging activites against DPPH and hydroxyl radicals, as well as notable in vitro immunomodulatory properties. Furthermore, the mechanisms underlying the immunomodulatory effects of NCEP, involving enhancement of immunity, were investigated, revealing potential regulation of MAPK and TLR4-IRF7-NF-κB signaling pathways through RNA-Seq and Western blot analyses. These findings highlight the promising potential of NCEP as an organic immunomodulatory agent and functional food ingredient.
... Decrease mortality, increase Th1, decrease Th2, increase macrophage activation, increase mitogenesis [23,41,43,44] Polysaccharide Alpha-D-glucan RR1 Increase phagocytosis; increase Th1 cytokines [45] Protein Guduchi immunomodulatory protein (ImP) -Increase phagocytosis; increase mitogenesis, increase bactericidal [46] Molecules 2023, 28, 7073 4 of 28 ...
Article
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Natural products with curative properties are gaining immense popularity in scientific and food research, possessing no side effects in contrast to other drugs. Guduchi, or Tinospora cordifolia, belongs to the menispermaceae family of universal drugs used to treat various diseases in traditional Indian literature. It has received attention in recent decades because of its utilization in folklore medicine for treating several disorders. Lately, the findings of active phytoconstituents present in herbal plants and their pharmacological function in disease treatment and control have stimulated interest in plants around the world. Guduchi is ethnobotanically used for jaundice, diabetes, urinary problems, stomachaches, prolonged diarrhea, skin ailments, and dysentery. The treatment with Guduchi extracts was accredited to phytochemical constituents, which include glycosides, alkaloids, steroids, and diterpenoid lactones. This review places emphasis on providing in-depth information on the budding applications of herbal medicine in the advancement of functional foods and nutraceuticals to natural product researchers.
... TLR4, a crucial membrane receptor expressed on the surface of macrophages, mediates the activation of macrophages by transforming extracellular signals [51]. An experiment shows that a polysaccharide G1-4A could activate macrophages through the TLR4 pathway, and macrophage activity may be reduced after blocking TLR4 action using siRNA and antibodies [52]. After TLR4 is activated, it binds to a ligand to form a complex between the cytoplasmic region and myeloid differentiation primary response gene 88 (Myd88), activates tumor necrosis factor receptorassociated molecule 6 (TRAF6), and finally initiates the expression of mitogen-activated protein kinase (MAPK) signaling pathway [53]. ...
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Morchella esculenta (L.) Pers., referred to as Morel, is a medicinal and edible homologous fungus, which contains many bioactive substances. In Morel, polysaccharides are the most abundant and have various bioactivities. In the present work, two novel polysaccharides, Se-MPS and MPS, were prepared and purified from selenium-enriched (Se-enriched) and common Morel mycelia, respectively, and their structural and immunomodulatory properties were evaluated. The results show that Se-enriched treatment significantly changed the polysaccharides’ chemical composition, molecular weight, and sugar chain configuration. In addition, the Se-enriched treatment also improved the polysaccharides’ fragmentation and thermal stability. Importantly, Se-enriched Morel polysaccharide (Se-MPS) could significantly enhance phagocytosis of RAW 264.7 macrophage cells and, remarkably, activate their immune response via activating the TLR4-TRAF6-MAPKs-NF-κB cascade signaling pathway, finally exerting an immunomodulatory function. Based on these findings, selenium-enriched Morel polysaccharide appears to have more potential for development and utilization in functional foods or medicines than ordinary Morel polysaccharide.
... Specifically, the activated TLR4 can promote the phosphorylation of interleukin-1 receptor-related kinase (IRAK-1) to activate TRAF6 (61). Further, the MAKPs family (including JNK, ERK, and p38) is activated to produce phosphorylation and promote the secretion of downstream related immune cytokines (62). In this study, SLNP could promote TLR4 expression, upregulated the mRNA expression of TRAF6, IRF3, JNK, ERK and p38, the protein expression of TRAF6, IRF3, p-JNK, p-ERK, and p-p38, which was proved by the study of JCH-1, a purified polysaccharide isolated from Isaria cicadae Miquel. ...
Article
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Background Sparassis latifolia (S. latifolia) is a precious edible fungus with multiple biological activities. To date, no study has been investigated the underlying molecular mechanism of immunoregulation caused by the neutral polysaccharide of S. latifolia. Materials and methods To investigate immunomodulatory mechanism of S. latifolia neutral polysaccharide (SLNP), SLNP was obtained from S. latifolia and its structure, immune receptors and regulation mechanism were studied. Results S. latifolia neutral polysaccharide consisted of arabinose, galactose, glucose, xylose, and mannose with a molar ratio of 6:12:63:10:5. SLNP was a pyran polysaccharide with a relative molecular weight of 3.2 × 10⁵ Da. SLNP promoted the proliferation of RAW264.7, which further induced the secretions of nitric oxide, TNF-α, IL-6, and IFN-β, and upregulated the immune receptor TLR4 expression. Moreover, SLNP increased remarkably the levels of TRAF6, IRF3, JNK, ERK, p38, and p38 mRNA and protein mediated by TLR4. Conclusion S. latifolia neutral polysaccharide regulated the immune function of RAW264.7 through MyD88-dependent and -independent signaling pathways mediated by TLR4 receptor, which suggests that SLNP is a new immunomodulator.
... Thus, the mechanism of action occurs through the binding of polysaccharides to groups of transmembrane type I proteins, known as Toll-like receptors (TLRs). These receptors stimulate signaling pathways in order to activate macrophages [63]. Therefore, macrophages act by damaging pathogens by phagocytosis, triggering the release of antigens responsible for immunological responses [64]. ...
Article
There is a current tendency towards bioactive natural products that can be used in different areas such as food, pharmaceutical, and biomedical. In the last decades, the polysaccharides have attracted an increasing interest because of the potent nontoxic effects, therapeutic properties, and the diversified range of applications. Polysaccharides are complex and heterogeneous macromolecules, constituted of different monosaccharides, and in some cases of glucuronic acid and sulphate groups. Polysaccharides with biological activity can be derived from plants, animals and microorganisms, especially microalgae. Microalgae are considered one of most promising source of these compounds that have already proved to have several important biological properties. In this sense, our objective is to elucidate the use of bioactive polysaccharides from microalgae in biomedical applications, emphasizing the biological activity of these compounds. Furthermore, the microalgal biomass production systems and polysaccharides extraction methods were presented and discussed.
... Elevated expression levels of IFNs and MCP-1 were detected, but the levels of IFNs were much lower than that of IL-1β (Fig. 2). Our result was in agreement with other findings that IFNs were less abundantly produced by the stimulated macrophages, compared to IL-1β or TNF-α [44][45][46]. However, the degree of increasing in the expression level of IFNs was obviously higher than that of IL-1β in PM patients [47][48][49]. ...
Article
Full-text available
Objective This study was designed to investigate the role of the nucleotide-binding-domain -and leucine-rich repeat -containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM). Methods Immunochemistry was performed to analyze the NLRP3, caspase-1 and interleukin-1 beta (IL-1β) expression in the muscle tissue of PM patients. Rat model of PM and C2C12 cell were used to investigate the potential role of NLRP3 inflammasome in PM. Results The percentage of CD 68+ macrophages, and the expression levels of NLRP3, caspase-1 and IL-1β in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment resulted in activation of NLRP3 inflammasome and secretion of IL-1β as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1) in the Raw 264.7 macrophages. Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular of PM in the co-cultured C2C12 cells. The effect was decreased by treatment of NLRP3 inflammasome inhibitor MCC950 or siRNA of NLRP3 inflammasome. These findings suggested certain levels of IL-1β rather than IFNs up-regulated MHC-I expression in C2C12 cells. IL-1β blockade using neutralizing IL-1β monoclonal antibody or siRNA of IL-1β suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition by MCC950 reduced the expression of NLRP3, IL-1β and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum. Conclusion NLRP3/caspase-1/IL-1β axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM.
... In general, pectin-containing scaffolds are biocompatible [13][14][15][16][17][18]. However, nonspecific adsorption of blood proteins [19], including proteins of the complement system [20][21][22], and stimulation of macrophages to secrete pro-inflammatory cytokines and nitric oxide [23][24][25][26] has been reported with pectin materials. Non-specific protein adsorption, complement activation, and inflammation develop a foreign body response (FBR), which hinders the development of tissue engineering scaffolds due to the failure of integration of the implant with native tissue [27]. ...
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The study aims to develop gel beads with improved functional properties and biocompatibility from hogweed (HS) pectin. HS4 and AP4 gel beads were prepared from the HS pectin and apple pectin (AP) using gelling with calcium ions. HS4 and AP4 gel beads swelled in PBS in dependence on pH. The swelling degree of HS4 and AP4 gel beads was 191 and 136%, respectively, in PBS at pH 7.4. The hardness of HS4 and AP4 gel beads reduced 8.2 and 60 times, respectively, compared with the initial value after 24 h incubation. Both pectin gel beads swelled less in Hanks' solution than in PBS and swelled less in Hanks' solution containing peritoneal macrophages than in cell-free Hanks' solution. Serum protein adsorption by HS4 and AP4 gel beads was 118 ± 44 and 196 ± 68 μg/cm2 after 24 h of incubation. Both pectin gel beads demonstrated low rates of hemolysis and complement activation. However, HS4 gel beads inhibited the LPS-stimulated secretion of TNF-α and the expression of TLR4 and NF-κB by macrophages, whereas AP4 gel beads stimulated the inflammatory response of macrophages. HS4 gel beads adsorbed 1.3 times more LPS and adhered to 1.6 times more macrophages than AP4 gel beads. Thus, HS pectin gel has advantages over AP gel concerning swelling behavior, protein adsorption, and biocompatibility.
... A variety of Toll-like receptors (TLR) are expressed on the surface of macrophages [5]. TLR4 is an important TLR, which could be activated by a variety of PAMPs [6]. The high expression of TLR4 receptor on macrophages enables macrophages to quickly activate and plays a role in response to pathogen invasion [7]. ...
Preprint
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Hydrogen (H 2 ), a new type of medical gas molecule, which has significant preventive effect on numerous diseases and its anti-inflammatory properties has been proven in previous studies. However, the mechanisms of H 2 anti-inflammatory activity in signal transduction pathway or protein level regulation are inadequately inexplicit. In the current study, the effect of H 2 on LPS-induced inflammation in RAW 264.7 cells were assessed and its molecular mechanisms were clarified. The in vitro model of inflammation was induced by lipopolysaccharide (LPS) in RAW264.7 cells. Cell viability was evaluated by MTT assay. Protein expression of inflammatory mediators were analyzed by ELISA and Western blot. mRNA levels were detected by RT-qPCR. In addition, RNA sequencing (RNA-seq) was conducted to explore the molecular targets of H 2 anti-inflammatory. According to the findings, H 2 reversed LPS-induced variety in NO levels and TNF-a production as well as IL-6, IL-10 proteins and related mRNA levels in macrophages. RNA-seq newly discovered that H 2 acted on inflammatory signaling molecule protein kinase C 8 (PKC8) and heterodimer activator protein-1 (AP-1). The WB analysis was then used to determine the key proteins in the inflammatory signaling pathway involved in PKC8 and AP-1, which found that H 2 inhibited the phosphorylation of key proteins in the NF-kB and MAPKs pathways, thereby the expression of mRNA and inflammatory mediators were affected. The findings of this study show that H 2 may serve as a promising anti-inflammatory gas in mitigating inflammatory conditions.
... Macrophages have gained great interest within the previous decade and currently their role in the stimulation of innate immunity to potentially prevent IDs is getting appreciated (Gupta et al., 2017). Macrophages or mononuclear phagocytes are majorly found in connective tissues and every organ in the body and these cells are also well known as professional phagocytes in which they express a multitude of receptors on their surfaces (Mitchell and Isberg, 2017;Murray and Wynn, 2012). ...
Article
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Macrophages play a vital role in primary immune responses mainly by carrying out phagocytosis that involves the production of nitric oxide (NO). NO is synthesized by inducible nitric oxide synthase (iNOS) to combat aetiological agents that are able to cause infectious diseases (IDs). Asiatic acid (AA) and madecassoside (MA) are two pentacyclic triterpene compounds derived from Centella asiatica (Linn.) Urban that involved in many pharmacological activities of this plant. However, there is still limited study using a normal immune model that resembles a healthy community to test the immunomodulatory effect of these compounds. Thus, this study used unstimulated macrophages as an in vitro normal model to investigate the effect of both compounds on phagocytosis activity. To achieve the aim of this study, the effects of AA and MA, alone and in combination, on the phagocytosis uptake, NO production, and iNOS expression of macrophages after 24 hours of treatment were measured. Briefly, macrophages (J774A.1) were cultured in five groups, namely untreated macrophages, macrophages treated with lipopolysaccharides (LPS) as a positive control, and macrophages treated with AA and MA alone and in combination (AA + MA). The investigation on phagocytosis uptake, NO production, and iNOS expression were conducted by using microscopic analysis on Giemsastained slides, the Griess assay, and Western blot, respectively. The results presented that the combination (AA + MA) treatment enhanced phagocytosis uptake, NO production, and iNOS expression of macrophages when compared to the untreated macrophages as well as macrophages treated with AA and MA, respectively. In conclusion, the combination (AA + MA) treatment is able to stimulate phagocytosis activity of macrophages and this new finding provides initial knowledge for the development of a natural product-based preventive agent against IDs © 2021 Nurul Hikmah Harun et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
... Elevated expression levels of IFNs and MCP-1 were detected, but the levels of IFNs were much lower than that of IL-1β ( Figure 2). Our result was in agreement with other ndings that IFNs were less abundantly produced by the stimulated macrophages, compared to IL-1β or TNF-α [44][45][46]. However, the degree of increasing in the expression level of IFNs was obviously higher than that of IL-1β in PM patients [47][48][49]. ...
Preprint
Full-text available
Backgrounds: This study was designed to investigate the role of the nucleotide-binding-domain (NBD)-and leucine-rich repeat (LRR)-containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM). Results: We found that the percentage of CD68+ cells, and the expression levels of NLRP3, caspase-1 and interleukin-1 beta (IL-1β) in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment in the Raw 264.7 macrophages resulted in activation of NLRP3 inflammasome and secretion of IL-1β as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1). Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular to develop to PM, in the co-cultured C2C12 cells. Genetic knockdown of NLRP3 inflammasome using siRNA or pharmacological inhibition of NLRP3 inflammasome using MCC950 effectively suppressed MHC-I overexpression in the co-cultured C2C12 cells. Certain levels of IL-1β rather than IFNs showed the effect of up-regulating MHC-I expression in C2C12 cells. IL-1β blockade using neutralizing IL-1β monoclonal antibody or siRNA of IL-1β suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition using MCC950 reduced the expression of NLRP3, IL-1β and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum. Conclusions: Collectively, these results suggested that NLRP3/caspase-1/IL-1β axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM.
... demonstrated that polysaccharides derived from Tinospora cordifolia induce the secretion of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-12, and IFN-γ, by RAW 264.7. Moreover, NO levels are also enhanced along with the up-regulation of iNOS and surface MHC-II and CD-86 expression in murine Mfs post-treatment with T. cordifolia polysaccharides (Gupta et al., 2017). as basal antibody background reference. ...
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Marine seaweeds are a rich source of sulfated polysaccharides (SPs) with several biological activities, including antitumor effect. Some polysaccharides are also described to activate macrophages (MΦs) to an antitumor M1-like phenotype. Here, we evaluated the capacity of SPs extracts obtained from three seaweed species, Gracilaria cornea (Gc-E), Gracilaria birdiae (Gb-E), and Solieria filiformis (Sf-E), to activate the MΦs antitumor M1 phenotype. The nitric oxide production, MHCII, and CD86 M1 markers were evaluated to screening the bioactive SPs profile on murine MΦs (RAW 264.7 cells). The direct SPs antiproliferative effect was tested on melanoma B16-F10 cells. In another experimental setting, B16-F10 cells were incubated with a conditioned medium obtained from MΦs exposed to SPs. The three SPs tested induced NO release. Sf-E directly inhibited B16-F10 cells proliferation compared with the saline group, but Gc-E and Gb-E failed to inhibit cell proliferation. Notably, a conditioned medium (CM) of MΦs incubated with Gc-E and Sf-E, but not of Gb-E, inhibited the proliferation of B16-F10 cells. Gc-E also induced TNF-α release and increase of M1 markers such as iNOS, MHCII, and CD86. Therefore, Gc-E activates a macrophage M1 phenotype, which in turn releases a factor that inhibits B16-F10 proliferation.
... The anti-inflammatory properties of Tinospora cordifolia extract (TCE) is mediated via suppression of proinflammatory cytokines such as IL-1β, IL-6, IL-17 and TNF-α in LPS induced Raw 264.7 macrophages, neuroinflammatory rat model and in arthritis model [87][88][89]. The polysaccharide G1-4A from Tinospora cordifolia shows anti-microbial activity by inhibiting the survival of both drug sensitive as well as multiple drug resistant Mycobacterium tuberculosis (MTB) strains under both in vitro and in vivo conditions through the modulation of the host immune system in a TLR4-dependent manner [89,90]. Thus, these studies suggest that Tinospora cordifolia exhibits anti-viral and anti-inflammatory properties. ...
Article
In 2020, a novel strain of coronavirus (COVID-19) has led to a significant morbidity and mortality worldwide. As of the date of this writing, a total of 116 M cases has been diagnosed worldwide leading to 2.5 M deaths. The number of mortalities is directly correlated with the rise of innate immune cells (especially macrophages) in the lungs that secrete inflammatory cytokines (IL-1β and IL-6) leading to the development of "Cytokine Storm Syndrome" (CSS), multi-organ-failure and death. Given that currently the treatment of this condition is rare and release of effective vaccine might be months away, here, we review the plants and their pharmacologically active-compounds as potential phytopharmaceuticals for the virus induced inflammatory response. Experimental validation of the effectiveness of these natural compounds to prevent or reduce the cytokine storm might be beneficial as an adjunct treatment of SARS-CoV-2.
... 16 When they are activated, macrophages can increase the secretion of the immune molecules, including Nitric Oxide (NO) and other pro-inflammatory cytokines, such as Tumour Necrosis Factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8, IL-12 and Interferon (IFN)-γ. [17][18][19] Especially, NF-κB is recognized as a key regulator of cytokine expression and is closely associated with the generation of ROS and induction of apoptosis in macrophages. 20 Besides secretion the immune molecules, macrophages can exert their immunoregulation effects by devouring foreign pathogens and cell fragments. ...
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PCp-I is a polysaccharide isolated and identified from the Psoralea corylifolia L. by our research group. In this study, the immunomodulatory effects of PCp-I on RAW264.7 cells was evaluated. PCp-I could enhance the level of NO along with up-regulation of iNOS mRNA in RAW264.7 cells. The PCp-I could significantly up-regulate the mRNA expression of TNF- α and IL-6 in RAW264.7 cells, and then the expression of TNF- α, IL-6, ROS and the phagocytic activity were increased. Additionally, PCp-I could significantly up-regulate the phosphorylation level of p65, p38, ERK and JNK proteins, which proved that PCp-I could activate the macrophages by MAPKs and NF- κB signalling pathway and the TLR4 may be one of the receptors of PCp-I regulate the RAW264.7 cells.
... Thus, the acidic arabinogalactan were capable of modulating both innate and adaptive immune responses. Gupta, Rajan & Kulkarni [67] reported up regulation of expression of TNF-α, IL-β, IL-6, IL-12, IL-10 and IFN-γ in RAW 264.7 cell line and peritoneal macrophages after treatment with the same acidic arabinogalactan. Nitric oxide levels were also enhanced along with up-regulation of NOS2 expression in murine macrophages due to treatment of G1-4A. ...
Article
The emergence of the novel coronavirus, SARS-CoV-2 has pushed forward the world to experience the first pandemic of this century. Any specific drug against this RNA virus is yet to be discovered and presently, the COVID-19 infected patients are being treated symptomatically. During the last few decades, a number of polysaccharides with potential biological activities have been invented from Indian medicinal plants. Many polysaccharides, such as sulfated xylomannan, xylan, pectins, fucoidans, glucans, glucoarabinan, and arabinoxylan from Indian medicinal plants, have been shown to exhibit antiviral and immunomodulating activities. Plant polysaccharides exhibit antiviral activities through interference with the viral life cycle and inhibition of attachment of virus to host cell. Intake of certain immune stimulating plant polysaccharides may also protect from the virus to a certain extent. In process of continuous search for most potent drug, Indian plant polysaccharides may emerge as significant biomaterial to combat COVID-19. This review explores a number of polysaccharides from Indian medicinal plants which showed antiviral and immunomodulating activities. It is aimed to provide an overview about the composition, molecular mass, branching configuration and related bioactivities of polysaccharides which is crucial for their classification as possible drug to induce immune response in viral diseases.
... Previous reports of G1-4A's ability to activate murine macrophages, as evidenced by increased phagocytosis, were confirmed and found to be dependent upon ERK and NF-jB. In later studies, Gupta et al. also found that G1-4A elicited a TLR4-MyD88 dependent Th1 cytokine response characterized by up-regulation of TNFa and IL-1b and an M1 phenotype highlighted by increased MHC-II and CD-86 surface expression in murine macrophages (Gupta et al. 2017). Pharmacologic inhibitors demonstrated the role of key cell signaling pathways, including p38, ERK, and JNK MAPKs, in macrophage activation by G1-4A. ...
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Emergent health threats have heightened human awareness of the need for health and wellness measures that promote resilience to disease. In addition to proper nutrition and exercise, health-conscious consumers are seeking natural-based modalities, e.g. botanical preparations, that positively impact the immune system. In Ayurvedic ethnomedicine, Tinospora cordifolia (T. cordifolia), a deciduous climbing shrub indigenous to India, has been used to historically to combat acute and chronic inflammation as well as to promote a balanced immune response. As a dietary supplement, T. cordifolia has been administered most often as a decoction either alone or in compositions containing other medicinal plant extracts of the Terminalia and Phyllanthus species. Extensive phytochemical characterization of aqueous and alcoholic extracts of different Tinospora species has identified over two hundred different phytochemicals from non-overlapping chemical classes with the most abundant being diterpenoids containing the clerodane-type skeleton. Numerous pharmacology studies have demonstrated that T. cordifolia modulates key signaling pathways related to cell proliferation, inflammation, and immunomodulation. However, rigorous dereplication studies to identify active constituents in various T. cordifolia extracts and their fractions are lacking. In this review, we will summarize the current information regarding T. cordifolia’s ethnomedicinal uses, phytochemistry, pharmacological activities, and safety in order to highlight its potential as an immunomodulatory dietary supplement.
... The extract was found more active towards KB and SiHa cell lines than pure molecules, which showed specific activity. In addition, a study by Gupta, Rajan and Kulkarni [117] revealed that treatment of G1-4A activates murine macrophages through the classical pathway in TLR4 dependent manner. It also promotes the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, IFN-γ, IL-12 and IL-6 in RAW 264.7 cells. ...
Article
Tinospora cordifolia (Giloy) is a medicinal plant used in folk and Ayurvedic medicines throughout India since ancient time. All the parts of the plant are immensely useful due to the presence of different compounds of pharmaceutical importance belonging to various groups as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, and phenolics. These compounds possess pharmacological properties which makes it anti-diabetic, antipyretic, anti-inflammatory, anti-oxidant, hepatoprotective, and immuno-modulatory. However, due to the increasing population, there is an inadequate supply of drugs. Therefore, this review focuses on the phytochemistry, ethnopharmacology, clinical application and its conservation strategies so that the plant can be conserved for future generations and utilized as an alternative medicine as well as to design various pharmacologically important drugs.
... Among them, IL-6 level had no difference between each surface, while IL-10 level in Ti-SLA, Ti-NW and Ti-NW-Zn groups were significantly higher than those in the cp-Ti group. IL-6 is recognized to be involved in pro-inflammation regulation, and IL-10 is the anti-inflammatory cytokine associated with the polarization of M2 macrophages and wound healing [46]. These results suggested that the preferences of macrophages in all four surfaces were tended to be the M2 phenotype rather than M1 phenotype, and Ti-SLA, Ti-NW and Ti-NW-Zn surfaces were more preferred to induce the M2 phenotype than the cp-Ti surface. ...
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Titanium (Ti) and its alloys as bio-implants have excellent biocompatibilities and osteogenic properties after modification of chemical composition and topography via various methods. The corrosion resistance of these modified materials is of great importance for changing oral system, while few researches have reported this point. Recently, oxidative corrosion induced by cellular metabolites has been well concerned. In this study, we explored the corrosion behaviors of four common materials (commercially pure Ti, cp-Ti; Sandblasting and acid etching-modified Ti, Ti-SLA; nanowires-modified Ti, Ti-NW; and zinc-containing nanowires-modified Ti, Ti-NW-Zn) with excellent biocompatibilities and osteogenic capacities under the macrophages induced-oxidizing microenvironment. The results showed that the materials immersed into a high oxidizing environment were more vulnerable to corrode. Meanwhile, different surfaces also showed various corrosion susceptibilities under oxidizing condition. Samples embed with zinc element exhibited more excellent corrosion resistance compared with other three surfaces exposure to excessive H2O2. Besides, we found that zinc-decorated Ti surfaces inhibited the adhesion and proliferation of macrophages on its surface and induced the M2 states of macrophages to better healing and tissue reconstruction. Most importantly, zinc-decorated Ti surfaces markedly increased the expressions of antioxidant enzyme relative genes in macrophages. It improved the oxidation microenvironment around the materials and further protected their properties. In summary, our results demonstrated that Ti-NW-Zn surfaces not only provided excellent corrosion resistance properties, but also inhibited the adhesion of macrophages. These aspects were necessary for maintaining osseointegration capacity and enhancing the corrosion resistance of Ti in numerous medical applications, particularly in dentistry.
... At the cellular level, many polysaccharides can activate macrophages to increase immune molecules, including nitric oxide (NO) and other proinflammatory cytokines. [89][90][91] At the genetic level, some polysaccharides are able to increase messenger RNA (mRNA) expression of inducible nitric oxide synthase (iNOS) and other cytokines. 31,92,93 At the protein level, the use of western blot analysis reveals that several natural polysaccharides can induce the activation of signal proteins, such as p38, extracellular signal-regulated kinase (ERK), JNK, p65 and p50. ...
Article
In recent years, natural polysaccharides have received increasing attention and become one kind of popular dietary nutrients owing to their various biological functions. Similarly, intestinal microbiota is a hot topic because it is closely associated with human health. Firstly, the summary of microbiota includes methods to study intestinal microorganisms, the changes in microbial composition and main factors to affect gut microbiota composition. Besides, the summary of the immune system contains information on T cells, macrophages, innate lymphoid cells and pattern recognition receptors. Meanwhile, the summary of polysaccharides mainly introduces source, extraction and purification methods, and structural determination of polysaccharides. Gut microbiota can affect the immune system through its composition, structural components and metabolites, while immune deficiency gives rise to dysbiosis of intestinal microbes. Natural polysaccharides not only enhance immunity, but also suppress excessive immune responses caused by various stimuli through directly regulating immune cells or/and improving microbial composition. Notably, natural polysaccharides exhibit potential applications in functional foods due to their abilities to suppress inflammation and cancer. Therefore, we present a comprehensive overview on the gut microbiota, immunity and polysaccharides in many aspects.
... Receptors on surface of macrophages, e.g. Toll-like receptors (TLRs) and complement receptor type 3 (CR3), may interact with polysaccharides [17], stimulating macrophages to release nitric oxide (NO) and cytokines to kill pathogens [18]. Consequently, exogenous antioxidants and phagocytosis ability of macrophages may have vital roles in anti-viral defenses. ...
Article
Rhizome of the fern Dryopteris crassirhizoma Nakai is used as an antiviral drug in China. The objectivewas to characterize physicochemical properties, structural features and antioxidant and immunological activities of D. crassirhizoma polysaccharides. An acidic polysaccharide fraction (DCP-3) was obtained from Dryopteris crassirhizoma Nakai by purification with DEAE-52 and Sephadex G-100. DCP-3was a novel triple-helical polysaccharide with an average MW of 273.2 kDa. This fraction was mainly composed of galactose (36.65%), xylose (34.75%), arabinose (17.07%) and mannose (9.22%). DCP-3 had strong activity for scavenging DPPH radical (IC50: 2.04 mg/mL), hydroxyl radical (IC50: 1.70 mg/mL), and superoxide anions (IC50: 4.20 mg/mL) and also was capable of reducing ferric ions. In addition, nitric oxide productionwas enhanced in RAW264.7 macrophages stimulated by DCP-3. Based on these bioactivities, we inferred that DCP-3 was a functional component of D. crassirhizoma and may confer antivirus activity, with potential applications in functional food and drug industries.
... Similarly, the effect of G1-4A on macrophage RAW264.7 is related to TLR4. An experiment showed that macrophage activity could be decreased after blocking TLR4 activity using siRNA and antibodies, which suggests that G1-4A activates macrophages via a TLR4-MyD88dependent pathway (22,68). ...
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Polysaccharides are among the most important members of the biopolymer family. They are natural macromolecules composed of monosaccharides. To date, more than 300 kinds of natural polysaccharide compounds have been identified. They are present in plants, animals, and microorganisms, and they engage in a variety of physiological functions. In the 1950s, due to the discovery of their immunoregulatory and anti-tumor activities, polysaccharides became a popular topic of research in pharmacology, especially in immunopharmacology. Plants are an important source of natural polysaccharides. Pharmacological and clinical studies have shown that plant polysaccharides have many functions, such as immune regulation, anti-tumor activity, anti-inflammatory activity, anti-viral functions, anti-radiation functions, and a hypoglycaemic effect. The immunomodulatory effects of plant polysaccharides have received much attention. Polysaccharides with these effects are also referred to as biological response modifiers (BRMs), and research on them is one of the most active areas of polysaccharide research. Thus, we summarize immunomodulatory effects of botanical polysaccharides isolated from different species of plants on the macrophage. The primary effect of botanical polysaccharides is to enhance and/or activate macrophage immune responses, including increasing reactive oxygen species (ROS) production, and enhancing secretion of cytokines and chemokines. Therefore, it is believed that botanical polysaccharides have significant therapeutic potential, and represent a new method for discovery and development of novel immunomodulatory medicine.
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The great potential of polysaccharides in immunological regulation has recently been highlighted in pharmacological and clinical studies. Polysaccharides can trigger immunostimulatory responses through molecular identification, intra- and intercellular communication via direct or indirect interactions with the immune system. Various immunostimulatory polysaccharides or their derivative compounds interacts at cellular level to boost the immune system, including arabinogalactans, fucoidans, mannans, xylans, galactans, hyaluronans, fructans, pectin and arabinogalactans, etc. These natural polysaccharides are derived from various plants, animals and microbes. A unique structural diversity has been identified in polysaccharides, while monosaccharides and glucosidic bonds mainly confer diverse biological activities. These natural polysaccharides improve antioxidant capacity, reduce the production of pro-inflammatory mediators, strengthen the intestinal barrier, influence the composition of intestinal microbial populations and promote the synthesis of short-chain fatty acids. These natural polysaccharides are also known to reduce excessive inflammatory responses. It is crucial to develop polysaccharide-based immunomodulators that could be used to prevent or treat certain diseases. This review highlights the structural features, immunomodulatory properties, underlying immunomodulatory mechanisms of naturally occurring polysaccharides, and activities related to immune effects by elucidating a complex relationship between polysaccharides and immunity. In addition, the future of these molecules as potential immunomodulatory components that could transform pharmaceutical applications at clinical level will also be highlighted.
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Objective: Guduchi [Tinospora cordifolia (Willd.) f. and Thoms.], a rasayana (rejuvenator) in the traditional system of Indian medicine (Ayurveda), is known for its diverse bioactivities. The aim of this study was to isolate the immunomodulatory protein (ImP) from commercial guduchi churna (stem powder) and characterize it. Methods: Guduchi churna extract following 80% ammonium sulfate precipitation was chromatographed on Q-Sepharose. Purified guduchi ImP was evaluated for its lymphoproliferative and macrophage activation properties, structural relatedness to certain plant lectins, amino acid composition, stability to trypsin, and N-terminal sequencing. Results: The purified protein, obtained in a yield of 140[Formula: see text]mg/100[Formula: see text]g guduchi churna, showed a molecular mass of [Formula: see text] kDa by SDS-PAGE. Guduchi ImP (10 [Formula: see text]g) showed seven-fold increase over control in mitogenic activity of murine splenocytes, and a four-fold increase over control in nitric oxide (NO) release from murine peritoneal exudates cells (PECs). These activities were abolished in pronase-treated guduchi ImP. Guduchi ImP does not agglutinate rabbit erythrocytes. Rabbit antiserum to guduchi stem ImP strongly reacted with purified guduchi ImP, and did not recognize common plant lectins (concanavalin A (Con A), poke weed mitogen (PWM) and garlic lectin). Amino acid composition of guduchi ImP shows high content of acidic amino acids, serine (12.4%) and cysteine (10.2%); guduchi ImP is highly stable to trypsin and has a blocked N-terminus. Conclusion: Guduchi ImP is an acidic, non-lectin ImP with a high content of serine and cysteine, and appears to have an immense potential for future structural, immunological, and therapeutic studies.
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Polysaccharides extracted from natural resources have attracted extensive attention in biomedical research and pharmaceutical fields, due to their medical values in anti-tumor, immunomodulation, drug delivery, and many other aspects. At present, a variety of natural polysaccharides have been developed as adjuvant drugs in clinical application. Benefit from their structural variability, polysaccharides have great potential in regulating cellular signals. Some polysaccharides exert direct anti-tumor effects by inducing cell cycle arrest and apoptosis, while the majority of polysaccharides can regulate the host immune system and indirectly inhibit tumors by activating either non-specific or specific immune responses. As the essential of microenvironment in the process of tumor development has been gradually revealed, some polysaccharides were found to inhibit the proliferation and metastasis of tumor cells via tumoral niche modulation. Here, we focused on natural polysaccharides with biomedical application potential, reviewed the recent advancement in their immunomodulation function and highlighted the importance of their signaling transduction feature for the antitumor drug development.
Chapter
The natural body’s defence system plays a critical role to keep away the person from infections and minimize the risk of falling sick regularly. The smart way to improve immunity is changing the lifestyle by consuming food that has immunomodulatory activity. Spices/herbs have been used as preservatives as well as traditional medicines since ancient times due to their disease prevention capability. Numerous preclinical and clinical trials over few spans revealed the benefits of spices/herbs and their bioactive compounds in the control and prevention of several complications such as arthritis, respiratory diseases, cancer, cardiovascular disease, glucose impairment, and brain disorders. This chapter deals with the active compounds of spices and herbs and their potential health benefits in the management of the immune system. Overall, extensive research is required to support claims on the immune-boosting effects of foods. KeywordsImmunomodulatorPhytochemicalsBiomoleculesImmunoregulatorAutoimmune diseasesDetoxification
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The use of plant polysaccharides in aquaculture is recognized as a healthy strategy to enhance disease resistance and reduce medication use. Salvia miltiorrhiza polysaccharide (SMP) can regulate the immune function of higher vertebrates. However, the effects of SMP on fish have not been fully investigated. In this study, the ability of SMP to activate the macrophages of Siberian sturgeon (Acipenser bareii) was analyzed in vitro. The effects of SMP on immune cell activity of hybrid sturgeon (A. baerii ♀ × Acipenser schrenckii ♂) and resistance to Aeromonas hydrophila were further detected in vivo. The in vitro results showed that SMP up-regulated phagocytosis, respiratory burst, inducible nitric oxide synthase activity, nitric oxide (NO) concentration, and cytokine mRNA expression of macrophages. The in vivo results showed that dietary supplementation with SMP enhanced the respiratory burst of macrophages and proliferative activity of lymphocytes. Dietary supplementation with SMP increased serum concentrations of lysozyme and NO, and improved the survival rate of hybrid sturgeon challenged with A. hydrophila. Collectively, these results suggest that SMP can improve the immune function and disease resistance of sturgeon. This study provides a theoretical basis for the application of SMP for healthy farming of sturgeon.
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The stem of Opuntia species, a traditional medicinal plant, is widely used as food and functional raw material because of its rich polysaccharide content. There have been many studies on the immune function of polysaccharides from Opuntia stem, but only few have examined this function with respect to intestinal microbes. In this study, the effects of different concentrations of Opuntia stem polysaccharides on the immunity and intestinal microflora of cyclophosphamide (CTX)-induced immunocompromised mice were explored. The results showed that Tibet Opuntia ficus-indica (Linn.) Mill. polysaccharides (ODPs) could effectively increase the white blood cells (WBC) count index of mice and improve their thymus and spleen indices, while effectively promoting the secretion of IL-4, IL-1β, TNF-α and IFN-γ, with these effects being dependent on the concentration of crude polysaccharides. The intake of ODPs significantly regulated the relative abundance of Lactobacillus, Bacteroides and Akkermansia, and the new dominant intestinal bacterial species were Deferribacteres, Actinomycetes, Firmicutes, Tenericutes, Actinomycetes and Pasteurella. In addition, the ODPs could effectively enhance the metabolic level of lysine synthesis and decomposition, regulate the gene expression level after immune disorders, and enhance the overall health of the immunodeficient mice.
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This study aimed to investigate the influence of kappa (κ)-carrageenan on the initial stages of the foreign body response against pectin gel. Pectin-carrageenan (P-Car) gel beads were prepared from the apple pectin and κ-carrageenan using gelling with calcium ions. The inclusion of 0.5% κ-carrageenan (Car0.5) in the 1.5 (P1.5) and 2% pectin (P2) gel formulations decreased the gel strength by 2.5 times. Car0.5 was found to increase the swelling of P2 gel beads in the cell culture medium. P2 gel beads adsorbed 30–42 mg/g of bovine serum albumin (BSA) depending on pH. P2-Car0.2, P2-Car0.5, and P1.5-Car0.5 beads reduced BSA adsorption by 3.1, 5.2, and 4.0 times compared to P2 beads, respectively, at pH 7. The P1.5-Car0.5 beads activated complement and induced the haemolysis less than gel beads of pure pectin. Moreover, P1.5-Car0.5 gel beads allowed less adhesion of mouse peritoneal macrophages, TNF-α production, and NF-κB activation than the pure pectin gel beads. There were no differences in TLR4 and ICAM-1 levels in macrophages treated with P and P-Car gel beads. P2-Car0.5 hydrogel demonstrated lower adhesion to serous membrane than P2 hydrogel. Thus, the data obtained indicate that the inclusion of κ-carrageenan in the apple pectin gel improves its biocompatibility.
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Various structural types of polysaccharides are recognized by toll-like receptor 4 (TLR4). However, the mechanism of interaction between the polysaccharides with different structures and TLR4 is unclarified. This review summarized the primary structure of polysaccharides related to TLR4, mainly including molecular weight, monosaccharide composition, glycosidic bonds, functional groups, and branched-chain structure. The optimal primary structure for interacting with TLR4 was obtained by the statistical analysis. Besides, the dual-directional regulation of TLR4 signaling cascade by polysaccharides was also elucidated from an immune balance perspective. Finally, the 3D interaction model of polysaccharides to TLR4-myeloid differentiation factor 2 (MD2) complex was hypothesized according to the LPS-TLR4-MD2 dimerization model and the polysaccharides solution conformation. The essence of polysaccharides binding to TLR4-MD2 complex is a multivalent non-covalent bond interaction. All the arguments summarized in this review are intended to provide some new insights into the interaction between polysaccharides and TLR4.
Article
Ethnopharmacological relevance Tinospora cordifolia (Thunb.) Miers (Menispermaceae) is a Mediterranean herb, used in Ayurvedic, Siddha, Unani, and folk medicines. The herb is also used in conventional medicine to treat oxidative stress-related diseases and conditions, including inflammation, pain, diarrhea, asthma, respiratory infections, cancer, diabetes, and gastrointestinal disorders. Aim of the review The taxonomy, botanical classification, geographical distribution, and ethnobotanical uses of T. cordifolia, as well as the phytochemical compounds found in the herb, the toxicology of and pharmacological and clinical studies on the effects of T. cordifolia are all covered in this study. Materials and methods To gather information on T. cordifolia, we used a variety of scientific databases, including Scopus, Google Scholar, PubMed, Science Direct, and Springer Link. The information discussed focuses on biologically active compounds found in T. cordifolia, and common applications and pharmacological activity of the herb, as well as toxicological and clinical studies on its properties. Results The findings of this study reveal a connection between the use of T. cordifolia in conventional medicine and its antioxidant, anti-inflammatory, antihypertensive, antidiabetic, anticancer, immunomodulatory, and other biological effects. The entire plant, stem, leaves, root, and extracts of T. cordifolia have been shown to have a variety of biological activities, including antioxidant, antimicrobial, antiviral, antiparasitic, antidiabetic, anticancer, anti-inflammatory, analgesic and antipyretic, hepatoprotective, and cardioprotective impact. Toxicological testing demonstrated that this plant may have medicinal applications. T. cordifolia contains a variety of biologically active compounds from various chemical classes, including alkaloids, terpenoids, sitosterols, flavonoids, and phenolic acids. Based on the reports researched for this review, we believe that chemicals in T. cordifolia may activate Nrf2, which leads to the overexpression of antioxidant enzymes such as CAT, GPx, GST, and GR, and thereby induces the adaptive response to oxidative stress. T. cordifolia is also able to reduce NF-κB signalling by inhibiting PI3K/Akt, activating AMPK and sirtuins, and downregulating PI3K/Akt. Conclusions Our findings indicate that the pharmacological properties displayed by T. cordifolia back up its conventional uses. Antimicrobial, antiviral, antioxidant, anticancer, anti-inflammatory, antimutagenic, antidiabetic, nephroprotective, gastroprotective, hepatoprotective, and cardioprotective activities were all demonstrated in T. cordifolia stem extracts. To validate pharmacodynamic targets, further research is needed to evaluate the molecular mechanisms of the known compounds against gastrointestinal diseases, inflammatory processes, and microbial infections, as immunostimulants, and in chemotherapy. The T. cordifolia safety profile was confirmed in a toxicological analysis, which prompted pharmacokinetic assessment testing to confirm its bioavailability.
Article
Pharmacological and clinical studies have consistently demonstrated that polysaccharides exhibit great potential on immune regulation. Polysaccharides can interact directly or indirectly with the immune system, triggering cell-cell communication and molecular recognition, leading to immunostimulatory responses. Gut microbiota is adept at foraging polysaccharides as energy sources and confers benefits in the context of immunity and chronic autoimmune disease, such as multiple sclerosis. A compelling set of interconnectedness between the gut microbiota, natural polysaccharides, and immune regulation has emerged. In this review, we highlighted the available avenues supporting the existence of these interactions, with a focus on cytokines-mediated and SCFAs-mediated pathways. Additionally, the neuroimmune mechanisms for gut microbiota communication with the brain in multiple sclerosis are also discussed, which will lay the ground for ameliorate multiple sclerosis via polysaccharide intervention.
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This study aimed to design dry powder inhaler formulations using a hydrophilic polymeric polysaccharide, phytoglycogen (PyG), as a multi-functional additive that increases the phagocytic activity of macrophage-like cells and enhances pulmonary delivery of drugs. The safety and usefulness of PyG were determined using in vitro cell-based studies. Dry powder inhaler formulations of an antitubercular drug, rifampicin, were fabricated by spray drying with PyG. The cytotoxicity, effects on phagocytosis, particle size, and morphology were evaluated. The aerosolization properties of the powder formulations were evaluated using an Andersen cascade impactor (ACI). Scanning electron microscope images of the particles on each ACI stage were captured to observe the deposition behavior. PyG showed no toxicity in A549, Calu-3, or RAW264.7 cell lines. At concentrations of 0.5 and 1 g/L, PyG facilitated the cellular uptake of latex beads and the expression of pro-inflammatory cytokine genes in RAW264.7 cells. Formulations with outstanding inhalation potential were produced. The fine particle fraction (aerodynamic size 2–7 µm) of the porous particle batch reached nearly 60%, whereas in the formulation containing wrinkled carrier particles, the extra-fine particle fraction (aerodynamic particle size < 2 μm) was 25.0%±1.7%. The deposition of porous and wrinkled particles on individual ACI stages was distinct. The inclusion of PyG dramatically improved the inhalation performance of porous and wrinkled powder formulations. These easily inhaled immunostimulatory carrier particles may advance the state of research by enhancing the therapeutic effect and alveolar delivery of antitubercular drugs.
Chapter
Polysaccharides are present in plants, animals, and microorganisms, and they engage in a variety of physiological functions, including the immune function. The immunomodulatory effects of polysaccharides have received much attention. The primary impact of polysaccharides is to enhance and/or activate macrophage immune responses, including increasing the synthesis of cytokines. The polysaccharides have significant therapeutic potential as immunomodulatory agents.
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The present study was to investigate the mechanisms involved in macrophage activation by polysaccharides from the fruits of Rubus chingii Hu (RFPs). The results showed that RFPs enhanced pinocytic and phagocytic activity, promoted the expression and secretion of inflammatory factors (ROS, PTGS2, iNOS, IL-6, IL-10 and TNF-α) and chemokines (CCL2 and CXCL10), and boosted the expression of accessory and costimulatory molecules (CD40, CD80, CD86, MHC-I and MHC-II). RNA-Seq analysis identified 2564 DEGs, 1710 GO terms and 101 KEGG pathways. TNF was identified as the core gene via analysis of pathway information integration and PPI network. The western blot analysis combined with functional verification assay confirmed that MAPK, NF-κB and Jak-STAT pathways were essential to RFPs-mediated macrophage activation. TLR2 was revealed to be the functional receptor and involved in the early recognition of RFPs. These results indicated that RFPs modulated macrophage immune response mainly through TLR2-dependent MAPK, NF-κB and Jak-STAT pathways.
Article
The immune effect and the underlying molecular mechanisms of AGPp, a purified polysaccharide extracted from Arca granosa, have been studied in RAW264.7 in vitro. The results showed that AGPp could increase the relative quantity of macrophages, enhance the phagocytosis, and improve the secretion of nitric oxide (NO) and cytokines. Moreover, the results of cell surface receptors screening found that AGPp could bind to the toll-like receptor 4 (TLR4) receptor which on the surface of the RAW264.7 cell membrane. Finally, mechanism studies showed that, AGPp promoted the expression of TLR4 pathway-related proteins, which included MyD88 dependent and TRIF-dependent. However, when TLR4 inhibitor was added, the protein expression and downstream factors in these two pathways were significantly changed. In a word, these results exhibited that AGPp could be a promising functional food in immune-modulation, and this effect was mainly related to the mediating of TLR4/MyD88/NFκB and TLR4/TRIF signaling pathways.
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Tuberculosis (TB), is one of the deadliest infectious‐diseases of human‐civilization. Approximately one‐third of global‐population is latently‐infected with the TB‐pathogen Mycobacterium tuberculosis (M.tb). The discovery of anti‐TB antibiotics leads to decline in death‐rate of TB. However, the evolution of antibiotic‐resistant, M.tb‐strain, and the resurgence of different immune compromised diseases re‐escalated the death‐rate of TB. WHO has already cautioned about the chances of pandemic‐situation in TB endemic countries unless the discovery of new antitubercular drugs, i.e., the need of the hour. Analysing the pathogenesis of TB it was found that M.tb evades the host by altering the balance of immune‐response and affects either by killing the cells or by creating inflammation. In the pre‐antibiotic era, traditional medicines were only therapeutic measures for different infectious‐diseases including tuberculosis. The ancient‐literatures of India or ample Indian traditional knowledge and ethnomedicinal‐practices are evidence for the treatment of TB using different indigenous plants. However, in the light of modern scientific approach, anti‐TB effects of those plants and their bioactive‐molecules were not established thoroughly. In this review, focus has been given on five bioactive‐molecules of different traditionally used Indian ethnomedicinal plants for treatment of TB or TB‐like symptom. These compounds are also validated with proper identification and their mode of action with modern scientific approaches. The effectiveness of these molecules for sensitive or drug‐resistant TB‐pathogen in clinical or preclinical studies were also evaluated. Thus, our specific aim is to highlight such scientifically validated bioactive compounds having anti‐mycobacterial and immuno‐modulatory activity for future use as medicine or adjunct‐therapeutic molecule for TB management.
Article
Alfalfa polysaccharide (APS) has been proposed to exhibit growth-promoting and immune-enhancing bodily functions in vivo. However, little is known about its downstream immunomodulatory and intrinsic molecular mechanisms. Herein, mouse splenic lymphocytes were isolated to characterize the immunomodulatory effects and molecular mechanisms of APS in vitro. The results demonstrated that APS selectively improved the cell viability and IgM production of B cells, but no effects on T cell viability or secretion of IL-2, IL-4 and IFN-γ were observed in vitro. The receptor blocking assay showed that TLR4 was the primary receptor involved in APS-mediated B cell activation, which was confirmed by the results obtained using C57BL/10ScNJ (TLR4 gene-deficient) mice. Moreover, APS activated the TLR4-MyD88 signaling pathway at the translational level by significantly increasing the protein expression of TLR4 and MyD88. Downstream pathway blocking assay demonstrated that both the MAPK and NF-κB pathways were involved in APS-induced B cell activation. Additionally, APS significantly enhanced the phosphorylation of p38, ERK, and JNK and activated the nuclear translocation of the NF-κB p65 subunit. Therefore, we concluded that APS specifically activates the immune functions of splenic B cells by TLR4, acting through the MAPK and NF-κB signaling pathways, and potently activates the p38 pathway.
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The immunomodulatory effect of a novel purified polysaccharide (JCH-1) isolated from Isaria cicadae Miquel had been confirmed to promote secretion of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) in our previous study. However, the immunomodulatory mechanism was still unclear. The purpose of this study was to investigate the immunomodulatory mechanism of JCH-1. Experimental data showed that JCH-1 could increase protein expression of toll-like receptor 4 (TLR4), promote the phosphorylation of mitogen-activated protein kinase (MAPK), as well as nuclear factor-kappa B (NF-κB) p65. Importantly, TLR4 inhibitor inhibited JCH-1-induced activation of MAPK-NF-κB signaling pathway, thus suppressed JCH-1-induced secretion of NO, TNF-α and IL-6. Collectively, these results indicated that JCH-1 actives RAW264.7 cells through TLR4-MAPK-NF-κB signaling pathway.
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Abstract: Background: Plants have been known as an integral part of traditional medicine because of their phytoconstituents with their miraculous substances. Tinospora cordifolia (Guduchi/ Giloy) is one such plant having pharmacological functions and medicinal values due to its several constituents such as terpenes, glycosides, alkaloids, steroids and flavonoids. Thus, it has been rightly mentioned in old texts as “Amrita”. Objective: The objective of the present review is to extend the current knowledge, importance and beneficial pharmacological applications of guduchi in humans for safeguarding various health issues. Methods: We extensively reviewed, analyzed and compiled salient information from the published literature available in PubMed and other scientific databases. Results: The present review describes medicinal applications of T. cordifolia in countering various disorders and usages as anti-oxidant, anti-hyperglycemic, antihyperlipidemic, hepatoprotective, cardiovascular protective, neuroprotective, osteoprotective, radioprotective, anti-anxiety, adaptogenic agent, analgesic, anti-inflammatory, antipyretic, a thrombolytic agent, anti-diarrheal, anti-ulcer, anti-microbial and anti-cancer agent. The plant is also a source of micronutrients viz. copper, calcium, phosphorus, iron, zinc and manganese. A special focus has been made on its health benefits in treating endocrine and metabolic disorders and its potential as an immune booster. Several patents have been filed and granted to inventions encompassing T. cordifolia as a major component of therapeutics for ameliorating metabolic, endocrinal and several other ailments, aiding in the betterment of human life expectancy. Conclusion: The information presented would be beneficial for researchers, medical professionals and pharmaceutical companies to design and develop effective medicines, drugs and healthical products exploiting the multiple as well as specific modes of actions of T. cordifolia, and also help in promoting and popularizing this rich herb having promising potentials to prevent and treat various ailments.
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Rapid emergence of drug resistance in Mycobacterium tuberculosis (MTB) is a major health concern and demands the development of novel adjunct immunotherapeutic agents capable of modulating the host immune responses in order to control the pathogen. In the present study, we sought to investigate the immunomodulatory effects of G1-4A, a polysaccharide derived from the Indian medicinal plant Tinospora cordifolia, in in-vitro and aerosol mouse models of MTB infection. G1-4A treatment of MTB infected RAW264.7 macrophages significantly induced the surface expression of MHC-II and CD-86 molecules, secretion of proinflammatory cytokines (TNF-α, IL-β, IL-6, IL-12, IFN-γ) and nitric oxide leading to reduced intracellular survival of both drug sensitive (H37Rv) as well as multi drug resistant strains (Beijing and LAM) of MTB, which was partially attributed to G1-4A induced NO production in TLR4-MyD88 dependent manner. Similarly, bacillary burden was significantly reduced in the lungs of MTB infected BALB/c mice treated with G1-4A, with simultaneous up-regulation of the expression of TNF-α, INF-γ and NOS2 in the mouse lung along with increased levels of Th1 cytokines like IFN-γ, IL-12 and decreased levels of Th2 cytokine like IL-4 in the serum. Furthermore, combination of G1-4A with Isoniazid (INH) exhibited better protection against MTB compared to that due to INH or G1-4A alone, suggesting its potential as adjunct therapy. Our results demonstrate that modulation of host immune responses by G1-4A might improve the therapeutic efficacy of existing anti-tubercular drugs and provide an attractive strategy for the development of alternative therapies to control tuberculosis.
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Macrophages are myeloid cells that play an essential role in inflammation and host defense, regulating immune responses and maintaining tissue homeostasis. Depending on the microenvironment, macrophages can polarize to two distinct phenotypes. The M1 phenotype is activated by IFN-γ and bacterial products, and displays an inflammatory profile, while M2 macrophages are activated by IL-4 and tend to be anti-inflammatory or immunosupressive. It was observed that DnaK from Mycobacterium tuberculosis has immunosuppressive properties, inducing a tolerogenic phenotype in dendritic cells and MDSCs, contributing to graft acceptance and tumor growth. However, its role in macrophage polarization remains to be elucidated. We asked whether DnaK was able to modulate macrophage phenotype. Murine macrophages, derived from bone marrow, or from the peritoneum, were incubated with DnaK and their phenotype compared to M1 or M2 polarized macrophages. Treatment with DnaK leads macrophages to present higher arginase I activity, IL-10 production and FIZZ1 and Ym1 expression. Furthermore, DnaK increased surface levels of CD206. Importantly, DnaK-treated macrophages were able to promote tumor growth in an allogeneic melanoma model. Our results suggest that DnaK polarizes macrophages to the M2-like phenotype and could constitute a virulence factor and is an important immunomodulator of macrophage responses.
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The polysaccharide fraction from Solanum nigrum Linne has been shown to have antitumor activity by enhancing the CD4+/CD8+ ratio of the T-lymphocyte subpopulation. In this study, we analyzed a polysaccharide extract of S. nigrum to determine its modulating effects on RAW 264.7 murine macrophage cells since macrophages play a key role in inducing both innate and adaptive immune responses. Crude polysaccharide was extracted from the stem of S. nigrum and subjected to ion-exchange chromatography to partially purify the extract. Five polysaccharide fractions were then subjected to a cytotoxicity assay and a nitric oxide production assay. To further analyze the ability of the fractionated polysaccharide extract to activate macrophages, the phagocytosis activity and cytokine production were also measured. The polysaccharide fractions were not cytotoxic, but all of the fractions induced nitric oxide in RAW 264.7 cells. Of the five fractions tested, SN-ppF3 was the least toxic and also induced the greatest amount of nitric oxide, which was comparable to the inducible nitric oxide synthase expression detected in the cell lysate. This fraction also significantly induced phagocytosis activity and stimulated the production of tumor necrosis factor-α and interleukin-6. Our study showed that fraction SN-ppF3 could classically activate macrophages. Macrophage induction may be the manner in which polysaccharides from S. nigrum are able to prevent tumor growth.
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Dendritic cells (DC) play a central role in the development of an adaptive immune response against tumour. In addition to its role in antigen presentation, DC also possesses cytotoxic activity against tumour cells. We have earlier shown phenotypic and functional maturation of bone marrow derived dendritic cells (BMDC) by G1-4A, an arabinogalactan derived from Tinospora cordifolia. In this study, we have investigated the killer phenotype of BMDC matured in the presence of G1-4A, [mBMDC (G1-4A)] on tumour cells. We have observed several fold increase in killing of tumour cells by mBMDC (G1-4A). The tumouricidal activity was not specific to syngeneic tumour cells but could kill xenogenic tumours also. Nitric oxide released by mBMDC (G1-4A) generates peroxynitrite in tumour cells and is responsible for killing of target cells. This killing was completely abrogated by inducible nitric oxide synthase (iNOS) inhibitor 1400W and NADPH oxidase inhibitor apocyanin. The killed target cells are phagocytosed by BMDC which further activate syngeneic cytotoxic T cells. These results thus show that G1-4A treated mBMDC acquire killer phenotype along with maturation which plays an important role in activation of cytotoxic T cells.
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Within the last decade, macrophages have been shown to be capable of differentiating toward a classically activated phenotype (M1) with a high antimicrobial potential or an alternatively activated phenotype (M2). Some pathogens are capable of interfering with differentiation in order to down-regulate the anti-microbial activity and enhance their survival in the host. To test this ability in Salmonella enterica serovar Typhimurium, we infected porcine alveolar macrophages with wild-type Salmonella Typhimurium and its isogenic mutants devoid of two major pathogenicity islands, SPI-1 and SPI-2. The induction of genes linked with M1 or M2 polarization was determined by quantification of gene expression by RT-qPCR. The ΔSPI-1 mutant induced a high, dose-dependent M1 response but a low M2 response in infected macrophages. On the other hand, wild-type Salmonella Typhimurium induced a low M1 response but a high, dose-dependent M2 response in infected macrophages. The response to ΔSPI-2 mutant infection was virtually the same as the wild-type strain. We therefore propose that Salmonella Typhimurium DT104 studied here can polarize macrophages towards the less bactericidal M2 phenotype and that this polarization is dependent on the type III secretion system encoded by SPI-1.
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Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
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Macrophages are terminally differentiated cells of the mononuclear phagocyte system that also encompasses dendritic cells, circulating blood monocytes, and committed myeloid progenitor cells in the bone marrow. Both macrophages and their monocytic precursors can change their functional state in response to microenvironmental cues exhibiting a marked heterogeneity. However, there are still uncertainties regarding distinct expression patterns of surface markers that clearly define macrophage subsets, particularly in the case of human macrophages. In addition to their tissue distribution, macrophages can be functionally polarized into M1 (proinflammatory) and M2 (alternatively activated) as well as regulatory cells in response to both exogenous infections and solid tumors as well as by systems biology approaches.
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The expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) are important host defense mechanisms against pathogens in mononuclear phagocytes. The objectives of this study were to examine the roles of mitogen-activated protein kinases (MAPKs) and transcription factors (nuclear factor-κB [NF-κB] and activating protein 1 [AP-1]) in peptidoglycan (PGN)-induced iNOS expression and NO production in macrophages. PGN is a cell wall component of Gram-positive bacteria that stimulates inflammatory responses both ex vivo and in vivo. PGN stimulates the activation of all three classes of MAPKs, extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38(mapk) in macrophages, albeit with differential activation kinetics. Using a selective inhibitor of JNK (SP600125) and JNK1/2 small interfering RNA (siRNA) knocked-down macrophages, it was observed that PGN-induced iNOS and NO expression is significantly inhibited. This suggested that JNK MAPK plays an essential role in PGN-induced iNOS expression and NO production. In contrast, inhibition of the ERK pathway using PD98059 dose dependently enhanced PGN-induced iNOS expression and NO production. PGN-induced ERK activation was attenuated in ERK1/2 siRNA knocked-down macrophages; however, NO and iNOS expression were significantly enhanced. An electrophoretic mobility shift assay showed that SP600125 inhibited PGN-induced NF-κB and AP-1 activation, whereas inhibition of the ERK pathway enhanced NF-κB activation, but with no effect on AP-1. These results indicate that the JNK MAPK positively regulate PGN-induced iNOS and NO expression by activating NF-κB and AP-1 transcription factors, whereas the ERK pathway plays a negative regulatory role via affecting NF-κB activity.
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IL-12 is a dimeric cytokine that is produced primarily by APCs. In this study we examined the role that the p38 MAPKs (MAPK/p38) play in regulating IL-12 production. We show that inhibition of p38 dramatically increased IL-12 production upon stimulation, while decreasing TNF-α. This reciprocal effect on these two cytokines following MAPK/p38 inhibition occurred in many different APCs, following a variety of different stimuli. IL-12 production was also increased in macrophages treated with small interfering RNA to limit p38α expression, and in macrophages deficient in MKK3, a kinase upstream of p38. The increase in IL-12 production following MAPK/p38 inhibition appears to be due to enhanced IL-12 (p40) mRNA stability. We show that MAPK/p38 inhibition can promote Th1 immune responses and thereby enhance vaccine efficacy against leishmaniasis. In a mouse model of Leishmania major infection, vaccination with heat-killed L. major plus CpG and SB203580 elicited complete protection against infection compared with heat-killed L. major plus CpG without SB203580. Thus, this work suggests that MAPK/p38 inhibitors may be applied as adjuvants to bias immune responses and improve vaccinations against intracellular pathogens.
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Although an abundance of evidence has indicated that tumor-associated macrophages (TAMs) are associated with a favorable prognosis in patients with colon cancer, it is still unknown how TAMs exert a protective effect. This study examined whether TAMs are involved in hepatic metastasis of colon cancer. One hundred and sixty cases of pathologically-confirmed specimens were obtained from colon carcinoma patients with TNM stage IIIB and IV between January 1997 and July 2004 at the Cancer Center of Sun Yat-Sen University. The density of macrophages in the invasive front (CD68TFHotspot) was scored with an immunohistochemical assay. The relationship between the CD68TFHotspot and the clinicopathologic parameters, the potential of hepatic metastasis, and the 5-year survival rate were analyzed. TAMs were associated with the incidence of hepatic metastasis and the 5-year survival rate in patients with colon cancers. Both univariate and multivariate analyses revealed that the CD68TFHotspot was independently prognostic of survival. A higher 5-year survival rate among patients with stage IIIB after radical resection occurred in patients with a higher macrophage infiltration in the invasive front (81.0%) than in those with a lower macrophage infiltration (48.6%). Most importantly, the CD68TFHotspot was associated with both the potential of hepatic metastasis and the interval between colon resection and the occurrence of hepatic metastasis. This study showed evidence that TAMs infiltrated in the invasive front are associated with improvement in both hepatic metastasis and overall survival in colon cancer, implying that TAMs have protective potential in colon cancers and might serve as a novel therapeutic target.
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YCP, a novel (1,4)-alpha-D-glucan, was isolated from the mycelium of the marine filamentous fungus Phoma herbarum YS4108. In this work, we investigated a YCP-binding cellular receptor expressed by macrophages and the intracellular signal transduction pathways involved in YCP-induced macrophage activation. Fluorescence-labeled YCP (fl-YCP) was prepared using the CDAP-activation method. Fluorescence confocal laser microscopy and fluorescence-activated cell sorting (FACS) were used to analyze the effect of fl-YCP on macrophages. To characterize the properties of the YCP receptor, carbohydrates and antibodies were used to inhibit the binding of fl-YCP to macrophages. Moreover, we investigated the role of membrane receptors Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), Toll-like receptor 6 (TLR6) and complement receptor 3 (CR3). We also examined the role of the p38 kinase pathway in mediating nitric oxide (NO) production. YCP had an in vitro stimulatory effect on the release of NO in macrophage, and fl-YCP can bind directly to receptors on the surface of macrophages in a time- and dose-dependent manner. Competition studies show that LPS, laminarin, anti-TLR4 antibody and anti-CD11b (CR3) antibody could inhibit fl-YCP binding to macrophages. Conversely, mannose, anti-TLR2 and anti-TLR6 antibody could not. Treatment of RAW264.7 cells with YCP resulted in significant activation of p38 in a time-dependent manner. The specific p38 inhibitor SB203580 abrogated YCP-induced NO generation. Treatment of RAW264.7 cells with anti-TLR4 antibody and anti-CR3 antibody significantly reduced YCP-induced NO production and p38 activation. We have demonstrated that YCP-induced NO production occurs through the TLR4 and CR3 membrane receptors in a p38 kinase-dependent manner in macrophages.Acta Pharmacologica Sinica (2009) 30: 1008-1014; doi: 10.1038/aps.2009.93.
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The adverse effects of lipopolysaccharide (LPS) are mediated primarily by tumor necrosis factor alpha (TNF-alpha). TNF-alpha production by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. We set out to determine which MAPK signaling pathways are activated in our system and which MAPK pathways are required for TNF-alpha gene transcription or TNF-alpha mRNA translation. We confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). We demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, we demonstrate that dexamethasone, which inhibits the production of cytokines, including TNF-alpha, significantly inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase-defective mutant of SAPKbeta, SAPKbeta K-A, blocked translation of TNF-alpha, as determined by using a TNF-alpha translational reporting system. Finally, overexpression of wild-type SAPKbeta was able to overcome the dexamethasone-induced block of TNF-alpha translation. These data confirm that three MAPK family members and their upstream activators are stimulated by LPS and demonstrate that JNK/SAPK is required for LPS-induced translation of TNF-alpha mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF-alpha is also revealed.
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Tumor necrosis factor-alpha (TNFalpha) and nitric oxide (NO), the product of inducible NO synthase (iNOS), mediate inflammatory and immune responses in the CNS under a variety of neuropathological situations. They are produced mainly by "activated" astrocytes and microglia, the two immune regulatory cells of the CNS. In this study we have examined the regulation of TNFalpha and iNOS gene expression in endotoxin-stimulated primary glial cultures, focusing on the role of mitogen-activated protein (MAP) kinase cascades. The bacterial lipopolysaccharide (LPS) was able to activate extracellular signal-regulated kinase (ERK) and p38 kinase subgroups of MAP kinases in microglia and astrocytes. ERK activation was sensitive to PD98059, the kinase inhibitor that is specific for ERK kinase. The activity of p38 kinase was inhibited by SB203580, a member of the novel class of cytokine suppressive anti-inflammatory drugs (CSAIDs), as revealed by blocked activation of the downstream kinase, MAP kinase-activated protein kinase-2. The treatment of glial cells with either LPS alone (microglia) or a combination of LPS and interferon-gamma (astrocytes) resulted in an induced production of NO and TNFalpha. The two kinase inhibitors, at micromolar concentrations, individually suppressed and, in combination, almost completely blocked glial production of NO and the expression of iNOS and TNFalpha, as determined by Western blot analysis. Reverse transcriptase-PCR analysis showed changes in iNOS mRNA levels that paralleled iNOS protein and NO while indicating a lack of effect of either of the kinase inhibitors on TNFalpha mRNA expression. The results demonstrate key roles for ERK and p38 MAP kinase cascades in the transcriptional and post-transcriptional regulation of iNOS and TNFalpha gene expression in endotoxin-activated glial cells.
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Macrophage activation by cytokines or microbial products such as LPS results in the induction and release of several key immune effector molecules including NO and IL-12. These have been shown to play crucial roles in the development of immunity to intracellular pathogens such as Leishmania. The molecular mechanisms underlying the induction of these effector molecules are not fully understood. We now show that the extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases play differential roles in the regulation of LPS-stimulated inducible NO synthase and IL-12 gene expression. In macrophages, LPS stimulates the simultaneous activation of all three classes of MAP kinases, ERK, c-jun N-terminal kinase, and p38, albeit with differential activation kinetics. However, studies using inhibitors selective for ERK (PD98059) and p38 (SB203580) show that while p38 plays an essential role in the induction of inducible NO synthase, ERK MAP kinases play only a minor role in promoting NO generation. In contrast, while p38 promotes induction of IL-12 (p40) mRNA, ERK activation suppresses LPS-mediated IL-12 transcription. The biological relevance of these regulatory signals is demonstrated by our finding that Leishmania lipophosphoglycans, which promote parasite survival, act by stimulating ERK MAP kinase to inhibit macrophage IL-12 production. Thus, as ERK and p38 MAP kinases differentially regulate the induction of the macrophage effector molecules, inducible NO synthase and IL-12, these kinases are potential targets not only for the development of novel strategies to combat intracellular pathogens but also for therapeutic immunomodulation.
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Macrophage activation determines the outcome of infection by Mycobacterium tuberculosis (Mtb). Interferon-γ (IFN-γ) activates macrophages by driving Janus tyrosine kinase (JAK)/signal transducer and activator of transcription–dependent induction of transcription and PKR-dependent suppression of translation. Microarray-based experiments reported here enlarge this picture. Exposure to IFN-γ and/or Mtb led to altered expression of 25% of the monitored genome in macrophages. The number of genes suppressed by IFN-γ exceeded the number of genes induced, and much of the suppression was transcriptional. Five times as many genes related to immunity and inflammation were induced than suppressed. Mtb mimicked or synergized with IFN-γ more than antagonized its actions. Phagocytosis of nonviable Mtb or polystyrene beads affected many genes, but the transcriptional signature of macrophages infected with viable Mtb was distinct. Studies involving macrophages deficient in inducible nitric oxide synthase and/or phagocyte oxidase revealed that these two antimicrobial enzymes help orchestrate the profound transcriptional remodeling that underlies macrophage activation.
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It has been shown recently that different genotypes of Mycobacterium tuberculosis induce distinct immune responses in the host, as reflected by variations in cytokine and iNOS expression. Because these molecules are probably regulated by multiple factors in vivo this complex phenomenon was partially analysed by assessing cytokine and iNOS expression by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in an in vitro model of bone marrow-derived macrophages infected with three different M. tuberculosis genotypes: Canetti, H37 Rv and Beijing. Although the three genotypes induced production of iNOS and the different cytokines tested at 24 h post-infection, macrophages infected with the Beijing isolate expressed the highest levels of mRNA for iNOS, interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, IL-12 cytokines and lower levels of IL-10 compared with cells infected with other genotypes. This expression pattern has been associated with infection control, but during infection in vivo with the Beijing genotype it is lost upon progression to chronic phase. The failure to control infection is likely to be influenced by cytokines produced by other cell types and bacterial molecules expressed during the course of disease. Results presented in this work show that each genotype has the ability to induce different levels of cytokine expression that could be related to its pathogenesis during infection.
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Botanical polysaccharides exhibit a number of beneficial therapeutic properties, and it is thought that the mechanisms involved in these effects are due to the modulation of innate immunity and, more specifically, macrophage function. In this review, we summarize our current state of understanding of the macrophage modulatory effects of botanical polysaccharides isolated from a wide array of different species of flora, including higher plants, mushrooms, lichens and algae. Overall, the primary effect of botanical polysaccharides is to enhance and/or activate macrophage immune responses, leading to immunomodulation, anti-tumor activity, wound-healing and other therapeutic effects. Furthermore, botanical and microbial polysaccharides bind to common surface receptors and induce similar immunomodulatory responses in macrophages, suggesting that evolutionarily conserved polysaccharide structural features are shared between these organisms. Thus, the evaluation of botanical polysaccharides provides a unique opportunity for the discovery of novel therapeutic agents and adjuvants that exhibit beneficial immunomodulatory properties.
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Comprehensive analysis of the gene expression profiles associated with human monocyte-to-macrophage differentiation and polarization toward M1 or M2 phenotypes led to the following main results: 1) M-CSF-driven monocyte-to-macrophage differentiation is associated with activation of cell cycle genes, substantiating the underestimated proliferation potential of monocytes. 2) M-CSF leads to expression of a substantial part of the M2 transcriptome, suggesting that under homeostatic conditions a default shift toward M2 occurs. 3) Modulation of genes involved in metabolic activities is a prominent feature of macrophage differentiation and polarization. 4) Lipid metabolism is a main category of modulated transcripts, with expected up-regulation of cyclo-oxygenase 2 in M1 cells and unexpected cyclo-oxygenase 1 up-regulation in M2 cells. 5) Each step is characterized by a different repertoire of G protein-coupled receptors, with five nucleotide receptors as novel M2-associated genes. 6) The chemokinome of polarized macrophages is profoundly diverse and new differentially expressed chemokines are reported. Thus, transcriptome profiling reveals novel molecules and signatures associated with human monocyte-to-macrophage differentiation and polarized activation which may represent candidate targets in pathophysiology.
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The Toll-like receptor (TLR) family plays a fundamental role in host innate immunity by mounting a rapid and potent inflammatory response to pathogen infection. TLRs recognize distinct microbial components and activate intracellular signaling pathways that induce expression of host inflammatory genes. Extensive research in the past decade to understand TLR-mediated mechanisms of innate immunity has enabled pharmaceutical companies to begin to develop novel therapeutics for the purpose of controlling inflammatory disease. Initially, extracellular TLR agonists were designed to compete with natural microbial ligands for binding to TLRs. More recently, basic research to identify new targets for drug development has begun to explore modulation of TLR intracellular signaling pathways, in addition to TLR ligand binding. In this review, we will discuss recent strategies, including the use of decoy peptides and mimetics, plant polyphenols, and chemically modified antisense oligonucleotides, that inhibit different molecular events in TLR signaling pathways to modulate the inflammatory response. The molecular mechanisms of these inhibitors range from interference with protein-protein interactions between signaling proteins, to inhibition of transcription factor activity, to perturbation of the plasma membrane, and are derived from host, pathogen, and plant sources and by rational design. Taken together, these studies represent promising avenues for the development of novel tailored immune therapeutics that can relieve the great toll inflicted by inflammatory disease on human health and quality of life.
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Macrophages are key players of tissue homeostasis and are cells involved in all major human diseases including infections, tumors, western life-style associated diseases and even neurodegenerative diseases. Therefore, specifically targeting macrophages seems to be an attractive therapeutic approach, yet such strategies have not been successfully translated to the clinic. An important hallmark of macrophages is their astounding plasticity and their capacity to integrate microenvironmental signals to perform distinct biological functions. Understanding the cellular programming of macrophages during such events will be a fundamental pre-requisite to develop targeted therapeutic approaches in human diseases. Here, I highlight recent findings of how macrophage activation is regulated and how one can envision much more specific approaches of targeting macrophages.
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Pro-inflammatory macrophages are involved in vascular inflammation and serve as the major effector cells in the pathophysiology of atherosclerosis. Phosphatidylcholine (PC) is a major phospholipid moiety affixed to oxidized low-density lipoprotein (oxLDL) and thought to play important roles in the development of atherosclerosis. In this study we described that a bioactive lipid derivative, lysophosphatidylcholine (lysoPC), generated from hydrolysis of the PC moiety of oxidized LDL, promoted and stabilized a strong M1 phenotype in macrophage polarization. Another derivative, 9-hydroxyoctadecadienoic Acid (9-HODE), did not show the similar biological function. Blockade of G protein coupled receptor, G2A, which mediates the signal transduction of lysoPC, diminished the effects of lysoPC on the macrophage polarization toward M1 phenotype. The results provide insights into the new mechanism on how oxidized LDL participates in tissue inflammation in atherosclerosis.
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Schisandra chinensis (Turcz.) Baill has been used in traditional Chinese medicine for centuries(1). Previous studies have shown that Schisandra polysaccharide (SCPP11) has robust antitumor activity in vivo. In this study, the immunomodulatory activity and mechanisms of action of SCPP11 were investigated further to reveal its mechanism of action against tumors. Results showed that SCPP11 increased the thymus and spleen indices, pinocytic activity of peritoneal macrophages, and hemolysin formation in CTX-induced immunosuppressed mice. Moreover, SCPP11 significantly increased immunoglobulin levels, cytokines levels in vivo and induced RAW264.7 cells to secrete cytokines in vitro. RAW264.7 cells pretreated with SCPP11 significantly inhibited the proliferation of HepG-2 cells. In addition, SCPP11 promoted both the expression of iNOS protein and of iNOS and TNF-α mRNA. TLR-4 is a possible receptor for SCPP11-mediated macrophage activation. Therefore, the data suggest that SCPP11 exerted its antitumor activity by improving immune system functions through TLR-4-mediated up-regulation of NO and TNF-α.
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Chlamydia are intracellular bacteria which infect many vertebrates, including humans. They cause a myriad of severe diseases, ranging from asymptomatic infection to pneumonia, blindness or infertility. IFN-γ plays an important role in defense against acute infection and in the establishment of persistence. Chlamydia have evolved mechanisms to escape IFN-γ functions. IFN-γ-mediated effector mechanisms may involve effects on the metabolism of tryptophan or iron, on the inducible NO synthase (iNOS), on the secretion of chemokines and adhesion molecules or on the regulation of T-cell activities. IFN-γ is secreted by the innate and the adaptive arms of the immune system. Within the former, Chlamydia-infected macrophages express IFN-γ that in turn mediates resistance to infection. IFN-α/β are pivotal for both IFN-γ- and iNOS-mediated resistance to chlamydial infection in macrophages.
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Polarized activation of cells of the monocyte-macrophage lineage into M1 and M2 cells is an operationally useful, simplified descriptor of the functional plasticity of these cells. Ghassabeh and colleagues now put to the test the actual in vivo validity and significance of the M1/M2 paradigm.
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Mononuclear phagocytes play a fundamental role in the tissue homeostasis and innate defenses against viruses and other microbial pathogens. In addition, they are likely involved in several steps of cancer development. Circulating monocytes and tissue macrophages are target cells of viral infections, including human cytomegalovirus, human herpes virus 8, and the HIV, and alterations of their functional and phenotypic properties are likely involved in many tissue-degenerative diseases, including atherosclerosis and cancer. Different tissue microenvironments as well as their pathological alterations can profoundly affect the polarization state of macrophages toward the extreme phenotypes conventionally termed M1 and M2. Thus, targeting disease-associated macrophages is considered a potential approach particularly in the context of cancer-associated tumor-associated macrophages, supporting malignant cell growth and progression toward a metastatic phenotype. Of note is the fact that tumor-associated macrophages isolated from established tumors display phenotypic and functional features similar to those of in vitro-derived M2-polarized cells. Concerning HIV-1 infection, viral eradication strategies in the context of combination antiretroviral therapy should also consider the possibility to deplete, at least transiently, certain mononuclear phagocytes subsets, although the possibility of distinguishing those that are either infected or pathogenically altered remains a goal of future research. In the present review, we will focus on the recent literature concerning the role of human macrophage polarization in viral infections and cancer.
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We report, herein, an attempt to determine whether an IL-10-induced immunological state affects the response of macrophages against Salmonella Typhimurium (ST). Pretreatment with mrIL-10 induced the intracellular invasion of ST into macrophages in a dose-dependent manner. It also activated AKT phosphorylation, cyclin D1, Bcl-X(L), and COX-2 upon ST infection, which may correlate with Salmonella's survival within the macrophages. However, I-κB phosphorylation was shown to be inhibited, along with the expression of TNF-α and MIP-2α mRNA. Therefore, IL-10 not only suppresses the bactericidal response of macrophages against ST, but also ultimately causes infected macrophages to function as hosts for ST replication.
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Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.
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The concept of an alternative pathway of macrophage activation has stimulated interest in its definition, mechanism, and functional significance in homeostasis and disease. We assess recent research in this field, argue for a restricted definition, and explore pathways by which the T helper 2 (Th2) cell cytokines interleukin-4 (IL-4) and IL-13 mediate their effects on macrophage cell biology, their biosynthesis, and responses to a normal and pathological microenvironment. The stage is now set to gain deeper insights into the role of alternatively activated macrophages in immunobiology.
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G1-4A, a polysaccharide from an Indian medicinal plant Tinospora cordifolia, was recently shown to protect mice against septic shock by modulating the proinflammatory cytokines. G1-4A also activated B cells polyclonally. The present report describes in detail the molecular events associated with G1-4A-induced immunomodulation in vitro and in vivo. G1-4A treatment led to an increase in the CD69 expression in lymphocytes. G1-4A-induced proliferation of B cells was completely inhibited by PI3K inhibitor Ly294002, mTOR inhibitor rapamycin and NF-kappaB inhibitor plumbagin. Akt, ERK and JNK were activated by G1-4A which finally resulted in the activation of IKK, degradation of IkappaB-alpha and translocation of NF-kappaB to the nucleus. Administration of G1-4A to mice led to splenomegaly and an increase in the numbers of T cells, B cells and macrophages. This increase in spleen cellularity was due to in vivo proliferation of lymphocytes and upregulation of anti-apoptotic genes. Anti-TLR4-MD2 complex antibody inhibited G1-4A-induced B cell proliferation and degradation of IkappaB-alpha suggesting that TLR-4 was a receptor for G1-4A on B cells. Activation of RAW 264.7 macrophages by G1-4A was found to be dependent on ERK and NF-kappaB-mediated signals. The phagocytosis index in peritoneal exudate cells (PEC) isolated from G1-4A treated mice was significantly higher as compared to that in PEC from control mice. G1-4A administration also increased the number of CD11b(+) cells in the PEC without an increase in the total number of PEC. Thus the present understanding of the molecular mechanism of action of G1-4A, a novel non-microbial TLR4 agonist, will pave the way for its application as an immunomodulator and adjuvant.
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Macrophages are innate immune cells with well-established roles in the primary response to pathogens, but also in tissue homeostasis, coordination of the adaptive immune response, inflammation, resolution, and repair. These cells recognize danger signals through receptors capable of inducing specialized activation programs. The classically known macrophage activation is induced by IFN-gamma, which triggers a harsh proinflammatory response that is required to kill intracellular pathogens. Macrophages also undergo alternative activation by IL-4 and IL-13, which trigger a different phenotype that is important for the immune response to parasites. Here we review the cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures. We draw attention to discrepancies found between mouse and human models of alternative activation. The evidence for in vivo alternative activation of macrophages is also analyzed, with nematode infection as prototypic disease. Finally, we revisit the concept of macrophage activation in the context of the immune response.