Showing papers in "Immunopharmacology and Immunotoxicology in 2014"
TL;DR: Recent and ongoing clinical trials in this field are presented, including clinical studies which combine anti-CD40 treatment with other cancer-treatments, such as Rituximab and Tremelimumab.
Abstract: The costimulatory molecule CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on various antigen presenting cells (APCs) as well as some tumor cells. The binding to the natural ligand CD40L, which is expressed on T helper cells, leads to APC activation and thus enhancement of immune responses. Treatment with anti-CD40 monoclonal antibodies has been exploited in several cancer immunotherapy studies in mice and led to the development of anti-CD40 antibodies for clinical use. Here, Dacetuzumab and Lucatumumab are in the most advanced stage and are being tested as treatment for malignancies such as chronic lymphatic leukemia (CLL), Multiple Myeloma (MM), and non-Hodgkin's lymphoma (NHL). The promising results from these early clinical trials have encouraged clinical drug development in order to investigate the effect of CD40 mAbs in combination with other cancer immunotherapies, in particular interleukin (IL)-2. An in-depth analysis of this immunotherapy is provided elsewhere. In the present review, we provide an update of the most recent clinical trials with anti-CD40 antibodies. We present and discuss recent and ongoing clinical trials in this field, including clinical studies which combine anti-CD40 treatment with other cancer-treatments, such as Rituximab and Tremelimumab.
94 citations
TL;DR: Galangin was found to elicit anti-inflammatory effects by inhibiting ERK and NF-κB-p65 phosphorylation, and galangin-inhibited IL-1β production in LPS-activated macrophages.
Abstract: Inflammation is the major symptom of the innate immune response to microbial infection. Macrophages, immune response-related cells, play a role in the inflammatory response. Galangin is a member of the flavonols and is found in Alpinia officinarum, galangal root and propolis. Previous studies have demonstrated that galangin has antioxidant, anticancer, and antineoplastic activities. However, the anti-inflammatory effects of galangin are still unknown. In this study, we investigated the anti-inflammatory effects of galangin on RAW 264.7 murine macrophages. Galagin was not cytotoxic to RAW 264.7 cells, and nitric oxide (NO) production induced by lipopolysaccharide (LPS)-stimulated macrophages was significantly decreased by the addition of 50 μM galangin. Moreover, galangin treatment reduced mRNA levels of cytokines, including IL-1β and IL-6, and proinflammatory genes, such as iNOS in LPS-activated macrophages in a dose-dependent manner. Galangin treatment also decreased the protein expression levels...
70 citations
TL;DR: In vitro antibody-display technologies such as phage display, cell surface display, ribosome display and mRNA display are reviewed that can be used to isolate high specificity and affinity single-chain antibodies against a wide variety of targets.
Abstract: Recombinant antibodies are increasingly being employed as therapeutic agents especially in combination with anti-cancer drugs. The single-chain antibody fragments are small antigen-binding proteins which provide the most commonly used antibody formats for diagnostic and therapeutic purposes. These antibody fragments have more rapid tumor penetration and clearance from the serum relative to full-length monoclonal antibodies. There are in vitro antibody-display technologies such as phage display, cell surface display, ribosome display and mRNA display that can be used to isolate high specificity and affinity single-chain antibodies against a wide variety of targets. We review these strategies for generation of stable and active antibody fragments in the present article.
55 citations
TL;DR: The novel findings indicate that AFB1 more intensively stimulates CYP genes expression in monocytes than in lymphocytes, which could explain a more pronounced immunotoxicity of AFB1 in myeloid thanin lymphoid lineage cells in vitro/situ/vivo.
Abstract: Context: Aflatoxins (AFs) are highly hazardous mycotoxins with potent carcinogenic, mutagenic and immune disregulatory properties. Cytochrome P450 (CYP) isoforms are central for enhanced AFB1 toxicity in situ. It remains to be seen whether and how these AFB1 activators work in human leukocytes.Objective: To investigate the involvement of CYP isoforms in AFB1 toxicity of circulating mononuclear cells, we examined the impact of environmentally relevant levels of AFB1 on lymphocytes and monocytes.Materials and methods: Very low and moderate doses of AFB1 with/without CYP inducers on transcription of key CYP isoforms and toll-like receptor 4 (TLR4) were examined in human lymphocytes, monocytes and HepG2 cells; cell cycle distribution and viability were also analyzed in AFB1-exposed lymphocytes and monocytes.Results: Only CYP1A1, CYP1B1, CYP3A4, CYP3A5 and CYP3A7 expressed in lymphocytes and monocytes. TLR4 much more expressed in monocytes than in lymphocytes, but HepG2 showed little TLR4 transcription...
50 citations
TL;DR: Of note, EGTE treatment decreased the production antigen-specific IgE via increased the proportion of CD4+ CD25+ regulatory T lymphocytes in the spleen, suggesting that EGTE may play a role in regulating the allergic response.
Abstract: Green tea is a widely consumed beverage known for its beneficial anti-inflammatory, anti-oxidative, anti-mutagenic, anti-carcinogenic, and cardioprotective properties. Here, we administered epigallocatechin gallate fraction of green tea extract (EGTE) to mice for 6 weeks and examined the effects on the innate and adaptive immune responses by measuring phagocytic and natural killer (NK) cell activity, as well as antigen-specific proliferation, cytolysis, cytokine secretion, and antibody production. Our data show that EGTE administration increased NK cell cytolysis and peritoneal cell phagocytosis, as well as splenocyte proliferation and secretion of IL-2 and IFN-γ. Of note, EGTE treatment decreased the production antigen-specific IgE via increased the proportion of CD4+ CD25+ regulatory T lymphocytes in the spleen, suggesting that EGTE may play a role in regulating the allergic response.
50 citations
TL;DR: At indicated dosage, PPar-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-αligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.
Abstract: Context: The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity.Objective: To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats.Methods: Rats were given FEN or PIO (150 or 5 mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20 mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists.Results: MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or...
43 citations
TL;DR: The data suggest that ATL-I shows an anti-inflammatory effect by inhibiting TNF-α and IL-6 production and may be associated with the inhibition of the NF-κB, ERK1/2 and p38 signaling pathways.
Abstract: Atractylenolide I (ATL-I) is a bioactive component of Rhizoma Atractylodis macrocephalae. Although increasing evidence shows that ATL-I has an anti-inflammatory effect, the anti-inflammatory molecular mechanism of ATL-I is still unknown. In this study, we investigated the effect of ATL-I on cell viability by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and the level of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by enzyme-linked immunosorbent assay (ELISA) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further, we examined the effect of ATL-I on the activation of nuclear factor-kappaB (NF-κB) and phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38) by Western blot. We also investigated the effect of ATL-I on the expression of myeloid differentiation protein-2 (MD-2), CD14, complement receptor 3 (CR3), scavenger receptor class A (SR-A), toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). We found that ATL-I showed no inhibitory effect on cell viability at concentrations ranging from 1 µM to 100 µM and markedly reduced the release of IL-6 and TNF-α at a concentrate-dependent manner. In addition, ATL-I suppressed the activity of nuclear NF-κB and the phosphorylation of ERK1/2 and p38 in LPS-treated RAW264.7 cells. Further analysis showed that ATL-I inhibited the expression of MD-2, CD14, SR-A, TLR4 and MyD88, but the expression of CR3 was unaffected. These data suggest that ATL-I shows an anti-inflammatory effect by inhibiting TNF-α and IL-6 production. The anti-inflammatory effects of ATL-I may be associated with the inhibition of the NF-κB, ERK1/2 and p38 signaling pathways.
39 citations
TL;DR: The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood–brain barrier (BBB), and inhibited matrix metalloproteinase 9 and aquaporin 4 expression, implying thatRapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression.
Abstract: Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 μg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood–brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BB...
31 citations
TL;DR: The data suggest the presence of imbalanced immune condition involving inflammation and immunosuppression in thalassemia patients, which could be modulated to a more effective immune response by silymarin.
Abstract: Several immunological abnormalities have been characterized in β-thalassemia, many of which are linked to or identified with cytokines. In this study, we investigated the serum levels of TGF-β, IL-10, IL-17 and IL-23 in β-thalassemia major patients in comparison with healthy controls. The immunomodulatory effect of silymarin (a flavonoid complex obtained from Silybum marinum) on the serum levels of cytokines was further evaluated in thalassemia patients receiving silymarin (420 mg/day) and compared with patients treated with placebo for 6-month. Serum cytokines levels were measured by enzyme linked immunosorbent assay (ELISA). The results showed a significant higher concentration of TGF-β and IL-23 in the patient group than control group. Among studied cytokines, a significant reduction in serum IL-10 levels was found in patients treated with silymarin when compared with IL-10 values at baseline. However, no significant difference was observed between baseline values of cytokine compared with end ...
30 citations
TL;DR: CK suppressed the severity of AA rats by attenuating the paw swelling and histopathology of joint and influencing the function of immunocyte (B cell and macrophage) and effectors’ cells (FLS) in AA.
Abstract: Objective: To investigate the effects of ginsenoside metabolite compound K (CK) on adjuvant-induced arthritis (AA) rats and the partial mechanisms focused on the function of immunocyte (B cell and macrophage) and effectors’ cell (fibroblast-like synoviocyte, FLS).Methods: Animals were divided randomly into nine groups including control, AA, CK (5, 10, 20, 40, 80, and 160 mg/kg, i.g.), and MTX (0.5 mg/kg, i.g.). The effects of CK on AA rats are evaluated by swelling of the paw, histopathology of joint, and inflammatory cytokine production in serum. To further investigate the effects of CK on the function of B cell, peritoneal macrophage, and FLS from AA rats, we examined the proliferation of B cell and FLS by [3H] thymidine incorporation, and the phagocytic function of peritoneal macrophage was measured by neutral red uptake. Cytokines and antibodies in serum and the supernatant from peritoneal macrophage and FLS were measured by ELISA kit.Results: CK suppressed the severity of AA rats by attenuati...
29 citations
TL;DR: Taraxasterol has a protective effect on murine endotoxic shock induced by LPS through modulating inflammatory cytokine and mediator secretion, and this finding might provide a new strategy for the treatment of endotoxicshock and associated inflammation.
Abstract: Taraxasterol, a pentacyclic-triterpene, was isolated from the Chinese medicinal herb Taraxacum officinale. In the present study, we investigated the protective effect of taraxasterol on murine model of endotoxic shock and the mechanism of its action. Mice were treated with 2.5, 5 and 10 mg/kg of taraxasterol prior to a lethal dose of lipopolysaccharide (LPS) challenge. Survival of mice was monitored twice a day for 7 days. To further understand the mechanism, the serum levels of inflammatory cytokine tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6) and mediator nitric oxide (NO), prostaglandin E₂ (PGE₂) as well as histology of lungs were examined. The results showed that taraxasterol significantly improved mouse survival and attenuated tissue injury of the lungs in LPS-induced endotoxemic mice. Further studies revealed that taraxasterol significantly reduced TNF-α, IFN-γ, IL-1β, IL-6, NO and PGE₂ levels in sera from mice with endotoxic shock. These results indicate that taraxasterol has a protective effect on murine endotoxic shock induced by LPS through modulating inflammatory cytokine and mediator secretion. This finding might provide a new strategy for the treatment of endotoxic shock and associated inflammation.
TL;DR: The results reveal the molecular mechanism of of MSM indicating that MSM supplementation may be beneficial for complications related to nitric oxide-dependent apoptosis in inflammatory conditions, however, the optimum concentration of MSM must be chosen carefully to elicit the desired effect.
Abstract: Methylsulfonylmethane (MSM) is a non-toxic, natural organosulfur compound, which is known to possess antioxidant and anti-inflammatory activities. In recent years, MSM has been widely used as a dietary supplement for its beneficial effects against various diseases, especially arthritis. Despite being a popular supplement product, the mechanism of action of MSM is not well known. This study was designed to investigate the effects of MSM on cytotoxic signals induced by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) in RAW 264.7 macrophage-like cells. The results showed that MSM reversed apoptosis of RAW 264.7 macrophage-like cells at non-cytotoxic concentrations probably through the modulation of apoptotic proteins. After pre-treatment of cells with non-toxic doses of MSM; caspase-3 activation, p53 accumulation, cytochrome c release and Bax/Bcl-2 ratio were significantly decreased and full length poly ADP-ribose polymerase (PARP) was significantly increased. In addition, the loss of mitochond...
TL;DR: Compared with vitamin E, it seems that selenium could assert an important effect against the immunotoxic effects of T-2 toxin against T lymphocytes.
Abstract: Context: T-2 toxin, a potent mycotoxin, has serious effects on immune system.Objective: Here, the effects of a sublethal dose of this toxin on T lymphocyte sub-population levels and the potential protective effects from treatment with selenium or vitamin E were studied.Materials and methods: After having determined the sublethal dose of the T-2 toxin in Balb/c mice hosts, the post-injection kinetics of changes in T lymphocyte sub-population (CD3+, CD4+ and CD8+ cells) profiles were analyzed via flow cytometry. For these studies, the selenium and vitamin E were either provided to the mice before or concurrent with the toxin.Results: The results show that after a sublethal dose of T-2 alone, the number of CD8+ T-lymphocytes was significantly decreased at 12 h and normalized at 48 h. In contrast, level of CD3+ and CD4+ T-lymphocytes were significantly increased at 24 h and returned to normal after 48 h. When selenium was injected into the mice 24 h before or concurrent with the T-2, the effects on CD...
TL;DR: Because of the safety and possible prolongation of OS, a clinical trial of PPV without chemotherapy during the 1st to 12th vaccination in recurrent ovarian cancer patients is merited.
Abstract: Context: To develop a personalized peptide vaccine (PPV) for recurrent ovarian cancer patients and evaluate its efficacy from the point of view of overall survival (OS), Phase II study of PPV was performed.Patients and methods: Forty-two patients, 17 with platinum-sensitive and 25 with platinum-resistant recurrent ovarian cancer, were enrolled in this study and received a maximum of four peptides based on HLA-A types and IgG responses to the peptides in pre-vaccination plasma.Results: Expression of 13 of the 15 parental tumor-associated antigens encoding the vaccine peptides, with the two prostate-related antigens being the exceptions, was confirmed in the ovarian cancer tissues. No vaccine-related systemic severe adverse events were observed in any patients. Boosting of cytotoxic T lymphocytes or IgG responses specific for the peptides used for vaccination was observed in 18 or 13 of 42 cases at 6th vaccination, and 19 or 29 of 30 cases at 12th vaccination, respectively. The median survival time ...
TL;DR: The results show that the anti-inflammatory properties of GA potentially result from the inhibition of COX-2, iNOS, IL-6, TNF-α and NO through the down-regulation of RIP2 and NF-κB activation, which impact the development of potential health products for preventing and treating inflammatory diseases.
Abstract: Gomisin A (GA), a lignan component contained in the fruit of Schisandra chinensis Baillon, improves hepatic cell degeneration, vasodilatory activity and insulin sensitivity. These effects also impact the immune system, including various inflammatory mediators and cytokines. In this study, the anti-inflammatory effect of GA on lipopolysaccharide-stimulated mouse peritoneal macrophages was studied. Pretreatment with GA attenuated the expression of receptor-interacting protein 2 (RIP2) and IκB kinase-β (IKK-β) as well as IKK-β phosphorylation. The activation of nuclear factor-kappa B (NF-κB) in the nucleus, the phosphorylation of IκBα and degradation of IκBα in the cytosol were suppressed by GA. GA decreased the production and mRNA expression of the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. In addition, expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and production of nitric oxide were decreased by pretreatment with GA. In conclusion, these results show that the anti-inflammatory properties of GA potentially result from the inhibition of COX-2, iNOS, IL-6, TNF-α and NO through the down-regulation of RIP2 and NF-κB activation. These results impact the development of potential health products for preventing and treating inflammatory diseases.
TL;DR: It is suggested that clobetasol induces the relief of IMQ-induced psoriasis-like inflammation in a mouse model but that calcipotriol, camptothecin and tazarotene cannot.
Abstract: The interleukin-23/interleukin 17A (IL-23/IL-17A) cytokine axis plays a critical role in the pathogenesis of psoriasis. In this study, we report the effects of topical calcipotriol, camptothecin, clobetasol and tazarotene on the treatment of imiquimod (IMQ)-induced psoriasis-like inflammation, the development of which is dependent on the IL-23/IL-17A axis. IMQ-induced epidermal hyperplasia and inflammation in the BALB/c mouse ear were significantly inhibited following clobetasol treatment but not calcipotriol, camptothecin or tazarotene treatments. Real-time polymerase chain reaction showed that the mRNA levels of IL-17A, IL-17F, IL-22, IL-1β, IL-6 and TNF-α in ear skin were significantly decreased by clobetasol. In addition, we observed that calcipotriol, camptothecin and tazarotene failed to show any inhibitory effects on the IL-23/IL-17A/IL-22 axis. We also found that clobetasol treatment inhibited the proliferation of γδ T cells and C-C chemokine receptor type 6 (CCR6) expression induced by IM...
TL;DR: High doses of ZEN-induced immunomodulatory effects on early pregnant rats by altering immunological parameters are found.
Abstract: Context Zearalenone (ZEN) is a common contaminant that is present in feedstuff of high humidity and high temperatures. Objective The aim of this study was to investigate the effects of diets contaminated with different concentrations of ZEN on immunomodulation in early pregnant rats. Materials and methods Forty-eight pregnant Sprague Dawley (SD) rats were randomly divided into four treatment groups fed on a diet supplemented with one of four concentrations of ZEN: 0 mg/kg (ZEN 0), 50 mg/kg (ZEN 50), 100 mg/kg (ZEN 100) and 150 mg/kg (ZEN 150). The pregnant rats were fed ZEN-treated diets from gestation days 0 to 7 and a basal diet from gestation days 8 to 20. Results ZEN exposure (ZEN 100 and 150) caused significant decreases in splenic coefficients, viability of splenocyte and T-cell proliferation and induced histopathological damage in the spleen of early pregnant rats compared with other groups. Levels of IgG and IgA were decreased, while IgM was increased, in high doses of ZEN (ZEN 100 and ZEN 150) compared with other groups. ZEN 150 caused increases in white blood cells and hemoglobin and induced a significant decrease in platelets in blood of the pregnant rats compared with other groups. ZEN 150 increased the mRNA expression levels of interleukin (IL)-6, IL-18 and IL-1β and decreased the mRNA expression levels of interferon-γ, tumor necrosis factor-α and IL-10 in the spleen of pregnant rats compared with ZEN 0. Conclusion High doses of ZEN-induced immunomodulatory effects on early pregnant rats by altering immunological parameters.
TL;DR: Umbelliprenin has shown a partially Th1 bias with a reduction of regulatory immune response in Lewis lung cancer mouse model, and it is speculated that upon changing the Th1/Th2 balance in favour of Th1, umbelliprein induces its antitumor activity.
Abstract: Umbelliprenin is a member of the 7-prenyloxycoumarins with potential therapeutic properties such as cytotoxic effects on various cancer cells. The present study investigates the effect of umbelliprenin on predominance of Th1 and Th2 responses in Lewis lung cancer (LLC) mouse model. The cytotoxic effect of umbelliprenin was explored on LLC cells and mouse splenocytes by MTT assay. Mice into which LLC had been transplanted were treated with umbelliprenin on alternate days, at 2.5 mg/200 µl intraperitoneally. Foxp3, TNF-α and TGF-β mRNA expressions were assessed in tumor and lung tissues of LLC mice. In addition, IL-10, IFN-γ and IL-4 levels were determined in sera and also in splenocyte culture supernatants at the presence of tumor cell lysate (10 µg/ml) and Con A (3 µg/ml) after 72 h. Results showed the cytotoxic effects of umbelliprenin on LLC cells (IC50 = 51.6 ± 5.4 µM) while no adverse effect was seen at this concentration on normal splenocytes. TNF-α mRNA expression in both lung and tumor tiss...
TL;DR: Tea saponin can markedly inhibit the proliferation and invasiveness of T-lymphoma (EL4) cells, possibly due to TNF-α- and NF-κB-mediated regulation of MAPK signaling pathway.
Abstract: The anti-cancer activity of saponins and phenolic compounds present in green tea was previously reported. However, the immunomodulatory and adjuvanticity activity of tea saponin has never been studied. In this study, we investigated the immunomodulatory effect of tea saponin in T-lymphocytes and EL4 cells via regulation of cytokine response and mitogen-activated protein kinases (MAPK) signaling pathway. Quantitative analysis of mRNA expression level of cytokines were performed by reverse transcription polymerase chain reaction following stimulation with tea saponin, ovalbumin (OVA) alone or tea saponin in combination with OVA. Tea saponin inhibited the proliferation of EL4 cells measured in a dose-dependent manner. No cytotoxicity effect of tea saponin was detected in T-lymphocytes; rather, tea saponin enhanced the proliferation of T-lymphocytes. Tea saponin with OVA increased the expression of interleukin (IL)-1, IL-2, IL-12, interferon-γ and tumor necrosis factor (TNF)-α and decreased the expression level of IL-10 and IL-8 in T-lymphocytes. Furthermore, tea saponin, in the presence of OVA, downregulated the MAPK signaling pathway via inhibition of IL-4, IL-8 and nuclear factor kappaB (NF-κB) in EL4 cells. Th1 cytokines enhancer and Th2 cytokines and NF-κB inhibitor, tea saponin can markedly inhibit the proliferation and invasiveness of T-lymphoma (EL4) cells, possibly due to TNF-α- and NF-κB-mediated regulation of MAPK signaling pathway.
TL;DR: The result suggested that the β-sitosteryl-3-O-β-glucopyranoside inhibited NO and pro- inflammatory productions by down-regulating the gene expression of pro-inflammatory mediators via the negative regulation of the NF-кB pathway in LPS-stimulated RAW 264.7 cells.
Abstract: The bark of Sorbus commixta has been used in Asian traditional medicine for treatment of cough, asthma, bronchial disorders, gastritis and dropsy. However, the anti-inflammatory effect of β-sitosteryl-3-O-β-glucopyranoside, a major compound of the bark of S. commixta, is poorly understood. In this study, we investigated the anti-inflammatory effect and the underlying molecular mechanisms of β-sitosteryl-3-O-β-glucopyranoside in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Prostaglandin E₂ (PGE₂) and cytokines released from cells were measured using EIA assay kit. The expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, Tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) was measured by real-time polymerase chain reaction (RT-PCR) and/or Western blot analysis. β-sitosteryl-3-O-β-glucopyranoside inhibited the production of nitric oxide (NO) and PGE₂ along with the expression of iNOS and COX-2 in LPS-stimulated RAW264.7 cells. In addition, β-sitosteryl-3-O-β-glucopyranoside reduced the release of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6. Moreover, β-sitosteryl-3-O-β-glucopyranoside inhibited the NF-κB activation induced by LPS, which was associated with the abrogation of IκBα degradation and subsequent decreases in nuclear p65 levels. The result suggested that the β-sitosteryl-3-O-β-glucopyranoside inhibited NO and pro-inflammatory productions by down-regulating the gene expression of pro-inflammatory mediators via the negative regulation of the NF-кB pathway in LPS-stimulated RAW 264.7 cells.
TL;DR: Alpinetin have potential effects in downregulating the immune system and might be developed as a useful immunosuppressive agent in treating undesired immune responses.
Abstract: Alpinetin, a flavonoid compound extracted from the seeds of Alpinia katsumadai Hayata, has been known to possess antibacterial, anti-inflammatory and other important therapeutic activities. In the current study, we investigated alpinetin for its immunosuppressive effect on activation and cytokines secretion of murine T lymphocytes. The data showed that alpinetin markedly suppressed ConA-induced murine splenocyte proliferation, Th1/Th2 cytokines production, CD4(+) T-cell populations and ratio of CD4(+)/CD8(+). This inspired us to further study the effects of alpinetin in vivo. The results showed that administration of alpinetin suppressed T-cell-mediated delayed-type hypersensitivity reaction in mice. In addition, we studied signal transduction pathways about T-cell activation on puried murine T lymphocytes by Western-blot assay. The data revealed that alpinetin could shock the activation of NF-κB, NFAT2 signal transduction pathways. These observations indicated that alpinetin have potential effects in downregulating the immune system and might be developed as a useful immunosuppressive agent in treating undesired immune responses.
TL;DR: The toxicity of TLR9 agonists is generally acceptable, except when the agonist is combined with immunosuppressive agents in patients with advanced non-small-cell lung cancer.
Abstract: Context: The promising efficacy of Toll-like receptor 9 (TLR9) agonists for use against pathogenic infections, allergies, malignant neoplasms and autoimmunity have been demonstrated well in clinical studies, but the safety of TLR9 agonists is controversial.Objective: In light of the safety concerns, we conducted a systematic review and meta-analysis of clinical studies of TLR9 agonists.Methods: A systematic literature search was conducted. We selected studies in which the subjects were treated with a TLR9 agonist and in which the safety of the TLR9 agonist was monitored. We extracted data on adverse events (AEs) when available. A meta-analysis was performed to determine the commonest and clinical significant AEs observed in the controlled studies.Results: Nine single-arm studies and 12 controlled studies met our selection criteria. Subjects treated with TLR9 agonists were at a higher risk of anemia (risk ratio [RR] 1.04, 95% confidence interval [CI]: 1.02–1.06), neutropenia (RR 1.16, 95% CI: 1.11–...
TL;DR: Rh2-B1 could stimulate cell proliferation and IFN-γ production by activating the p38 MAPK- and ERK-dependent signaling pathways in cytotoxic T cells and may be a novel medicine for treatment of viral infections.
Abstract: Context: Ginsenoside Rh2, an active component of ginseng, exhibits immunoregulatory and anti-inflammatory properties. Rh2-B1, a sulfated derivative, was prepared to enhance its water solubility. We studied the effect of Rh2-B1 on CTLL-2, a CD8+ cytotoxic T cell line that was known for protecting against viral infection.Objective: We aimed to investigate the effect of Rh2-B1 on interferon (IFN)-γ production and cell proliferation and its possible mechanism.Materials and methods: Enzyme-linked immunosorbent assay (ELISA) was employed to analyze the IFN-γ concentration of the whole blood and the supernatant of CTLL-2 cell culture. Cell proliferation assay was conducted using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Western blots were used to evaluate changes in signal transduction pathways in CTLL-2 cells.Results: Rh2-B1 was able to enhance IFN-γ production from whole blood culture of Balb/c mice. We then evaluated the effect of Rh2-B1 on a cytotoxic T cell line, ...
TL;DR: Overall, PHA-L possesses characteristics of allergens and may play a potential role in the red kidney bean induced allergy.
Abstract: Red kidney bean (Phaseolus vulgaris) is consumed worldwide as a vegetarian protein source. But, at the same time the allergenicity potential of red kidney bean is a matter of concern. This study is aimed towards purification, characterization, thermal stability, proteolytic digestion and allergenicity assessment of one of the clinically relevant allergens of red kidney bean. The purification of red kidney bean allergic protein was carried out with the help of column chromatography, IgE immunoblotting and reverse phase high-pressure liquid chromatography (RP-HPLC). The purified protein was characterized by peptide mass finger printing (PMF) and studied for its thermal stability, and proteolytic resistance using simulated gastric fluid (SGF) assay. The allergenicity potential of the purified protein was studied in BALB/c mice. The purified protein was identified as leucoagglutinating phytohemagglutinin (PHA-L) with molecular weight 29.5 kDa. The PHA-L showed resistance to heat as well as proteolytic...
TL;DR: SPIR is suggested to inhibit LPS-induced proinflammatory mediators via inactivation of IKK/NF-κB in LPS signaling through inhibition of phosphorylation of p65 nuclear factor (NF)-κB and IKK in response to LPS.
Abstract: The effect of spironolactone (SPIR) on lipopolysaccharide (LPS)-induced production of proinflammatory mediators was examined using RAW 264.7 macrophage-like cells and mouse peritoneal macrophages. SPIR significantly inhibited LPS-induced production of nitric oxide (NO), tumor necrosis factor-α and prostaglandin E2. The inhibition was not mediated by cell death. SPIR reduced the expression of an inducible NO synthase mRNA in response to LPS. SPIR significantly inhibited phosphorylation of p65 nuclear factor (NF)-κB in response to LPS. Furthermore, SPIR inhibited phosphorylation of IκB kinase (IKK) as an upstream molecule of NF-κB in response to LPS. LPS did not induce the production of aldosterone in RAW 264.7 cells. Taken together, SPIR is suggested to inhibit LPS-induced proinflammatory mediators via inactivation of IKK/NF-κB in LPS signaling.
TL;DR: Investigation of its effect to suppress airway inflammation, hyper-responsiveness and remodeling in a murine model of chronic asthma indicated that nodakenin might mitigate the development of chronic experimental allergic asthma.
Abstract: Context: Nodakenin is a major coumarin glucoside in the root of Peucedanum decursivum Maxim, a commonly used traditional Chinese medicine for the treatment of asthma and chronic bronchitis for thousands of years.Objective: In this work, the anti-asthma potential of nodakenin was studied by investigation of its effect to suppress airway inflammation, hyper-responsiveness and remodeling in a murine model of chronic asthma.Materials and methods: BALB/c mice sensitized to ovalbumin (OVA) were challenged with aerosolized OVA for 8 weeks, orally administered with nodakenin at doses of 5, 10 and 20 mg/kg before each OVA challenge.Results: Compared with the model group, nodakenin treatment markedly inhibited airway inflammation, hyper-responsiveness and remodeling, showing improvement in subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia, and decreased levels of interleukin (IL)-4, IL-5, IL-13 and matrix metalloproteinase-2/-9 in bronchoalveolar lavage fluid, and the level of O...
TL;DR: The protective role of iNKT cells in the pathogenesis of EAE and human disease is shown to show that they might be a target for therapeutic purposes, but needs more extensive studies of their biology.
Abstract: Multiple sclerosis (MS) is an autoimmune disorder associated with neurological signs and chronic inflammatory demyelination of the central nervous system (CNS). MS has been thought as Th1 (T helper) and Th17 cells mediated disease, but cells of the innate immune system play an important role both in the initiation and progression of MS. The invariant Natural Killer T (iNKT) cells are the unique innate lymphocytes subtype involved in inflammation and autoimmune disorders and secretes cytokines such as interferon gamma (IFN-γ), Interleukin (IL)-10, IL-4 and IL-13. A reduction in number or defect in function of iNKT cells has been associated with an increased prevalence of autoimmune disorders indicating that iNKT cells have an immune-regulatory role in autoimmune disorders. Also, the protective role of iNKT cells has been extensively studied in EAE and the results of these studies show that iNKT cells might be a target for therapeutic purposes, but needs more extensive studies of their biology. In this review, we will attempt to show the protective role of iNKT cells in the pathogenesis of EAE and human disease.
TL;DR: Results indicate that GA and GB may insert their immunomodulatory effects by enhancing DC maturation and modulating Th1/Th2 response through an increase in Th1 responses, implying their beneficial in host defense against infectious diseases.
Abstract: Various studies have described glycyrrhizin (GL), an active triterpenoic saponin extract of licorice roots, as an anti-inflammatory, antiviral, antimicrobial, anti-tumor and immunomodulating agent. The activity of GL has been mainly attributed to its metabolites, 18-alpha (GA) and 18-beta-glycyrrhetinic acid (GB), which their mechanism of action on the immune system cells is not clearly known. In this study, we have investigated the effects of GA and GB on the immune system by targeting dendritic cells and analyzing phenotypic and functional maturity of murine dendritic cells (DCs) after treatment with these components. Stimulation of DCs with GA and GB resulted in up-regulation of CD40, CD86 and MHC-II molecules indicating their effects on the maturation of DCs. These components induced the allogenic immunostimulatory capacity of DCs by stimulating the proliferation of T cells and production of the T helper (h)1-promoting cytokine, IL-12. They also increased the production of IFN-γ by T cells in ...
TL;DR: Results suggested that CsV attenuated LPS-induced inflammatory responses partly via TLR4/CD14-mediated NF-κB and MAPK pathways.
Abstract: Excessive activation of macrophages is implicated in various inflammation resulted injuries. Saponins from Panax japonicus (SPJ) have been shown to possess anti-inflammatory activities. However, whether Chikusetsusaponin V (CsV), the most abundant component of SPJ, can exert anti-inflammatory activities is unknown. The present study was aimed to investigate the anti-inflammatory effects of CsV in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells and the underlying mechanisms. Our data showed that CsV dose-dependently inhibited NO, iNOS, TNF-α and IL-1β expressions in LPS-stimulated RAW264.7 cells. Increased protein levels of nuclear NF-κB and elevated phosphorylation levels of ERK and JNK in LPS-stimulated RAW 264.7 cells were also found downregulated by CsV treatment. Furthermore, the increase of CD14 and TLR4 mRNA expression due to LPS stimulation were significantly reversed by CsV treatment. These results suggested that CsV attenuated LPS-induced inflammatory responses partly via T...
TL;DR: The findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs.
Abstract: Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of immunosuppressive network are present in the tumor microenvironment suppress antitumor immunity by subverting Th1 response in tumor site and considered as a great obstacle for advancement of different cancer immunotherapeutic protocols. Till date, various pharmacological approaches have been explored to modulate the suppressive functions of MDSCs in vivo. The present study describes our endeavor to explore a possibility of eradicating MDSCs by the application of a copper chelate, namely copper N-(2-hydroxy acetophenone) glycinate (CuNG), previously found to be a potential immunomodulator that can elicit antitumorogenic Th1 response in doxorubicin-resistant EAC (EAC/Dox) bearing mice. Herein, we demonstrated that CuNG treatment could reduce Gr-1+CD11b+ MDSC accumulation in ascitic fluid and spleen of EAC/Dox tumor model. Furthermore, we found that CuNG mediated reduction in MDSCs is associated with induction of Th1 response and reduction in Treg cells. Moreover, we observed that CuNG could deplete MDSCs by inducing Fas-FasL mediated apoptotic cell death where death receptor Fas expression is enhanced in MDSCs and FasL is provided by activated T cells. However, MDSC expansion from bone marrow cells and their differentiation was not affected by CuNG. Altogether, these findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs. So, this preclinical study unveils a new mechanism of regulating MDSC levels in drug-resistant cancer model and holds promise of translating the findings into clinical settings.