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Curcumin attenuates proangiogenic and proinflammatory factors in human eutopic endometrial stromal cells through the NF-κB signaling pathway.
Chowdhury, I, Banerjee, S, Driss, A, Xu, W, Mehrabi, S, Nezhat, C, Sidell, N, Taylor, RN, Thompson, WE
Journal of cellular physiology. 2019;(5):6298-6312
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Abstract
Endometriosis is a chronic gynecological inflammatory disorder in which immune system dysregulation is thought to play a role in its initiation and progression. Due to altered sex steroid receptor concentrations and other signaling defects, eutopic endometriotic tissues have an attenuated response to progesterone. This progesterone-resistance contributes to lesion survival, proliferation, pain, and infertility. The current agency-approved hormonal therapies, including synthetic progestins, GnRH agonists, and danazol are often of limited efficacy and counterproductive to fertility and cause systemic side effects due to suppression of endogenous steroid hormone levels. In the current study, we examined the effects of curcumin (CUR, diferuloylmethane), which has long been used as an anti-inflammatory folk medicine in Asian countries for this condition. The basal levels of proinflammatory and proangiogenic chemokines and cytokines expression were higher in primary cultures of stromal cells derived from eutopic endometrium of endometriosis (EESC) subjects compared with normal endometrial stromal cells (NESC). The treatment of EESC and NESC with CUR significantly and dose-dependently reduced chemokine and cytokine secretion over the time course. Notably, CUR treatment significantly decreased phosphorylation of the IKKα/β, NF-κB, STAT3, and JNK signaling pathways under these experimental conditions. Taken together, our findings suggest that CUR has therapeutic potential to abrogate aberrant activation of chemokines and cytokines, and IKKα/β, NF-κB, STAT3, and JNK signaling pathways to reduce inflammation associated with endometriosis.
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Influence of Resveratrol on the Immune Response.
Malaguarnera, L
Nutrients. 2019;(5)
Abstract
Resveratrol is the most well-known polyphenolic stilbenoid, present in grapes, mulberries, peanuts, rhubarb, and in several other plants. Resveratrol can play a beneficial role in the prevention and in the progression of chronic diseases related to inflammation such as diabetes, obesity, cardiovascular diseases, neurodegeneration, and cancers among other conditions. Moreover, resveratrol regulates immunity by interfering with immune cell regulation, proinflammatory cytokines' synthesis, and gene expression. At the molecular level, it targets sirtuin, adenosine monophosphate kinase, nuclear factor-κB, inflammatory cytokines, anti-oxidant enzymes along with cellular processes such as gluconeogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis, and apoptosis. Resveratrol can suppress the toll-like receptor (TLR) and pro-inflammatory genes' expression. The antioxidant activity of resveratrol and the ability to inhibit enzymes involved in the production of eicosanoids contribute to its anti-inflammation properties. The effects of this biologically active compound on the immune system are associated with widespread health benefits for different autoimmune and chronic inflammatory diseases. This review offers a systematic understanding of how resveratrol targets multiple inflammatory components and exerts immune-regulatory effects on immune cells.
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Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes.
Cao, Y, Nishihara, R, Qian, ZR, Song, M, Mima, K, Inamura, K, Nowak, JA, Drew, DA, Lochhead, P, Nosho, K, et al
Gastroenterology. 2016;(5):879-892.e4
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Abstract
BACKGROUND & AIMS Aspirin use reduces colorectal cancer risk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell-mediated adaptive immunity. We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates. METHODS We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study. Participants were asked whether they took aspirin in most weeks, the number of tablets taken per week, and years of aspirin use. We collected available tumor specimens (n = 1458) from pathology laboratories in the United States. A pathologist confirmed the diagnosis of colorectal adenocarcinoma (excluding anal squamous cell carcinoma), and evaluated histopathology features, including patterns and degrees of lymphocytic infiltrates within and around tumor areas. Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis, death, or the end of follow-up evaluation (June 2010). Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral reaction, or Crohn's-like reaction. RESULTS We documented 1458 rectal and colon cancers. The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs (Pheterogeneity = .007). Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63-0.81), and strength of the association depended on aspirin dose and duration (both Ptrend < .001). In contrast, aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs. This differential association was consistent regardless of the status of tumor microsatellite instability, mutations in BRAF, or expression of PTGS2. Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3+ T cells, CD8+ T cells, or CD45RO (PTPRC)+ T cells (measured by immunohistochemistry and computer-assisted image analysis). CONCLUSIONS Based on data from the prospective cohort studies, regular use of aspirin is associated with a lower risk of colorectal carcinomas with low concentrations of TILs. These findings indicate that the immune response in the tumor microenvironment could be involved in the chemopreventive effects of aspirin.
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Salsalate treatment improves glycemia without altering adipose tissue in nondiabetic obese hispanics.
Alderete, TL, Sattler, FR, Richey, JM, Allayee, H, Mittelman, SD, Sheng, X, Tucci, J, Gyllenhammer, LE, Grant, EG, Goran, MI
Obesity (Silver Spring, Md.). 2015;(3):543-51
Abstract
OBJECTIVE Salsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue. METHODS A randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation. RESULTS In those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01). CONCLUSIONS Findings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation.
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Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update.
Sommer, IE, van Westrhenen, R, Begemann, MJ, de Witte, LD, Leucht, S, Kahn, RS
Schizophrenia bulletin. 2014;(1):181-91
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Abstract
BACKGROUND The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest because more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory agents to improve symptoms of schizophrenia. This study provides an update regarding the efficacy of anti-inflammatory agents on schizophrenic symptoms in clinical studies performed so far. METHODS An electronic search was performed using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. Only randomized, double-blind, placebo-controlled studies that investigated clinical outcome were included. RESULTS Our search yielded 26 double-blind randomized controlled trials that provided information on the efficacy on symptom severity of the following components: aspirin, celecoxib, davunetide, fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06-0.537, I(2) = 0), estrogens (ES: 0.51, n = 262, 95% CI: 0.043-0.972, I(2) = 69%), and NAC (ES: 0.45, n = 140, 95% CI: 0.112-0.779) showed significant effects. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect. CONCLUSION The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.
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The plant-based immunomodulator curcumin as a potential candidate for the development of an adjunctive therapy for cerebral malaria.
Mimche, PN, Taramelli, D, Vivas, L
Malaria journal. 2011;(Suppl 1):S10
Abstract
The clinical manifestations of cerebral malaria (CM) are well correlated with underlying major pathophysiological events occurring during an acute malaria infection, the most important of which, is the adherence of parasitized erythrocytes to endothelial cells ultimately leading to sequestration and obstruction of brain capillaries. The consequent reduction in blood flow, leads to cerebral hypoxia, localized inflammation and release of neurotoxic molecules and inflammatory cytokines by the endothelium. The pharmacological regulation of these immunopathological processes by immunomodulatory molecules may potentially benefit the management of this severe complication. Adjunctive therapy of CM patients with an appropriate immunomodulatory compound possessing even moderate anti-malarial activity with the capacity to down regulate excess production of proinflammatory cytokines and expression of adhesion molecules, could potentially reverse cytoadherence, improve survival and prevent neurological sequelae. Current major drug discovery programmes are mainly focused on novel parasite targets and mechanisms of action. However, the discovery of compounds targeting the host remains a largely unexplored but attractive area of drug discovery research for the treatment of CM. This review discusses the properties of the plant immune-modifier curcumin and its potential as an adjunctive therapy for the management of this complication.
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Chemoprevention in gastrointestinal cancers: current status.
Grau, MV, Rees, JR, Baron, JA
Basic & clinical pharmacology & toxicology. 2006;(3):281-7
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Abstract
Chemoprevention, pharmacological intervention for disease prevention, aims to intervene in pathways that lead to clinical disease before the disease occurs. Cancer chemoprevention is a relatively new field, but for gastrointestinal cancers, clinical trials have highlighted the chemopreventive potential of several agents. For colorectal neoplasia, trials with aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) and calcium have demonstrated the most significant reductions of risk. In observational studies, NSAIDs also consistently appear to protect against oesophageal and gastric cancer. Calcium, and perhaps vitamin D, are also promising and have the advantage of being inexpensive, safe interventions. For the prevention of oesophageal cancer, antitumour-B and retinamide have provided hopeful results, although it is not clear that these findings can be extrapolated from the study populations in Asia to western countries. Evidence from China suggests that a combination of beta-carotene, alpha-tocopherol and selenium may protect against oesophageal cancer, but the relative importance of each agent is unclear, and, again, their effects in other populations has not yet been assessed. Mass immunization against hepatitis B seems to be the most effective means of reducing the incidence of hepatocellular cancer worldwide. In addition, treatment with interferon alpha in patients chronically infected with hepatitis C virus shows considerable promise, given the increasing prevalence of hepatitis C virus carriage in recent years. TJ-9, polyprenoic acid and anti-aflatoxin compounds are also possible avenues that deserve future research.
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Effects of celecoxib, medroxyprogesterone, and dietary intervention on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study.
Cerchietti, LC, Navigante, AH, Peluffo, GD, Diament, MJ, Stillitani, I, Klein, SA, Cabalar, ME
Journal of pain and symptom management. 2004;(1):85-95
Abstract
Systemic syndromes characterized by a persistent activity of circulating mediators (cytokines) are frequently present with advanced cancer. We grouped under the general heading of "Systemic Immune-Metabolic Syndrome (SIMS)" a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis, with overlapping clinical manifestations. SIMS may include cachexia, anorexia, nausea, early satiety, fatigue, tumor fever, cognitive changes and superinfection. The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy. Fifteen patients with evidence of SIMS were studied. SIMS was defined as the presence of weight loss, anorexia, fatigue performance status≥2 and acute-phase protein response. Patients received medroxyprogesterone (MPA) (500 mg twice daily), celecoxib (200 mg twice daily), plus oral food supplementation for 6 weeks. After treatment, 13 patients either had stable weight (+/- 1%) or had gained weight. There were significant differences in improvement of body-weight-change rate, nausea, early satiety, fatigue, appetite and performance status. Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients (P=0.039). Our results suggest that patients with advanced lung adenocarcinoma, treated with MPA, celecoxib and dietary intervention, might have considerable improvement in certain SIMS outcomes. This multitargeted symptomatic approach deserves further study.
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Effect of Lactobacillus ingestion on the gastrointestinal mucosal barrier alterations induced by indometacin in humans.
Gotteland, M, Cruchet, S, Verbeke, S
Alimentary pharmacology & therapeutics. 2001;(1):11-7
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Abstract
BACKGROUND Chronic nonsteroidal anti-inflammatory drug (NSAID) ingestion strongly affects the gastrointestinal mucosa as a first stage before ulceration. Some Lactobacillus strains may stabilize the mucosal barrier by increasing mucin expression, reducing bacterial overgrowth, stimulating mucosal immunity and synthetizing antioxidant substances; these events are altered in NSAID-associated gastroenteropathy. AIM: To determine whether ingestion of the probiotic Lactobacillus GG (LGG) protects the gastrointestinal mucosa against indometacin-induced alterations of permeability. SUBJECTS AND METHODS Four gastrointestinal permeability tests were carried out in random order in 16 healthy volunteers: (i) basal; (ii) after indometacin; (iii) after 5 days of living LGG ingestion before indometacin administration; (iv) after 5 days of heat-killed LGG ingestion before indometacin administration. RESULTS Indometacin significantly increased basal sucrose urinary excretion (29.6 mg [17.1-42.1] vs. 108.5 mg [68.2-148.7], P=0.0030) (means [95% CI]) and lactulose/mannitol urinary excretion (1.03% [0.73-1. 32] vs. 2.93% [1.96-3.90], P=0.00012). Heat-killed LGG did not modify the indometacin-induced increase of gastrointestinal permeability, while live bacteria significantly reduced the alteration of gastric (47.8 mg [31.1-64.6], P=0.012) but not intestinal permeability induced by NSAID. CONCLUSIONS Regular ingestion of LGG protects the integrity of the gastric mucosal barrier against indometacin, but has no effect at the intestinal level.