Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 15, Issue 3, 2015

Hypoxia and Inflammation are strictly interconnected with important consequences at clinical and therapeutic level. While cell and tissue damage due to acute hypoxia mostly leads to cell necrosis, in chronic hypoxia, cells that are located closer to vessels are able to survive adapting their phenotype through the expression of a number of genes, including proinflammatory receptors for alarmins. These receptors are activated by alarmins released by necrotic cells and generate signals for master transcription factors such as NFkB, AP1, etc. which control hundreds of genes for innate immunity and damage repair. Clinical consequences of chronic inflammatory reparative response activation include cell and tissue remodeling, damage in the primary site and, the systemic involvement of distant organs and tissues. Thus every time a tissue environment becomes stably hypoxic, inflammation can be activated followed by chronic damage and cell death or repair with vessel proliferation and fibrosis. This pathway can occur in cancer, myocardial infarction and stroke, diabetes, obesity, neurodegenerative diseases, chronic and autoimmune diseases and age-related diseases. Interestingly, proinflammatory gene expression can be observed earlier in hypoxic tissue cells and, in addition, in activated resident or recruited leukocytes. Herewith, the reciprocal relationships between hypoxia and inflammation will be shortly reviewed to underline the possible therapeutic targets to control hypoxia-related inflammation in a number of epidemiologically important human diseases and conditions.

Resveratrol, a constituent of grapes and various other plants, has been an attractive compound for biomedical studies because moderate long-term drinking of red wine is associated with a reduced risk of lifestyle-related diseases, such as cardiovascular diseases and cancer. Resveratrol is as a phytoalexin, cyclooxygenase (COX) suppressor, and an activator of peroxisome proliferatoractivated receptor (PPAR) and SIRT1. As a major phytoalexin, resveratrol is produced by plants in response to various environmental stresses, such as pathogens and ultraviolet (UV) radiation, and promotes resistance to these stresses. A similar active ingredient, salicylic acid (SA), is also produced by plants. Aspirin, acetylated SA, is a major nonsteroidal anti-inflammatory drug (NSAID) because it inhibits COX activity in humans. The jasmonic acid (JA) pathway in plants and the COX pathway in humans are both defense systems against environmental stresses and involve lipid mediators derived from phospholipids. We can hypothesize that there is a molecular basis for the mutually beneficial relationship between plants and humans, which is important for understanding the mode of action of resveratrol in inflammation. Here we provide a review of the studies on resveratrol, especially with respect to the role of COX and PPAR in inflammation.

Metformin is an oral hypoglycemic agent which is most widely used as first-line therapy for type 2 diabetes. Metformin improves hyperglycemia by suppressing hepatic glucose production and increasing glucose uptake in muscle. Metformin also has been shown to reduce cardiovascular events in randomized controlled trials; however, the underlying mechanism remains to be established. Recent preclinical and clinical studies have suggested that metformin not only improves chronic inflammation through the improvement of metabolic parameters such as hyperglycemia, insulin resistance and atherogenic dyslipidemia, but also has a direct anti-inflammatory action. Studies have suggested that metformin suppresses inflammatory response by inhibition of nuclear factor κB (NFκB) via AMP-activated protein kinase (AMPK)-dependent and independent pathways. This review summarizes the basic and clinical evidence of the anti-inflammatory action of metformin and discusses its clinical implication.

Inflammation is a protective response to eliminate cytotoxic agents and pathogens. Various factors are thought to be involved in the pathological changes in tissues caused by inflammation. Interleukin 1, an inflammatory cytokine, is thought to have diverse physiological functions and to play an important role in inflammatory disease. In this review, we discuss interleukin-1 as a target of inflammatory disease.

Mucosal tissues and especially the intestine are constantly exposed to abundant non-self materials yet simultaneously establish immune homeostasis to prevent excessive inflammatory responses. The maintenance of intestinal homeostasis is achieved by a harmonized immune network mediated by endogenous factors (e.g., cytokines and chemokines) and exogenous factors (e.g., commensal bacteria and dietary matter). Specifically, vitamins from such exogenous sources function immunologically in the control of homeostatic immune responses; thus, their deficient or excessive intake is associated with the development of inflammatory diseases. The focus of this review is the immunologic functions of vitamins B3, B9, A, and D in the regulation and development of inflammation.

In different inflammatory diseases, many metalloproteinases are over expressed and thought to promote progression of the disease. Understanding roles of these enzymes in disease progression as well as in normal homeostasis is crucial to identify target enzymes for the disease. Rheumatoid arthritis (RA) is one of the autoimmune inflammatory diseases in which around 1-2 % of the world populations are suffered from. Roles of metalloproteinases are well documented in RA, but so far none of them is proposed to be a target enzyme. However, there are at least three enzymes that can potentially be molecular targets to inhibit progression of RA. Understanding roles of these enzymes in more detail and developing highly selective inhibitors to these enzymes would be essential for novel antimetalloproteinase therapies in future.

Blood pressure and lipid profile are important determinants of cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). To identify the pleiotropic effects of vildagliptin other than blood glucose lowering effect, a retrospective study was conducted in 128 patients with T2DM treated with vildagliptin 50 mg twice daily. The patients were separated into two groups: patients who were initiated with vildagliptin as monotherapy or add-on therapy (add-on group, n = 66) and patients who were switched from sitagliptin 100 mg once daily to vildagliptin (switching group, n = 62). Hemoglobin A1c (HbA1c), body mass index (BMI), systolic/diastolic blood pressure, lipid profiles, and uric acid (UA) at 3, 6, and 12 months of vildagliptin therapy were compared with those at baseline in each group. At baseline, there were no significant differences in HbA1c, BMI, blood pressures, lipid profiles, and UA levels between the two groups. After vildagliptin initiation, HbA1c decreased significantly but BMI and blood pressure did not change in both groups. Only in the add-on group, total cholesterol and low density lipoprotein cholesterol decreased significantly from baseline to 3, 6, and 12 months. On the other hand, triglyceride and high-density lipoprotein cholesterol did not change in both groups. Serum UA levels decreased only in the switching group from baseline to 3, 6, and 12 months. These results indicate that vildagliptin add-on treatment may have beneficial effects on lipid profiles, and switching from sitagliptin to vildagliptin reduces UA in patients with T2DM; these are important findings linked to the beneficial effects of vildagliptin on lipid and UA metabolisms in the treatment of T2DM.

Fibromyalgia (FM), clinical condition characterized by several signs and symptoms such as widespread pain, trigger point, morning stiffness and extreme tiredness for scarce hours of sleep, is linked to several changes in several brain neurotransmitters, particularly serotonin and norepinephrine. Consequently, the Neural Vegetative System works more and so it generates an exaggerated muscular contraction, sweating and constriction of blood vessels. The aim of our study was to treat a selected group of female patients suffering from FM with duloxetine with physiotherapy. We used two clinical scales (VAS and FIQ) and an objective evaluation such as myometric. The analysis of the data Myoton used during any inspection showed a statistically significant reduction in the values of muscle tone in each district analyzed. This finding was also confirmed by the patients themselves who have experienced a significant welfare and less muscle tension in different locations, as evidenced by data obtained from the clinical scales used by us. In addition, our patients were thought to be satisfied with the improvements not only subjective, but also with the objective witnessed myometry, making them a share of the study and feeling constantly monitored for treatment aimed at a real reduction in muscle stiffness. In conclusion, our study demonstrates combined treatment duloxetine- physiotherapy effectively reduces a symptom often disabling and particularly troublesome in patients with FM as the exaggerated muscle contraction.

Background: Lifestyle changes have led to a high global incidence of type 2 Diabetes mellitus (T2DM). Evidence suggests beneficial effects of the intake of n-3 and n-6 polyunsaturated fatty acids (PUFA) in patients with T2DM. Objective: To investigate the relationship between habitual fatty acid intake and inflammatory biomarkers in Mexican individuals with and without T2DM. Methods: A cross-sectional study of 120 adults with and 120 without T2DM; anthropometric assessments (BMI, waist circumference and body fat), blood pressure, PUFA intake, biochemical analyses (glucose and lipid profile) and inflammation biomarkers (IFN-γ, TNF-α, IL-1 β, IL-2, IL-6, IL-8 and IL-13) was undertaken. Results: Low n-3 intake was found in both groups (0.68 ± 0.55g/day in T2DM vs 0.81 ± 0.53 g/day in non-T2DM). Comparison between groups showed significantly higher concentrations of triacylglcerols (p=.001) and IL-6 (p=.018) in the T2DM group, as well as significant correlations between serum TNF-α and total n-3 fatty acid intake (r=.507, p= .001), EPA (r=.284, p=.002), DHA (r=.404, p=.001), and a weak but significant correlation between serum IL-1β and total PUFA (r=.245, p=.005), total n-3 (r=.214, p=.019) and total n-6 (r=.241, p=.008) intake. Conclusions: Patients with T2DM had a tendency for higher pro-inflammatory cytokines than subjects without T2DM. There was an association between PUFA intake and pro-inflammatory biomarkers in patients with T2DM. Further studies of anti-inflammatory nutrients and plasma and cell fatty acid profiles are needed to corroborate the present findings in patients with and without T2DM.

Idiopathic thrombocytopenic purpura (ITP) as an autoimmune disease is identified by low count platelet due to decreaed platelet production as well as increased platelet destruction by autoimmune mechanisms in which platelet autoantigen(s) react with the patient’s immune system. In ITP a shift toward B cells producing autoantibodies together with CD4+ T helper cells have been reported. T helper cell 22 (Th22) as a new subset of CD4+ T cells is distinctly apart from Th17 and other known CD4+ T cell subsets due to the expression of its specific gene and function. Th22 subset show chemokine receptor CCR4+ CCR6+ CCR10+ phenotype and its key transcription factor is aryl hydrocarbon receptor (AHR). In addition, Th22 cells can be recognized by secretion of a distinguished profile of effector cytokines, including interleukin (IL)- 22, IL- 13, and tumor necrosis factor-α (TNF-α). The amount of Th22 and IL-22 is increased in several autoimmune disorders and positively related to disease severity. The purpose of the present review is to discuss the role of Th22 and its cytokine IL-22 in the immunopathogenesis of ITP.