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OBJECTIVE: Polycystic ovary syndrome (PCOS) is a prevalent endocrine health problem during the childbearing period that seriously affects fertility in females. Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARa) agonist, showed beneficial effects in models of endocrine disturbances. Thus, we evaluated the potential therapeutic effect of fenofibrate in experimental PCOS. MATERIALS AND METHODS: Rats received oral fenofibrate (300 mg/kg/day) for three weeks following a three-week PCOS induction regimen using oral letrozole (1 mg/kg/day). We determined the changes in body weight, levels of serum testosterone, insulin, anti-Müllerian hormone (AMH), ovarian malondialdehyde (MDA), superoxide dismutase (SOD), and tissue tumor necrosis factor-alpha (TNFa) and CD95 protein expressions. The tissue expression of interleukin-10 (IL10) and PPARa genes was determined. RESULTS: Letrozole-treated rats showed successful induction of PCOS, confirmed by histopathology and significantly increased body weight, testosterone, insulin, AMH, and MDA, and decreased SOD. Ovaries of untreated PCOS rats showed increased TNFa and CD95 and decreased PPARa and IL10 expression. Administration of fenofibrate ameliorated the letrozole-induced PCOS changes. CONCLUSIONS: Fenofibrate-mediated amelioration of PCOS in rats is attributed partly to its antioxidant, anti-inflammatory, and anti-apoptotic properties and activation of PPARa. [ABSTRACT FROM AUTHOR]

Background: Tumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes. It is one of the key mediators of acute and chronic systemic inflammatory reactions and plays a central role in several autoimmune diseases. A number of approved monoclonal antibodies (mAbs) are widely used to subside these autoimmune diseases. However, there is a high rate of non-responsiveness to treatments with these mAbs. Therefore, it is important to be able to predict responses of the patients in an individualistic manner to these therapeutic antibodies before administration. In the present study, we used in silico tools to explore the effects of missense variants in the respective epitopes of four therapeutic anti-TNFA mAbs—adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM), and infliximab (IFX)—on their interactions with TNFA. Results: The binding affinities of CZP and ADA to corresponding epitopes appear to be reduced by four (TNFAR131Q, TNFAE135G, TNFAR138Q, and TNFAR138W) and two (TNFAG66C and TNFAG66S) variants, respectively. The binding of GLM and IFX appears to be affected by TNFAR141S and TNFAR138W, respectively. TNFAG66C and TNFAG66S may be associated with autoimmune diseases, whereas TNFAE135G, TNFAR138W, and TNFAR141S may be pathogenic per se. Conclusion: These variants may contribute to the observed inter-individual variability in response to anti-TNFA mAbs treatments and be used as markers to predict responses, and thus optimize therapeutic benefits to the patients. [ABSTRACT FROM AUTHOR]

Objective To evaluate gene polymorphisms and their association with susceptibility to dengue. Methods A retrospective case-control study was performed with 262 subjects, comprising 78 dengue fever (DF) patients, 49 dengue hemorrhagic fever (DHF) patients and 135 healthy controls. Genotypic and allelic profiles were identified using polymerase chain reaction based in real time and amplification-refractory mutation system. Results We observed a protective association of IL-10 (−819 C/T) C allele ( P = 0.028, OR = 0.56, CI = 0.34–0.91) against DHF, while the C/T ( P = 0.047, OR = 2.10, CI = 1.01–4.38) and T/T ( P = 0.008, OR = 3.82, CI = 1.38–10.59) genotypes were associated with DHF and DF, respectively. The dominant model TNFA −308 GA + AA ( P = 0.043, OR = 0.45, CI = 0.20–1.00) genotypes were found to have protective effect against dengue infection. A protective association among the IFNG (+874 A/T) A/T genotype against DF ( P = 0.02, OR = 0.46, CI = 0.24–0.89) and DHF ( P = 0.034, OR = 0.43, CI = 0.19–0.95) was observed. When the studied single-nucleotide polymorphism was analyzed in combination, the combination GTA ( P = 0.022, OR = 2.95, CI = 1.18–7.41) was statistically significantly associated with susceptibility to DF and the combination GCT ( P = 0.035, OR = 0.28, CI = 0.08–0.90) with protection against the development of DHF. Conclusions This research identifies the association of the IFNG (+874 A/T), TNFA (−308G/A), IL-10 (−819 C/T) genotypes as a factor for protection, susceptibility and severity to dengue. [ABSTRACT FROM AUTHOR]

Members of the inhibitor of apoptosis (IAP) family control several critical aspects of innate immunity, cell death, and tumorigenesis. Small molecule antagonists that target specific IAP oncoproteins, primarily cIAP1 and cIAP2, but potentially also XIAP and Livin, modulate distinct immune signal transduction pathways that can lead to an increased sensitivity of tumors cells to cytokine-mediated apoptosis. These antagonists are based on the structure of an endogenous cellular IAP inhibitor called Smac. Smac is normally sequestered within the mitochondria and is released into the cytoplasm upon cell death stimuli, thereby overcoming the anti-apoptotic action of the IAPs. The therapeutic usefulness of recombinant tumoricidal cytokines to treat cancer patients is principally limited due to their unacceptable adverse side effects. Therefore, investigators have sought to develop alternative regimens that do not rely on exogenously delivered death ligands. These approaches include the stimulation of the immune system with oncolytic virus-based agents or Toll-like receptor agonists in combination with Smac mimetics. Similarly, preclinical combination immunotherapy studies reveal that recombinant interferon synergizes with Smac mimetics to kill cancer. This strategy opens up new therapeutic avenues for anti-cancer therapy by modulating specific immune-mediated death pathways employing unique dual-pronged combinatorial approaches. [ABSTRACT FROM AUTHOR]

Abstract: It has been shown that coal dust exposure stimulates inflammatory response leading to increased release of cytokines from monocytes such as TNF-alpha and IL1. These released cytokines play the key role in the pathogenesis of pneumoconiosis including coal workers’ pneumoconiosis. In this study, we investigated TNFA, IL1A, IL1B and IL1RA genes variations on basal, lipopolysaccharide and coal dust-induced cytokine release from blood monocytes of homozygous allele and minor variant allele carriers in Turkish coal workers and CWP patients. According to the genotyping results, TNFA –238 gene polymorphism was found as a risk factor in CWP development (OR=3.79) and to in vitro results; release of both TNF-alpha and IL1 cytokines from the monocytes in CWP patients was significantly increased compared to the healthy workers. Also, LPS and coal dust stimulated release of TNF-alpha, which was significantly higher in allele 2 carriers compared to subjects carrying allele 1 in both the groups. These data suggest that the coal dust-induced release of TNF-alpha from monocytes may be a useful biomarker of CWP. [Copyright &y& Elsevier]

Etiology of cervical cancer is associated with excessive inflammation mediated tumorigenesis. Pro and anti-inflammatory cytokines (tumor necrosis factor α, TNFA and interleukin, IL-10) are involved in fighting against the tumorigenesis. Therefore, the present study was designed to evaluate the association of TNFA (-308G>A) and IL-10 (-819C>T) gene polymorphism with risk of cervical cancer. One hundred fifty histopathologically confirmed patients with cervical cancer and 162 age, ethnically-matched cervical cytology negative healthy controls were genotyped for TNFA (-308 G>A) and IL-10 (-819 C>T) polymorphisms using PCR-RFLP. Individuals with combination of TNFA -308GA+AA genotype and A allele were at elevated risk of cervical cancer (odds ratio (OR) = 2.24; P = 0.018 and OR, 2.05; P = 0.012). Frequency of IL-10 -819CT+TT genotype combination and T allele was slightly higher in cases as compared with controls but difference was not significant (OR = 1.52; P = 0.069 and OR = 1.38; P = 0.051). In association of genotypes with clinical characteristics, presence of TNFA -308GA+AA genotype conferred high risk for the stages (IB) (OR = 2.86, P = 0.039) and stages (III) (OR = 2.52; P = 0.015) of cervical cancer. In contrast, IL-10 -819TT genotype was not associated with higher risk of clinical characteristics of cervical cancer. In conclusion, individuals with TNFA -308∗A allele carriers were at significantly higher risk of cervical cancer particularly early (IB) and advanced stages (III). However, IL-10 (-819C>T) polymorphism was not associated with risk of cervical cancer. [ABSTRACT FROM AUTHOR]

Abstract: A relationship between inflammatory bowel disease and multiple sclerosis is supported by a higher than expected coexistence of these diseases among families and individuals. A 32 year-old male with Crohn''s disease of the terminal ileum diagnosed 4 years ago and HLA-B27 negative bilateral sacroiliitis diagnosed 2 years ago, was admitted in our hospital because of an acute episode of blurred vision. In addition the patient complained for urine incontinence. Before this admission the patient was administered methylprednisolone and Infliximab induction treatment. During admission the diagnosis of multiple sclerosis-associated bilateral optic neuritis was made and Infliximab was discontinued. The patient was started on therapy with interferon-beta for multiple sclerosis, prednizolone and azathioprine for Crohn''s disease and oxybutynin hydrochloride for urine incontinence. After 8 weeks of Infliximab discontinuation patient recovered totally from optic neuritis. This is a rare case of totally reversible bilateral optic neuritis associated with multiple sclerosis in a patient with Crohn''s disease and sacroiliitis receiving also Infliximab induction therapy. [Copyright &y& Elsevier]