Contribution of survivin to the immune system, allergies and autoimmune diseases.

In addition to malignancies, survivin (a member of the apoptosis inhibitor family) has been implicated in the pathogenesis of inflammatory disorders, including autoimmune and allergic diseases. Survivin is constantly expressed in the proliferating hematopoietic progenitor cells, and it is re-expressed in the mature cells of the innate and adaptive immunity, upon activation. Survivin enhances the expression of co-stimulatory molecules and MHC class II molecules in dendritic cells, and promotes the lifespan of macrophages, neutrophils, and eosinophils, while suppressing natural killer (NK) cell activity. Survivin has been implicated in T cell maturation, T cell expansion, effector CD4+ T cell differentiation, maintenance of memory CD4+ T and CD8+ T cells, as well as antibody production. Upregulated expression of survivin was indicated in the T cells as well as various samples collected from allergic patients. Survivin can contribute to the pathogenesis of allergic diseases via the promotion of the Th2 polarization, promoting IL-4 expression, compromising activation-induced cell death (AICD) in Th2 cells, and preventing apoptosis of eosinophils, as well as, amplification of eosinophilia. Moreover, survivin can interfere with clonal deletion of autoreactive T and B cells, as well as suppress Treg cell development and activity supporting the development of autoimmune diseases. This review discusses the role of survivin in immunity, allergy and autoimmunity as well as provides evidence that survivin may be considered as a novel therapeutic target for the treatment of allergic and autoimmune diseases.

MicroRNA-383: A tumor suppressor miRNA in human cancer.

Downregulated expression of anti-tumor miR-383 has been found in many kinds of cancer. MiR-383 family members can directly target the 3'-untranslated region (3'-UTR) of the mRNA of some pro-tumor genes to attenuate several cancer-related processes, including cell proliferation, invasion, migration, angiogenesis, immunosuppression, epithelial-mesenchymal transition, glycolysis, chemoresistance, and the development of cancer stem cells, whilst promoting apoptosis. Functionally, miR-383 operates as a tumor inhibitor miRNA in many types of cancer, including breast cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, colorectal cancer, esophageal cancer, lung cancer, head and neck cancer, glioma, medulloblastoma, melanoma, prostate cancer, cervical cancer, oral squamous cell carcinoma, thyroid cancer, and B-cell lymphoma. Both pro-tumor and anti-tumor effects have been attributed to miR-383 in ovarian cancer. However, only the pro-tumor effects of miR-383 were reported in cholangiocarcinoma. The restoration of miR-383 expression could be considered a possible treatment for cancer. This review discusses the anti-tumor effects of miR-383 in human cancers, emphasizing their downstream target genes and potential treatment approaches.

The impact of GSTM1 and GSTT1 polymorphisms on susceptibility to gestational diabetes in Iranian population.

BACKGROUND: Gestational diabetes mellitus (GDM) is characterized as a common metabolic disorder during pregnancy which is associated with glucose intolerance and insulin resistance. Genetic predisposition could contribute to the development of GDM. METHODS: We conducted a case-control study to inspect the impact of GSTM1 and GSTT1 polymorphism on GDM susceptibility in Iranian population. The population consisted of 149 pregnant women with GDM as cases, and 138 healthy pregnant women without any history of GDM as controls. Polymerase chain reaction-restriction fragment length polymorphism method was applied to determine the GSTM1 and GSTT1 gene polymorphisms. RESULTS: There were statistically significant differences between the cases and controls in terms of age (p = .005), BMI (p < .001), family history of gestational diabetes (p < .001), FBS (p = .001), TG (p ≤ .001), and HDL (p = .003). However, no significant differences were observed in TC (p = .078) and LDL (p = .062). There were significant differences between GSTM1 polymorphism (Null and present) in the case and controls groups [OR (95% CI); 2.3 (1.4-3.7), p < .001]. The distribution of GSTM1-null genotype was found to be significantly higher in GDM patients (68.6%) than the control group (48.5%). No significant variance was detected between GSTT1 polymorphism (Null and present) in the case and controls groups [OR (95% CI); 1.1 (0.6-1.6), p = .088]. The frequency of GSTM1 null/GSTT1 null [OR (95% CI); 2.7 (1.2-5.2), p = .01] and GSTM1 null/GSTT1 present [OR (95% CI); 2.6 (1.4-4.8), p = .002] genotypes significantly differed between the GDM and control groups. CONCLUSION: It seems that GSTM1 null genotype might be considered as GDM risk factor in Iranian population.

The association between TP53 rs1625895 polymorphism and the risk of sarcopenic obesity in Iranian older adults: a case-control study.

BACKGROUND: Aging and obesity are the two major global health concerns. Sarcopenia, an age-linked disease, wherein a progressive loss of muscle volume, muscle strength, and physical activity occurs. In this study we evaluated the association of TP53 rs1625895 polymorphism with the susceptibility to sarcopenic obesity in Iranian old-age subjects. METHODS: Total of 176 old individuals (45 sarcopenic and 131 healthy) were recruited in this research and genotyped by PCR-RFLP. BMI, Skeletal Muscle Mass Index, body composition, Handgrip Strength, Gait Speed (GS), and biochemical parameters were measured. Chi-square test was done for genotypes and alleles frequency. Linear regression was applied to find the correlation between TP53 rs1625895 polymorphism, and biochemical and anthropometric parameters. The correlation between TP53 rs1625895 and the risk of sarcopenia and sarcopenic obesity was investigated by logistic regression. RESULTS: G allele was significantly higher in sarcopenic obesity group [P = 0.037, OR (CI 95%) = 1.9 (1.03-3.5)] compared to A allele. BMI (P = 0.049) and LDL (P = 0.04) were significantly differed between genotypes when GG was compared to AA/AG genotype. The results revealed when GG genotype compared to AA/AG genotype in adjusted model for age, the risk of sarcopenic obesity [P value = 0.011, OR (CI 95%); 2.72 (1.25-5.91)] increased. Similarly, GG/AG genotype increased the risk of sarcopenic obesity [P value = 0.028, OR (CI 95%); 2.43 (1.10-5.36)] in adjusted model for age compared to AA genotype. CONCLUSIONS: We suggested that TP53 rs1625895 polymorphism may increase the risk of sarcopenic obesity in Iranian population.

Anti-androgenic effect of astaxanthin in LNCaP cells is mediated through the aryl hydrocarbon-androgen receptors cross talk.

The aim of this study was to investigate the anti-androgenic effects of astaxanthin (AST) on human prostatic cancer cell growth, and its impact on androgen receptor (AR) signaling using prostate cancer (PCa) cell line LNCaP. LNCaP cells were treated with AST alone and in combination with CH223191 and flutamide (Flu) in the presence and absence of testosterone. MTT assay, cellular prostate-specific antigen (PSA) and dihydrotestosterone (DHT) production, mRNA levels of CYP1A1, PSA, Kallikrein-Related Peptidase 2 (KLK2), Transmembrane Serine Protease 2 (TMPRSS2), and AR genes were measured as endpoints. The expression of CYP1A1, PSA, KLK2, TMPRSS2, and AR mRNA levels was decreased which results in reducing the production of PSA and DHT in the presence of testosterone. Our data clearly demonstrate that AST has a potential ability to suppress the human prostate LNCaP cells growth at high concentrations. AST was able to repress the testosterone-induced transcription of AR-target genes. PRACTICAL APPLICATIONS: Astaxanthin is a natural compound with the most potent antioxidant activity among other antioxidants. In the current study, ASX suppressed the LNCaP cells at high concentrations. Furthermore, AST inhibited testosterone-induced transcriptional activation of androgen-related genes. AST induced the expression of CYP1A1, which is able to metabolize the steroid hormones. It seems that AST can act as AhR exogenous ligand by induction of CYP1A1, which results in testosterone metabolism and consequent suppression of AR genes. So that, AST could prevent the growth of testosterone-dependent PCa cells, downregulate downstream genes in testosterone pathways, and enhance the metabolism of testosterone via AhR pathway. Collectively, AST could be considered as a potential candidate for the treatment of PCa.

The Effects of Astaxanthin on Proliferation and Differentiation of MG-63 Osteosarcoma Cells via Aryl Hydrocarbon Receptor (AhR) Pathway: A Comparison with AhR Endogenous Ligand.

Background: Osteosarcoma (OS) is the most prevalent bone-related malignancy with a high mortality rate among children and adolescents. In the present study, first we explored the effects of astaxanthin (AST) on proliferation and differentiation of the MG-63 osteosarcoma cell line, and then compared its effects with AhR endogenous ligand (FICZ).Methods: Cell proliferation and cytotoxicity assay were performed using MTT. To identify possible mechanisms underlying AST-induced changes in osteogenic metabolism via the AHR pathway, we defined changes in CYP1A1, osteocalcin, osteopontin, type I collagen, and Runx2 gene expression using RT-PCR.Results: AST upregulated CYP1A1, osteocalcin, osteopontin, type I collagen, and Runx2 expression in trends of increasing its concentration. FICZ showed a biphasic effect on MG-63 cell proliferation. At high concentrations, it significantly decreased the cell viability, while at lower concentrations it was increased as compared to the control. Increasing FICZ concentrations from 1 nm to 1 µM, down-regulated the expression of Runx2, osteopontin, osteocalcin and collagen type 1 at the transcriptional levels. It seems that AST can augment the proliferation and differentiation of MG-63 via the AhR-dependent pathway, while FICZ suppresses the proliferation and differentiation of MG-63.Conclusion: We concluded that various AhR ligands show different behaviors in the modulation of MG-63 cells.

Anti-androgenic effect of 6-formylindolo[3,2-b]carbazole (FICZ) in LNCaP cells is mediated by the aryl hydrocarbon-androgen receptors cross-talk.

The factual impact of endogenously activated AHR by 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand of AHR on androgen receptor (AR) was aim of this study. In this study, LNCaP cells were exposed to FICZ, CH223191 and flutamide (Flu) alone or in combination in the presence and absence of testosterone. CYP1A1 enzyme activity, cell viability, cellular prostate-specific antigen (PSA) and dihydrotestosterone (DHT) production, mRNA levels of PSA, KLK2, TMPRSS2, and AR genes were measured as endpoints. A declining in the expression of androgen- responsive target genes was seen by either Flu or FICZ in the presence of testosterone. Furthermore, the forced decrease in the expression of AR target genes resulted in 41% and 31% decline in the DHT and PSA concentrations respectively. Taken together, endogenously activated AHR plays a regulatory role on AR. Therefore, FICZ might be an effective chemical in treating prostate cancer.

Serum concentration of interleukin-35 and its association with tumor stages and FOXP3 gene polymorphism in patients with prostate cancer.

IL-35 is an immunosuppressive cytokine that is largely synthesized by regulatory T (Treg) cells and may inhibit antitumor immune responses. This investigation aimed to determine the serum IL-35 concentrations and a single nucleotide polymorphism (SNP) in position of rs3761548, within the promoter region of FOXP3 gene, in patients with prostate cancer (PC). The blood specimens were obtained from 150 PC patients prior to using radiation therapy, chemo- or immunotherapy and 150 age-matched healthy men as a control group. The serum IL-35 concentrations and the pattern of genetic variation at position of rs3761548 were assessed using ELISA and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), respectively. The mean serum IL-35 concentrations were significantly higher in PC patients when compared with healthy control group (20.01 ±â€¯7.03 Pg/mL vs. 11.60 ±â€¯2.49 Pg/mL, P < 0.001). The serum IL-35 concentrations raised with progression of PC stages so that there was a significant difference between PC stages concerning the IL-35 concentrations (P < 0.001). The mean serum IL-35 concentrations in patients with Gleason scores of 1-6 and Gleason scores 7-10 were significantly higher as compared with healthy controls (P < 0.001). Moreover, the serum IL-35 concentrations in patients with having Gleason scores of 7-10 were significantly higher as compared with patients with Gleason scores of 1-6 (P < 0.001). Evaluation of the genetic variations in position SNP rs3761548 revealed that the AA genotype and A allele were more prevalent whereas CC genotype and C allele were less prevalent in PC patients when compared with healthy men (P < 0.01, P < 0.001, P < 0.002 and P < 0.001, respectively). The AA genotype and A allele were associated with higher risk of PC incidence [OR: 2.42 (95% CI: 1.179-4.99); P < 0.001 and OR: 1.732 (95% CI: 1.244 - 2.413); P < 0.001, respectively]. The mean serum IL-35 concentrations were significantly higher in total subjects (PC patients + healthy individuals) with AA genotype and A allele than individuals with CC genotype and C allele at SNP rs3761548 (P < 0.05 and P < 0.01, respectively). Higher serum IL-35 concentrations observed in patients with PC that were increased with progressive tumor stages. These findings indicate that the IL-35 is possibly involve in tumor progression. Moreover, SNP rs3761548 may affect the susceptibility to PC and the serum IL-35 concentrations.

Association of elevated interleukin-33 serum levels with tumorstages in patients with prostate cancer.

BACKGROUND: Inflammation has a prominent role in cancer development and interleukin (IL)-33 has both inflammatory and anti-inflammatory properties. The aim of this study was to measure IL-33 quantities and genetic alterations in the rs1929992 SNP within IL-33 gene in patients with prostate cancer (PC). METHODS: This investigation was conducted on blood specimens from 150 newly diagnosed PC patients and 150 healthy age-matched controls. Serum IL-33 measurements and genotyping were performed by ELISA and PCR-RFLP, respectively. RESULTS: Elevated IL-33 quantities were detected in PC patients compared with controls (P < 0.001). The PC patients with Gleason scores 7-10 displayed greater IL-33 quantities than those who had Gleason scores 1-6 (P < 0.001). Significant differences were found between PC stages regarding the IL-33 serum levels (P < 0.001). The frequencies of the genotype GG and allele G in rs1929992 SNP were higher, whereas the frequencies of the genotype AA and allele A were lower in PC patients, as compared with controls (P < 0.05, 0.01, P < 0.002 and P < 0.01, respectively). The genotype GG and allele G of rs1929992 SNP were associated with a greater risk of cancer development (OR: 4.533; P < 0.001, and OR: 1.516; P < 0.01, respectively). The IL-33 levels were not significantly different between the subjects carrier genotypes AA, AG and GG, or alleles A and G in rs1929992 SNP, neither in patients nor in controls. CONCLUSION: Higher IL-33 quantities were found in patients with PC, especially in those with greater stages which raises the possiblity that IL-33 may contribute to PC progression. The rs1929992 SNP-related genotype GG and allele G were associated with an increased risk of cancer development.