Oenothera biennis improves pregnancy outcomes by suppressing inflammation and fibrosis in an intra-uterine adhesion rat model.

Intrauterine adhesion (IUA), also referred to as Asherman's syndrome, is characterized by fibrosis, inflammation, and can cause amenorrhea and infertility due to abnormal endometrial healing. Histological and Molecular methods were used to evaluate the efficacy of EPO, which is traditionally known for its anti-inflammatory and fibrinolytic properties, in preventing the formation of IUA. Oral administration of EPO reduced the formation of adhesion bands and promoted endometrial regeneration. EPO administration decreased extracellular matrix accumulation, evidenced by the down-regulation of tissue COL1A1 and COL3A1 expression. The anti-inflammatory effect of EPO was confirmed by a reduction in oxidants and down-regulation of pro-inflammatory cytokines including TNF-α, IL-6, IFN-γ, and IL-1ß. Furthermore, EPO improved embryonic development parameters, including size and weight of embryo, as well as increased embryo count and live embryo percentage in the rat IUA model. EPO also positively enhanced implantation markers, particularly enlargement and mass gain in the placenta of the treated group, consequently improving pregnancy outcomes such as the number of babies, percent of live babies, baby weight and gestation time. Histopathological investigation provides evidence that oral administration of EPO showed no toxicity on the main three organs including liver, kidney and heart. These results showed that EPO can be considered as a safe and natural product with potent anti-inflammatory and fibrinolytic properties without any observed side effects for the treatment of IUA.

Exploring new therapeutic potentials of curcumin against post-surgical adhesion bands.

BACKGROUND: Adhesion band formation is a common cause of morbidity for patients undergoing surgeries. Anti-inflammatory and anti-fibrotic properties of curcumin, a pharmacologically active component of Curcuma longa, have been investigated in several studies. The aim of this study is to explore the therapeutic potential of curcumin in attenuating post-operative adhesion band (PSAB) formation in both peritoneal and peritendinous surgeries in animal models. METHODS: Bio-mechanical, histological and quantitative evaluation of inflammation, and total fibrosis scores were graded and measured in the presence and absence of phytosomal curcumin. RESULTS: Results showed that phytosomal curcumin significantly decreased severity, length, density and tolerance of mobility of peritendinous adhesions as well as incidence and severity of abdominal fibrotic bands post-surgery. Curcumin may decrease inflammation by attenuating recruitment of inflammatory cells and regulating oxidant/anti-oxidant balance in post-operative tissue samples. Moreover, markedly lower fibrosis scores were obtained in the adhesive tissues of phytosomal curcumin-treated groups which correlated with a significant decrease in quantity, quality and grading of fibers, and collagen deposition in animal models. CONCLUSION: These results suggest that protective effects of phytosomal curcumin against PSAB formation is partially mediated by decreasing inflammation and fibrosis at site of surgery. Further studies are needed to investigate the therapeutic potential of this molecule in preventing PSAB.

Mebendazole, an anti-helminth drug, suppresses inflammation, oxidative stress and injury in a mouse model of ulcerative colitis.

Mebendazole (MBZ) is an efficacious anthelmintic with known anti-inflammatory and fibrinolytic properties. In this study, we aimed to explore the protective effects of this FDA-approved drug against DSS-induced colitis in a murine model either alone or in combination with Sulfasalazine (SSZ), a standard therapy for ulcerative colitis. We found that MBZ significantly improved colitis disease activity index as assessed by changes in body weight, degree of stool consistency, rectal bleeding, and prolapse. We also found that MBZ ameliorated the colon histopathological score by attenuating crypt loss, mucosal damage, and inflammation score in colitis tissues. Similarly, DSS-induced colon shortening, colon weight loss, and increase in spleen weight were all abrogated in the presence of MBZ. Moreover, MBZ decreased inflammation, possibly by reducing oxidative stress markers, suppressing inflammatory cell infiltration, and down-regulation of inflammatory genes in colon tissues. Furthermore, MBZ potently reduced fibrosis by decreasing collagen deposition and down-regulating pro-fibrotic genes including Col 1a1 and Col 1a2 in colitis tissue homogenates. In conclusion, our study showed that this broad-spectrum anthelminthic could be repurposed as a novel therapy for ulcerative colitis without any observed side effects, however, regarding the concerns about the potential toxicity of MBZ in UC patients, future experiments on MBZ therapy in other models of UC is needed to completely address the toxicity concerns.

The effects of the genetic polymorphisms of antioxidant enzymes on susceptibility to papillary thyroid carcinoma.

Several lines of evidences have indicated that inflammation play an important role in the carcinogenesis. During the inflammatory processes, free radical species are produced from oxidative stress. In normal conditions, enzymatic and nonenzymatic antioxidants remove these products. Manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPx-1), and catalase (CAT) are three important enzymes. Therefore, this study aimed to evaluate the effects of MnSOD (SOD2), GPX-1, and CAT genetic polymorphisms on papillary thyroid carcinoma (PTC) susceptibility. A total of 134 patients with PTC and 151 healthy controls were recruited to participate in this study. All samples were genotyped for SOD2 rs4880, GPX1 1050450, and CAT rs7943316 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism method. The frequencies of the rs1050450, rs4880, and rs7943316 alleles and genotypes were not different between PTC patients and controls. However, the TC genotype of SOD2 rs4880 polymorphism was significantly higher in males compared to that in females in PTC patients (odds ratio [OR], 3.9 [95% CI, 1.5-11], p = .007). The rs4880 polymorphism was also associated with higher stages (III-IV) of PTC in dominant model. No significant correlation was found between GPX1-rs1050450 and CAT-rs7943316 polymorphisms and demographic, clinical, and pathological features of the disease. The SOD2 rs4880CT genotype was more frequent in males with PTC and patients with higher stages (III-IV) of disease (OR, 2.9 [95% CI, 1.1-7.7], p = .04). However, no significant association was found between GPX1-rs1050450 and CAT-rs7943316 variants and PTC or its demographic, clinical, and pathological features.

Association between Genetic Polymorphisms in microRNA Machinery Genes and Risk of Papillary Thyroid Carcinoma.

Evidence suggests that the microRNAs are involved in tumorigenesis and progression of various types of malignant tumors. Therefore, the aim of current research was to examine association between genetic variants in the miRNA machinery genes and risk of papillary thyroid carcinoma(PTC) in Iranian population. Peripheral blood samples were collected from 120 PTC patients and 130 healthy subjects. Genotyping of polymorphisms in miRNA Machinery genes (DICER1 rs3742330, DROSHA rs6877842 and XPO5 rs11077) polymorphisms was performed using PCR-RFLP method. Chi square and independent sample t tests were applied for categorical and continuous variables, respectively. In this study, we found that frequency of DICER1 rs3742330G allele was significantly higher in controls compared to PTC patients. In addition, the DICER1 rs3742330 polymorphism was associated with lower risk of PTC in dominant (AG + GG vs. AA, OR = 0.5, 95%CI = 0.3-0.9, P = 0.03) model. No association was found between DROSHA rs6877842 and XPO5 rs11077 polymorphisms and PTC neither in dominant nor in recessive and allelic models. The frequency of DROSHA rs6877842GC genotype was higher in PTC patients with smaller tumor size (<1). Therefore, this polymorphism could be a protective factor for tumor development in PTC patients (OR = 0.3, 95%CI = 0.1-1, P = 0. 04). The current study indicated that DICER1 rs3742330 polymorphism was associated with lower risk of PTC. Furthermore, DROSHA rs6877842 polymorphism could be a protective factor for tumor development in PTC patients.

The role of TNF-α and TLR4 polymorphisms in the placenta of pregnant women complicated by preeclampsia and in silico analysis.

Evidence showed that, pro inflammatory cytokines and mediators of innate immune responses may involve in the pathogenesis of preeclampsia (PE). Therefore, the present investigation aimed to examine the possible effects of placental TNF-α and TLR4 polymorphisms on PE susceptibility. METHODS: The placental tissues were collected after delivery from 111 PE and 115 healthy pregnant women. The TNF-α-308G/A (rs1800629), TNF-α-238G/A (rs361525), TLR4 Asp299Gly (rs4986790) and TLR4 Thr399Ile (rs4986791) polymorphisms were genotyped using PCR-RFLP method. Moreover, in-silico analysis was performed to evaluate the potential functions of these polymorphisms. RESULTS: The TNF-α -308 GA genotype was associated with a decreased PE risk. The frequency of TNF-α -238G/A genotypes did not differ between two groups, however, the frequency of TNF-α -238A allele was significantly higher in controls. No relationship between TLR4 Thr399Ile and Asp299Gly polymorphisms and PE was found. In-silico analysis predicted that -308G to A substitution in the TNF-α promoter might lead to different allelic expressions. In addition, TLR4 Asp299Gly polymorphism would result in a major change in the mRNA and protein functions. CONCLUSION: Our study for the first time presented evidence on the association of the placental TNF-α -308GA genotype and TNF-α -238A allele with decreased risk of PE in an Iranian population.

Genetic and epigenetic analysis of the BAX and BCL2 in the placenta of pregnant women complicated by preeclampsia.

The current study examined the effects of BAX and BCL2 polymorphisms and methylation as well as mRNA expression on susceptibility to PE. After delivery, the placentas were collected from 92 women with PE, as well as 106 normotensive pregnant women. The BAX rs4645878 and BCL2 rs2279115 polymorphisms were genotyped by the PCR-RFLP method. Methylation-specific PCR (MSP) was used for analysis of promoter methylation. mRNA expression was assayed by Quantitative RT-PCR. In addition, in silico analysis was performed by bioinformatics tools. There was no relationship between PE and placental BAX rs4645878 and BCL2 rs2279115 polymorphisms. The groups were not significantly different regarding the promoter methylation of BAX gene. Nonetheless, the MM status of BCL2 promoter had a significantly higher frequency in the PE group and was associated with 2.7-fold higher risk of PE (OR = 2.7, 95% CI = 1.3-5.6; P = 0.01). The relative mRNA expression of BCL2 was decreased in the placentas of PE women (P < 0.0001). The expression of BAX gene was not significantly different between the two groups. There was no association between placental BAX rs4645878 and BCL2 rs2279115 polymorphisms and mRNA expression levels. In silico analysis indicated that BAX rs4645878 and BCL2 rs2279115 polymorphisms were located in the core recognition site of different transcription factors and these substitutions of wild allele resulted in the loss and/ or change of these binding sites and subsequently may alter BCL2 and BAX expression. This study showed that the BAX and BCL2 polymorphisms and BAX promoter methylation were not associated with PE risk. The BCL2 promoter methylation was associated with lower BCL2 expression and higher PE susceptibility.

Genetic polymorphisms of miRNA let7a-2 and pri-mir-34b/c are associated with an increased risk of papillary thyroid carcinoma and clinical/pathological features.

microRNAs (miRNAs) as a group of short noncoding RNAs are crucial molecules in transcriptional and translational regulation of oncogenes and tumor suppressor genes. Evidence showed there was an association between the miRNA polymorphisms and various cancers, including papillary thyroid carcinoma (PTC). The present study aims to evaluate the possible effects of let7a-2 rs1143770 and pri-mir-34b/c rs4938723 polymorphisms on PTC susceptibility. A total of 120 patients with PTC and 130 age, sex, and race matched controls were enrolled in the case-control study. The polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping of let7a-2 rs1143770 and pri-mir-34b/c rs4938723 polymorphisms. The let7a-2 rs1143770 CT and TT genotypes were associated with a 1.9-fold and 2.2-fold higher risk of PTC, respectively (P = 0.027 and P = 0.041). Moreover, the let7a-2 rs1143770 polymorphism was associated with increased PTC risk in both dominant (2-fold, P = 0.015) and the allelic model (1.5-fold, P = 0.03). The frequency of pri-mir-34b/c rs4938723TC genotype was significantly higher in patients with PTC and associated with a two-fold higher risk of PTC (P = 0.013). In addition, this polymorphism was associated with a 1.8-fold increased risk of PTC in dominant model (P = 0.021). The let7a-2 rs1143770CT genotype was associated with a 3.5-fold increased risk of N1 stage in PTC patients (P = 0.04), however, pri-mir-34b/c rs4938723TC genotype was associated with a 3.4-fold and 5.1-fold increased risk of III-IV stage and vascular invasion in PTC group, respectively (P = 0.04 and P = 0.04). In conclusion, the present study shows that let7a-2 rs1143770 and pri-mir-34b/c rs4938723 polymorphisms could be susceptible factors for PTC and some clinical features.