Higher expression of BRCA1, and CHUK and lower expression of NFKBIA, ESR1, PIK3R1, and PPARG in HAM/TSP compared to ATLL, a diverse pathological consequence.

BACKGROUND: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL) are both severe diseases caused by Human T-lymphotropic virus type 1 (HTLV-1) infection, while about 95% of infected cases remain asymptomatic. Genes that play a role in ATLL development are assumed to be dissimilar from the ones that are crucial factors for HAM/TSP occurrence. OBJECTIVE: The expression of six genes including BRCA1, CHUCK, ESR1, NFKBIA, PIK3R1, and PPARG were assessed in two groups of HAM/TSP and ATLL patients. Materials and Methods: cDNA was synthesized from purified RNA, and RT-qPCR was conducted to assess the expression of the genes in two groups. Any possible correlation among the genes' expression was also calculated. Results: BRCA1 and CHUCK expressions were higher in HAM/TSP patients in comparison with ATLL patients. However, ESR1, NFKBIA, PIK3R1, and PPARG are more expressed in ATLL cases than HAM/TSP. A significant positive correlation was observed between BRCA1 and NFKBIA in HAM/TSP group. In addition, a significant negative correlation between PIK3R1 and PPARG in HAM/TSP and between ESR1 and NFKBIA in the ATLL group was obtained. CONCLUSION: HAM/TSP or ATLL stem from a disturbance in the expression of diverse genes and these dissimilarities should be discovered to reach a better understanding of disease treatment as well as screening and assessing the asymptomatic carriers' condition for developing severe disease.

The mirror like expression of genes involved in the FOXO signaling pathway could be effective in the pathogenesis of human lymphotropic virus type 1 (HTLV-1) through disruption of the downstream pathways.

OBJECTIVES: Human lymphotropic virus type 1 (HTLV-1) is the cause of two major diseases, ATLL and HAM/TSP in a percentage of carriers. Despite progress in understanding the pathogenesis of these two diseases, the exact pathogenesis mechanism is still not well understood. High-throughput technologies have revolutionized medical research. This study aims to investigate the mechanism of pathogenesis of these two diseases using the results of high-throughput analysis of microarray datasets. RESULTS: A total of 100 differentially expressed genes were found between ATLL and HAM/TSP. After constructing protein-protein network and further analyzing, proteins including ATM, CD8, CXCR4, PIK3R1 and CD2 were found as the hub ones between ATLL and HAM/TSP. Finding the modules of the subnetwork revealed the enrichment of two common pathways including FOXO signaling pathway and Cell cycle with two common genes including ATM and CDKN2D. Unlike ATLL, ATM gene had higher expressions in HAM/TSP patients. The expression of CDKN2D was increased in ATLL patients. The results of this study could be helpful for understanding the pathogenic mechanism of these two diseases in the same signaling pathways.

Eryngium billardieri extract affects cardiac gene expression of master regulators of cardiomyaopathy in rats with high fatdiet-induced insulin resistance.

BACKGROUND: For years, numerous studies have focused on identifying approaches to increase insulin sensitivity by modifying the signaling factors. In the present study, we examined the effects of Eryngium billardieri extract, as an anti-diabetic herbal medication, on the heart mRNA level of Akt serine/threonine kinase (Akt), mechanistic target of rapamycin kinase (mTOR), peroxisome proliferator-activated receptor gamma (PPARγ), and Forkhead box o1 (Foxo1) in rats with high-fat diet (HFD)-induced insulin resistance (IR). We also assessed the anti-diabetic effects of E. billardieri extract in rats with insulin resistance. METHODS: Twenty-seven male Wistar rats were divided into two groups. Nine rats were fed a normal diet (control group), and 18 rats were fed an HFD for 13 weeks (HFD group). To confirm the induction of insulin resistance, the oral glucose tolerance test (OGTT) was performed and homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. Then rats with IR were randomly divided into the following groups: the HFD group, which continued an HFD, and the group treated with E. billardieri extract, which received the extract at a concentration of 50 mg/kg for 30 days. On the 30th day, the animals were sacrificed and serum samples were collected for biochemistry analyses. Furthermore, the expression of Akt, mTOR, PPARγ, and Foxo1 was measured in heart tissue using the real-time polymerase chain reaction (PCR) method. RESULTS: Real-time PCR analyses revealed that an HFD can significantly decrease the expression level of Akt, mTOR, and PPARγ in the heart tissue. However, an HFD significantly increased the expression level of Foxo1 in the HFD group compared to the control group (P < 0.05). In addition, our data showed that the administration of E. billardieri extract significantly enhanced the mRNA levels of Akt, PPARγ, and mTOR in the heart tissue compared to the HFD group (P < 0.05), while it significantly decreased the Foxo1 mRNA levels (P < 0.01). CONCLUSION: Given that Akt, mTOR, PPARγ, and Foxo1 are critical factors in insulin resistance, the present study suggests that E. billardieri could probably be used as an alternative treatment for IR as a major feature of metabolic syndrome.

Association of physical activity with increased PI3K and Akt mRNA levels in adipose tissues of obese and non-obese adults.

Phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway regulates glucose and lipid metabolism. We examined the association of PI3K and Akt expression in visceral (VAT) and subcutaneous adipose tissue (SAT) with daily physical activity (PA) in non-diabetic obese and non-obese adults. In this cross-sectional study, we included 105 obese (BMI ≥ 30 kg/m2) and 71 non-obese (BMI < 30 kg/m2) subjects (aged/ ≥ 18 years). PA was measured using a valid and reliable International Physical Activity Questionnaire(IPAQ)-long-form, and the metabolic equivalent of task(MET) was calculated. Real-time PCR was performed to analyze the mRNA relative expression. VAT PI3K expression had a lower level in obese compared to non-obese (P = 0.015), while its expression was higher in active individuals than inactive ones (P = 0.029). SAT PI3K expression was increased in active individuals compared to inactive ones (P = 0.031). There was a rise in VAT Akt expression in the actives compared to the inactive participants (P = 0.037) and in non-obese/active compared to non-obese/inactive individuals (P = 0.026). Obese individuals had a decreased expression level of SAT Akt compared to non-obsesses (P = 0.005). VAT PI3K was directly and significantly associated with PA in obsesses (ß = 1.457, P = 0.015). Positive association between PI3K and PA suggests beneficial effects of PA for obese individuals that can be partly described by PI3K/Akt pathway acceleration in adipose tissue.

Evaluation of the Anti-Metastatic Effect of Foeniculum Vulgare on the Protein Expression of HSP 70 & 90 in Balb/c Mice with 4t1 Model of Breast Cancer.

INTRODUCTION: Breast cancer is one of the important factors of cancer-related deaths. Considering the drug resistance, special attention has been paid to natural compounds. This study aimed at evaluating the anti-metastatic activity of fennel in a breast cancer mouse model. METHODS: A total of 35 adult female BALB/C mice were used in this study. Breast cancer was induced by subcutaneous injection of 4T1 cells in the right lower flank. The mice received fennel extracts daily via intraperitoneal injection for two weeks. Meanwhile, tumor volume was measured every day using calipers. After two weeks, each animal was anesthetized. The protein expression of HSP 70 & 90 was measured in liver tissue and ovary. The expression of her2 was measured in tumor tissue. The activity of Glutathione peroxidase and reductase as anti-oxidant agents were measured in serum. RESULTS: Tumor size significantly decreased after nine days' treatment of the fennel. The expression of HER2 increased in the tumor tissue and decrease with different dose of fennel. Fennel treatment caused a decrease in the protein expression of HSP 70 & 90 in the liver tissues. CONCLUSION: Based on our findings, fennel has anti-tumor and anti-metastatic activities against aggressive cancers.

Human tau fibrillization and neurotoxicity in the presence of magnesium oxide nanoparticle fabricated through laser ablation method.

In this study, the acceleratory effect of magnesium oxide nanoparticles (MgO NPs) on the amyloid fibrillization of human tau protein, a major protein involved in the onset of Alzheimer's disease (AD) was investigated. The MgO NPs were fabricated through laser ablation synthesis in solution (LASiS), well-characterized, and explored further for tau aggregation and relevant neurotoxicity by different assays. The results showed that the MgO NPs have a size of around 30 nm, a hydrodynamic radius of 57.09 nm, and a zeta potential of -18.06 mV. The data from ThT and ANS fluorescence-based assays along with circular dichroism (CD) spectroscopy clearly indicated that MgO NPs could significantly promote tau fibrillization, concentration-dependently. Considering the acceleratory effect of MgO NPs against tau fibrillization, cellular assays including cell viability, reactive oxygen species (ROS), and caspase-3 assays indicated that the neurotoxicity of tau amyloid fibrils formed with MgO NPs was higher than that of tau samples aged alone against N2a neuron-like cells. Therefore, it was concluded that the interaction of MgO NPs with tau can lead to acceleration of tau aggregation and underlying neurotoxicity. This study, then can provide useful information about the direct effect of MgO NPs against memory proteins and subsequent adverse effects.

In silico evidence for prednisone and progesterone efficacy in recurrent implantation failure treatment.

Increased expression and activation of tumor necrosis factor-α (TNF-α) could lead to recurrent implantation failure (RIF). Therefore, TNF-α inhibition may be a strategic way to enhance the implantation rate in women with RIF. Nowadays, monoclonal antibodies are considered an effective therapeutic method for TNF-α inhibition. Unfortunately, monoclonal antibody treatments have several disadvantages. Thus, the design of small molecules capable of inhibiting TNF-α has become critical in recent years. In silico drug repurposing of FDA-approved drugs for TNF-α inhibition was used in this study. PyRx tools were employed for virtual screening. Additionally, the free energy of binding, the number of hydrogen bonds, and the number of drug contacts with the protein were calculated using the molecular dynamics (MD) simulation method. Virtual screening results reveal that 17 of 2471 FDA-approved drugs benefited from favorable binding energy with TNF-α (delta G < - 10 kcal/mol). Two of the 17 drugs, progesterone and prednisone, were the most frequently used without adverse effects during pregnancy. As a result, MD simulation was used to investigate these two drugs further. According to the MD simulation results, prednisone appears to have a higher affinity for TNF-α than progesterone, and consequently, the prednisone complex stability is higher. For the first time, this study examined the possible role of prednisone and progesterone in inhibiting TNF-α using in silico methods.

HE4, A New Potential Tumor Marker for Early Diagnosis and Predicting of Breast Cancer Progression.

BACKGROUND & OBJECTIVE: This study examined the potential of human epididymis protein 4 (HE4) as a marker in early diagnosis or as a prognostic factor for breast cancer (BC) patients. METHODS: A total of 31 patients diagnosed with BC were enrolled in the study between 2008 and 2018. The mRNA and protein expression levels of HE4 were analyzed by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR) in the BC tissue and the non-tumoral adjacent tissue. Using ELISA technique, HE4 plasma levels were also measured in 43 BC patients compared to 43 healthy individuals. The correlation between HE4 expression and clinicopathological features was then investigated. RESULTS: An increase in HE4 expression was observed at mRNA and protein levels in the BC group compared to the control group (P<0.01, P<0.0001, respectively). In addition, the relative expression of HE4 mRNA in BC patients showed a significant correlation with the differentiation grade of cancer cells (P<0.001). Plasma levels of HE4 was also associated with grade (P<0.0001), stage, and tumor size in BC patients (for both P<0.01). Patients with metastatic BC (P<0.01), lymphatic invasion, and lymph node involvement (for both P<0.05) showed significantly higher plasma levels of HE4 expression than patients without metastasis. CONCLUSION: According to our findings, upregulation of HE4 may be related to invasive BC phenotype. Measuring plasma levels of HE4 could be useful as a screening test in early diagnosis of BC.

Putative mechanism for cancer suppression by PLGA nanoparticles loaded with Peganum harmala smoke extract.

Synthesis and investigation of biological activity of Peganum harmala smoke-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Peganum harmala smoke-loaded PLGA nanoparticles (PHSE-PNP) were produced by double emulsion solvent evaporation method and characterised by scanning electron microscopy (SEM), dynamic light scattering (DLS), and ζ-potential. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) for toxicity evaluation, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assay for antioxidant power, chorioallantoic membrane (CAM), qPCR, and scratch assay for angiogenesis and mouse cancer model for antitumor effects of PHSE-PNP's were used. PHSE-PNP with a size of 216.33 nm, polydispersity index (PDI): 0.22 and ζ-potential: -25.41 mV inhibited A2780, PC3, A549, HepG2, Mda-mb-231, HT-29 as cancer cells and HUVEC as an normal cells with half-maximal inhibitory concentration (IC50) at about 208.62, 479.05, 1092.6, 1103.9, 1299.21, 3467.5, and <4000 µg/ml, respectively. Also PHSE-PNP inhibited ABTS (IC50: 0.720 mg/ml), DPPH (IC50: 1.36 mg/ml) free radicals and decreased the size of murine tumours (88.3% in 11 days) and suppressed angiogenesis in the CAM and scratch assays. PHSE-PNP can be considered as a potential chemopreventive agent in cancer therapy.

Evaluation of the Effect of Foeniculum vulgare on the Expression of E-Cadherin, Dysadherin and Ki-67 in BALB/C Mice with 4T1 Model of Breast Cancer.

Introduction: Breast cancer is described as a serious disease and one of the important factors of cancer-related deaths. Considering the drug resistance, special attention has been paid to natural compounds. This study aimed at evaluating the anti-metastatic activity of fennel in a breast cancer mouse model.Methods: A total of 28 adult female BALB/C mice were used in this study. Breast cancer was induced by subcutaneous injection of 4T1 cells in the right lower flank. The mice received fennel extracts daily via intraperitoneal injection for two weeks. Meanwhile, tumor volume was measured every day using calipers. After two weeks, each animal was anesthetized. The expression levels of ki-67 and dysadherin as tumor markers, as well as E-cadherin as a tumor suppressor, were measured in tumor tissue and ovary. Also the expression of her2 was measured in ovary.Results: Tumor size significantly decreased after nine days treatment of the fennel. Fennel treatment caused an increase in the ratio of the expression of E-cadherin to Ki-67 and dysadherin in the tumor tissues. On the other hand, the expression of Ki-67 and HER2 decreased in the ovary.Conclusion: Based on our findings, fennel has anti-tumor and anti-metastatic activities against aggressive cancers.

In silico identification of new inhibitors for ßeta-2-glycoprotein I as a major antigen in antiphospholipid antibody syndrome.

Beta 2 glycoprotein I (ß2GPI) is a major antigen for autoantibodies present in antiphospholipid antibody syndrome (APS). ß2GPI is a single polypeptide with five repeated domains and different conformations. The activated J-shaped conformation of ß2GPI binds to negatively charged phospholipids in the membrane via the fifth domain and causes blood clotting reactions. We applied a drug repurposing strategy using virtual screening and molecular dynamics to find the best FDA drugs against the fifth domain of ß2GPI. In the first phase, FDA drugs that had the most favorable ΔG with the fifth domain of ß2GPI were selected by virtual screening. Among these drugs that had the most favorable ΔG, Vorapaxar and Antrafenine were selected for molecular dynamics (MD) simulation studies. MD simulation was performed to evaluate the stability of Vorapaxar and Antrafenine complexes and the effect of the two drugs on protein conformation. Also, MD simulation was done to investigate the effect of Antrafenine and Vorapaxar on the binding of ß2GPI to the platelet model membrane. According to the results, Vorapaxar and Antrafenine were bound to the protein with the favorable binding energy (Vorapaxar and Antrafenine binding energies are - 49.641 and - 38.803 kcal/mol, respectively). In this study, it was shown that unlike protein alone and protein in the Antrafenine complex, the protein in the Vorapaxar complex was completely separated from the model membrane after 350 ns. Moreover, Vorapaxar led to more changes in the activated J-shape of ß2GPI. Thus, Vorapaxar can be a suitable candidate for further investigations on the treatment of APS.

Investigating the expression and promoter methylation of RET gene in patients with medullary thyroid cancer with unmutated RET.

OBJECTIVE: Thyroid cancer is one of the most common endocrine malignancies. Mutations in the rearranged during transfection (RET) gene, especially in exon 10, 11, and 16, as well as epigenetic modifications, constitute the major underlying molecular events leading to medullary thyroid cancer (MTC). There are few studies on the mutations and epigenetic changes of RET gene in Iranian patients with MTC. In the present study, we aimed to address this question and explore the clinical relevance of such genetic alternations in an Iranian population. METHODS: Thirty-three patients with confirmed MTC who underwent thyroidectomy surgery in Imam Khomeini Hospital (Tehran, Iran) were enrolled. DNA extracted from cancerous tissues was amplified by polymerase chain reaction (PCR) and then was sequenced for identification of RET mutations. In patients with no identified mutations, the methylation status of RET promoter and its expression were further investigated using methylation-specific PCR and real-time PCR methods, respectively. RESULTS: In MTC patients with no RET mutations, the promoter of the proto-oncogene was hypomethylated. Furthermore, RET gene expression was elevated in patients who revealed no mutations in neither of exon 10, 11, or 16 of the RET gene. CONCLUSION: Hypomethylation of RET promoter may contribute to MTC pathogenesis. The methylation status of RET promoter could be a new potential prognostic, diagnostic and therapeutic marker in MTC.