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Multiple sclerosis (MS) is a chronic neurologic disease defined by inflammation and demyelination of the central nervous system that comes with variable degrees of axonal and neuronal damage. The efficacy of β-D-mannuronic acid (M2000) as a novel drug with immunosuppressive properties (patented: PCT/EP2017/067920), has been shown in an experimental model of MS. In this study, the effects of M2000 on interleukin (IL)-1β, IL-17A, signal transducer and activator of transcription (STAT) 1, and STAT3 gene expressions and Toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) molecules in patients with secondary progressive MS were evaluated. In this study, 14 patients with secondary progressive MS and 14 healthy subjects (as control group) were entered from the phase 2 clinical trial (Clinical Trial identifier, IRCT2016111313739N6). The gene expressions of IL-1β, IL-17A, STAT1, and STAT3 were assessed at the baseline and then measured after 6 months of therapy with M2000 by using the quantitative real-time polymerase chain reaction method. Moreover, the expressions of TLR2 and TLR4 molecules on peripheral blood mononuclear cells were evaluated by the flow cytometry method. The gene expressions of IL-17A, STAT1, and STAT3 in patients with MS decreased after 6 months of therapy with M2000 comparing before treatment. Also, the gene expression of IL-1β decreased numerically after 6 months. Furthermore, the expressions of TLR2 and TLR4 on PBMCs of the patients declined when compared to baseline. The results of this investigation revealed that M2000 could downregulate IL-17, STAT1, and STAT3 genes in patients with secondary progressive MS and also reduce the expressions of TLR2 and TLR4 on PBMCs. Moreover, M2000 declined numerically IL-β gene expression.

Obesity is among the most severe challenges of our era, with significant health consequences and a high economic burden for health systems. Therefore, many countries have developed political agendas to cope with this ever-rising challenge. Along with chemical medications developed to manage obesity, researchers have focused on some natural ingredients and herbal extracts that are effective in reducing weight. The current study investigated the association between Foeniculum vulgar (fennel) extracts and body weight, lipid profile, and leptin.In total, 35 adult male BALB/c mice were investigated in sham, fennel 50 mg/kg, fennel 100 mg/kg, and fennel 200 mg/kg (n=7) groups. The mice were administered fennel extracts for fourteen days while weighted at the intervention's beginning and end. Then, their weight, lipid profile, serum leptin, and expression of leptin protein in the hypothalamus were measured.After providing the intervention, leptin receptor protein expression was increased in all groups, while serum leptin didn't change significantly. Moreover, a significant decrease was observed in the cholesterol dose of 100 mg/kg/day, triglycerides in 100 and 200 mg/kg/day, and LDL in 50 and 100 mg/kg/day. Serum HDL was increased significantly in a dose of 100 mg/kg/day.Fennel extract can decrease the lipid profile by changing the expression of the leptin receptor.Obesity contributes to many health problems and dyslipidemia.Leptin is known for its hunger-blocking can regulate food intake and affects the levels of lipid. circulation.Fennel is a plant with strong antioxidant activities [18] that can influence (increase) satiety and (reduce) food intake.Fennel contains phytosterols that are known to reduce cholesterol solubilization that in turn decreases its absorption.Fennel extract can improve the lipid profile by influencing the leptin receptor expression.Obesity is one of the most serious challenges of our era, with significant health consequences. Researchers have focused on some natural ingredients and herbal extracts. The current study aimed to investigate the association between Foeniculum vulgar (fennel) extracts and body weight, lipid profile, and leptin. After treatment of fennel, leptin receptor protein expression was increased in all groups, while serum leptin didn't change significantly. A significant decrease was observed in the cholesterol, triglycerides and LDL in some doses of fennel. Serum HDL was increased significantly in a dose of 100 mg/kg/day. So fennel extract can decrease the lipid profile by changing the expression of the leptin receptor.

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) wer...

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.

BackgroundCoronary artery disease (CAD) is the main cause of death and is characterized by atherosclerosis in coronary arteries. Since Inflammation play an essential role in progression and development of atherosclerosis, we investigated the effects of interaction MMPs, TIMP and cytokines in the pathogensis of atherosclerosis.Method and resultsThe present study was consisted of 132 Iranian individuals underwent coronary angiography, 65 patients with CAD and 67 controls. The Matrix metallopeptidase 9 (MMP-9), tumor necrosis factor alpha (TNF-α), Interleukin 6 (IL-6) and vitamin D levels were measured by ELISA technique. The genes expression of MMP-9 and tissue inhibitor of metalloproteinases 1 (TIMP1) were estimated by Real time PCR assay. A considerable increase in both levels and PBMC gene expression of MMP-9, serum levels of IL-6 and TNF-α were found in CAD patients compared with controls. While a significant decrease was detected in vitamin D levels of CAD patients in comparison with controls. A considerable direct correlation was found between MMP-9 levels and MMP-9 and TIMP1 genes expression in CAD patients. MMP-9 levels positively correlated with LDL-C and in CAD. Correlation between TIMP1 gene expression and IL-6 levels was also negatively significant. Moreover, there were positive correlations between MMP-9 levels and IL-6 and TNF-α serum levels in CAD patients.ConclusionThis study showed that the interaction between MMPs, TIMP and cytokines could play a role in the pathogensis of atherosclerosis.

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.

Aim The aim of study was synthesized both silver- and zinc-oxide nanoparticles utilizing the Peganum harmala smoke extract (PHSE) bio-platform to evaluate their cytotoxicity on different types of human cancer cell lines and study their antioxidant, and antiangiogenic potentials. Material and Methods The Ag and ZnO nanoparticles were produced utilizing the green-synthesize method applying PHSE bio-platform. After characterization by XRD, DLS, FESEM, and FTIR methods, MTT assay was used for evaluation toxicity of nanoparticles. ABTS, DPPH, FRAP and ROS for antioxidant capacity, CAM and qPCR for antiangiogenesis effects of nanoparticle’s were used Results Ag-NPs (82.42 nm) and ZnO-NPs (163.05 nm) were inhibited prostate, ovarian and liver malignant cells. Inhibition ABTS•+ and DPPH•+ and increasing the rate of intracellular ROS exhibited the anti and pro-oxidant capacity of Ag and ZnO-NPs out and inside of malignant cells. Also, their anti-angiogenesis impact was verified by significant dose-dependent VEGF and VEGFR down-regulation and the decreased blood vessels in the chicks’ chorioallantoic membrane (CAM). Conclusion The antioxidant, cytotoxicity and anti-angiogenesis effects of Ag and ZnO-NPs synthesized from Pecan smoke extract make it possible to use these nanoparticles in cancer chemotherapy.

Background: Multiple sclerosis is an autoimmune chronic inflammatory disease of the central nervous system that can lead to some serious disabilities. Despite using various immunomodulatory and anti-inflammatory drugs that have therapeutic effects, they cannot reduce its progression completely and have some unwanted side effects too. The immunomodulatory and anti-inflammatory effects of the β-D-Mannuronic acid (M2000) have been proven in several surveys, and the present research was designed to determine its toxicity and therapeutic effects in MS patients. Methods: This study was performed on 15 MS patients who took 25 mg/kg/day the oral form of the β-D-Mannuronic acid for six months, and 15 healthy people as a control group. Serum levels of Urea, Creatinine, GGT, Vitamin D3, Uric acid, and Anti-Phospholipids were compared to evaluate the therapeutic and possible toxic effects of this drug after this period. Results: Non- toxic effects through the study of urea, creatinine, GGT, and non-significant changes in uric acid and anti-Phospholipids levels, besides a significant rise in vitamin, D3 levels in the M2000 treated cases were found. Conclusions: Our results suggested that β-D-Mannuronic acid is a safe drug and has no toxicity when administered orally and also has some therapeutic effects in MS patients.

Purpose: Breast cancer is one of the most common cancer among. Chemotherapy and radiation along with surgery are common methods for treating cancer, but they exhibit side effects on normal cells in the body. We used peptides, as new anti-cancer agents, seem to have fewer reactions on the body's natural cells and are specialized markers for targeting cancer cells. Materials and methods: Metabolomics data are obtained by 1HNMR, LC/MS and GC/MS spectrometry and analyzed by chemometrics techniques and the affected metabolic cycles identified using different databases. ZR-75-1 cells were collected with estradiol (positive control), without estradiol (negative control) and estradiol with peptide (treatment group) and the metabolites of these 3 groups were collected by chloroform/methanol or water extraction method. Spectra were analyzed by 1HNMR and chemometric methods using PLS-DA techniques by which differentiating chemical shifts and their respective metabolites were identified using the Human Metabolome Database. The differentiating metabolic pathways were detected using Metaboanalyst.ca website. Results: A concentration of 10-9 M estradiol induced the growth of estradiol-dependent ZR-75-1 cells compared to the control group. A concentration of 10-10 M MH-I peptide inhibited the growth of estradiol-induced growth in this ER + breast cancer cell line. Altered metabolites and metabolic pathway were distinguished. Conclusion: Changes were observed in different amino acids and carbohydrates. The pathways of aminoacyl-t-RNA, glycolysis. Gluconeogenesis and biosynthesis of biotin and amino acids showed the most changes. The results from this study introduces a new peptide drug lead for the treatment of breast cancer with estrogen positive receptor.

Purpose Evaluation of structural features, thermodynamics and kinetic properties of carbon nanofibers (CNFs) as artificial nanoscale enzymes (nanozyme). Methods Synthesis of CNFs was done using chemical vapor deposition, and transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM) and energy-dispersive x-ray spectroscopy (EDX) were used to provide information on the morphology, elemental monitoring and impurity assay of the CNFs. The thermal features of the CNFs were evaluated using differential thermal analysis (DTA), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) derivative and TGA. The calculated thermo-physical parameters were melting temperature (Tm), weight loss maximum temperature (Tmax ) and enthalpy of fusion (ΔHfusion ). Catalytic activity was assayed by a 4-aminoantypyrine (4-AAP)-H2O2 coupled colorimetric system by UV-visible spectroscopy. Results FE-SEM and TEM analysis demonstrated parallel graphitic layers and uniformity of atomic orientation and morphology. The EDX spectra approved carbon element as major signal and presence of partial Ti as impurities of CNFs during CVD process. The DTA thermogram showed the endothermic process had a maximum temperature of 82.27°C at -15.48 mV and that thermal decomposition occurred at about 200°C. The TGA-differential gravimetric analysis thermogram showed that Tmax was 700°C. The DSC heat flow curve showed a melting temperature (Tm) of 254.52°C, ΔHfusion of 3.84 J^.g-1, area under the curve of 58.58 mJ and Te (onset) and Tf (end set) temperatures of 246.60°C and 285.67°C, respectively. The peroxidase activity of the CNFs obeyed the Michaelis-Menten equation with a double-reciprocal curve and the calculated Km, Kcat and Vmax kinetic parameters. Conclusion CNFs as peroxidase nanozymes are intrinsically strong and stable nanocatalysts under difficult thermal conditions. The peroxidase activity was demonstrated, making these CNFs candidates for analytical tools under extreme conditions.

Synthesis and investigation of biological activity of

Beta 2 glycoprotein I (β2GPI) is a major antigen for autoantibodies present in antiphospholipid antibody syndrome (APS). β2GPI is a single polypeptide with five repeated domains and different conformations. The activated J-shaped conformation of β2GPI 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 β2GPI. In the first phase, FDA drugs that had the most favorable ΔG with the fifth domain of β2GPI 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 β2GPI 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 β2GPI. Thus, Vorapaxar can be a suitable candidate for further investigations on the treatment of APS.

Background: Apoptosis is a programmed cell death that occurs due to various factors such as reperfusion ischemia. As a purinergic receptor, A1AR acts as an oxidative stress sensor and an antioxidant during reperfusion ischemia. Objectives: The purpose of the present study was to investigate the effect of adenosine injection following cerebral reperfusion ischemia on A1AR gene expression and apoptosis in the brain hippocampal tissue of male Wistar rats. Methods: This experimental study was conducted at Shahid Mirghani Research Institute in Gorgan, Iran, from January 21, 2019, to March 18, 2019. The sample size was determined according to previous studies and a pilot study. Thus, 30 male Wistar rats were divided into three groups by simple random sampling (using a random-number table): Control group (n = 10), Reperfusion ischemia group (n = 10), and Reperfusion ischemia + adenosine group (n = 10). Ischemia was induced in animals by closing the carotid artery for 45 min. Adenosine was injected 24 h after ischemia. We measured A1AR gene expression, SOD protein expression, and apoptosis by real-time PCR, immunohistochemistry, and the TUNEL method, respectively. Results: The results showed that cerebral reperfusion ischemia significantly increased A1AR gene expression (596%) and apoptosis (378%) and decreased SOD protein expression (72%) compared to the control group (P < 0.001). On the other hand, adenosine significantly reduced A1AR gene expression (46%) and apoptosis (69%) and increased SOD protein expression (94%) compared to the ischemic group (P < 0.001). Conclusions: Ischemic brain reperfusion causes oxidative stress. Also, adenosine injection seems to be effective in reducing oxidative stress and apoptosis induced by cerebral reperfusion ischemia.

Recurrent implantation failure (RIF) refers to cases in which women have had the failure of the embryo implantation after several in vitro fertilization (IVF). The success rate for IVF depends on many different factors. Implantation is a complex step in a successful pregnancy. Antiphospholipid antibodies (aPLs) and platelet-activating factor (PAF) can be considered as effective factors in the embryo implantation. The first purpose of this study is to compare the levels of aPLs and PAF among RIF and fertile control women. The second purpose is evaluating correlations between the blood levels of these factors in this two groups. The levels of twelve types of aPL and PAF in peripheral blood samples of RIF and fertile control women were checked with ELISA method. The results showed that levels of Anti Cardiolipin antibody IgG was above the normal level in 3% of RIF patients. This study examined for the first time the correlation between twelve types of aPLs and PAF in RIF and fertile women. The results of these correlations show that the serum levels of aPLs affects themselves and the serum levels of PAF. The correlation of aPLs levels and PAF levels was different in the two groups. Differences in the correlations of aPLs levels and PAF levels in two groups show that the equal changes in the level of variables examined can have different effects in RIF and the fertile control groups. It is suggested that the correlation between these variables be evaluated in other studies.

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.

Background: Helicobacter pylori (H. pylori) plays the primary role in increasing oxidative stress and causing stomach inflammation, peptic ulcers, and gastric malignancy in the infected patients. L-arginine (Arg) has antibacterial and anti-inflammatory effects. Objectives: The current study aimed at investigating the beneficial effects of L-arginine on inflammation and oxidative stress in patients infected with H. pylori with dyspeptic symptoms. Methods: The current randomized, double-blind controlled, clinical trial was conducted on 34 patients with H. pylori infection referred to the center of digestive disorders affiliated to Isfahan University of Medical Sciences, Isfahan, Iran, in order to undergo endoscopy from December 2016 to September 2017. Patients were classified into two groups (control and treatment); the control group only received triple-drug therapy (including Amoxicillin, Clarithromycin, and Omeprazole), and the treatment group received standard triple-drug therapy and L-Arg capsules for three weeks. Gastric biopsies and serum samples were taken from all patients before and after the study. H. pylori infection was examined by a rapid urease test and antioxidant indices including superoxide dismutase (SOD), glutathione peroxidase (GPX), and total antioxidant capacity (TAC) were evaluated in gastric biopsies. In addition, serum samples were used to measure the inflammation factors including interleukin (IL)-8 and tumor necrosis factor (TNF)-α. Results: Level of SOD activity increased significantly in the treatment group compared with that of the control group (4.91 ± 95.21 vs. 4.0 ± 44.11 IU/mg) (P = 0.001). In the treatment group, compared with the control group, the level of TAC increased significantly (0.35 ± 0.60 vs. 0.30 ± 0.9 mM/L) (P = 0.006) and the level of GPX activity increased significantly in the treatment group compared with the control group (10.68 ± 2.39 vs. 5.16 ± 2.12 IU/mg) (P = 0.000). Regarding the inflammation factor, IL-8 decreased significantly in the treatment group compared with the control group (8.00 ± 1.94 vs. 10.28 ± 2.10 pg/mL) (P = 0.002); also TNF-α decreased significantly in the treatment group compared with the control group (9.71 ± 2.69 vs. 12.24 ± 3.29 pg/mL) (P = 0.036), while there was no significant difference in high sensitivity C-reactive protein (hs-CRP) decrease between the treatment and the control groups (2.34 ± 1.28 vs. 3.04 ± 1.58 mg/L) (P = 0.16). Conclusions: Consumption of L-arginine increased antioxidant indices and decreased inflammation in patients infected with H. pylori.

Background:: Rheumatoid arthritis (RA) is the most common chronic inflammatory disease of unknown etiology. In this regard, the role of bacterial superantigens (as an effective agent) were considered. Objectives:: This study aimed to assess staphylococcal enterotoxin E in the blood of patients with rheumatoid arthritis. Patients and Methods:: A total of 83 blood samples of patients with RA were studied. All of patient’s blood samples have been cultured. Polymerase chain reaction (PCR) and ELISA methods have been used to assess the existence of staphylococcal enterotoxin E (entE). The data were analyzed through descriptive statistics. Results:: During this study and after sequential sub cultures, only 5 bacterial strains were isolated. Based on the results of biochemical tests, just one case was detected as Staphylococcus aureus. The result of molecular diagnosis of enterotoxin E gene was 13.25%. The results of ELISA were 40.96% positive for staphylococcal enterotoxin E. Conclusions:: In this study, staphylococcal enterotoxin E (superantigen E) was detected in the blood of patients with RA, but its origin is unknown, because no staphylococcus enterotoxin E producer was isolated. This finding could provide a good model for the diagnosis and treatment of RA. However, the results of this study have shown some evidence regarding endogenous origin of involved superantigens in patients with rheumatoid arthritis.