Effect of melatonin in reducing second-generation antipsychotic metabolic effects: A double blind controlled clinical trial

Introduction The use of second-generation atypical antipsychotics has an increasing role in the development of metabolic syndrome. However, these medications due to metabolic disorders can lead to an increased risk of cardiovascular disease and subsequently mortality as well as reduced adherence to treatment. The main objective of current study was to determine the ability of melatonin to reduce the metabolic effects of second-generation antipsychotics. Methods This double blind controlled clinical trial was conducted on 100 patients aged 18–64 years old were treated with the second-generation antipsychotics for the first time. The patients were divided randomly into two groups of 50. The case group received slow-release melatonin at a dose of 3 mg and the control group was given oral placebo at 8 p.m. Results The findings in melatonin group indicated significantly increase of HDL and decreased fasting blood sugar and systolic blood pressure, as well as had statistically significant increase in waist circumference, weight and BMI compared with placebo group. Conclusion According to the findings, it can be claimed that the addition of melatonin to atypical antipsychotics has led to a reduction in some of the metabolic effects of these drugs. In this study, HDL level was increased, and the mean systolic blood pressure and FBS were decreased in the melatonin group. Considering that these factors are contributing to cardiovascular disease as a leading cause of mortality in psychiatric patients, so the use of melatonin can reduce some of the medical effects of long-term treatment of atypical antipsychotics. © 2017 Diabetes Indi

Evaluation of Cisplatin efficacy on HepG2 and E. coli Cells under acidic conditions

Background: Cisplatin (Cispt) is a common anticancer drug for the treatment of several malignancies, including hepatocarcinoma. However, this drug suffers from instability in aqueous solutions. The study aimed to evaluate cisplatin efficacy on HepG2 and E. coli cells under an acidic condition. Methods: Acidic Cispt was prepared via incubation in acidic condition (pH=2) for a month duration. The chemical structure of the acidic Cispt was evaluated by using Fourier Transform Infrared Spectroscopy (FTIR) method. The cytotoxicity of the standard and acidic Cispt were then determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and minimum inhibitory concentration (MIC) assays on HepG2 and E. coli cells, respectively. Results: After preparing of acidic Cispt, its chemical structure was determined by FTIR method. In addition, cytotoxicity effects of Cispt in the standard and acidic forms were calculated 58 ± 2.9 and 65 ± 3.25 μM, respectively. MIC results also confirmed the results of MTT assay. MIC results for the standard and acidic Cispt were estimated 9.5 ± 0.47 and 9.8 ± 0.49 μM, respectively. Conclusion: Preparing Cispt in acidic condition not only did not degrade the drug, but also kept the potency of the drug approximately equal to parent drug. Regarding the instability issues of Cispt, keeping Cispt in acidic condition could be a promising approach to preserve its efficacy. © 2019, Asian Pacific Journal of Cancer Prevention

The extracellular vesicles-derived from mesenchymal stromal cells: A new therapeutic option in regenerative medicine

ABSTRACT Mesenchymal stem cells (MSCs) are adult multipotent cells that due to their ability to homing to damaged tissues and differentiate into specialized cells, are remarkable cells in the field of regenerative medicine. It's suggested that the predominant mechanism of MSCs in tissue repair might be related to their paracrine activity. The utilization of MSCs for tissue repair is initially based on the differentiation ability of these cells; however now it has been revealed that only a small fraction of the transplanted MSCs actually fuse and survive in host tissues. Indeed, MSCs supply the microenvironment with the secretion of soluble trophic factors, survival signals and the release of extracellular vesicles (EVs) such as exosome. Also, the paracrine activity of EVs could mediate the cellular communication to induce cell- differentiation/self-renewal. Recent findings suggest that EVs released by MSCs may also be critical in the physiological function of these cells. This review provides an overview of MSC-derived extracellular vesicles as a hopeful opportunity to advance novel cell-free therapy strategies that might prevail over the obstacles and risks associated with the use of native or engineered stem cells. EVs are very stable; they can pass the biological barriers without rejection and can shuttle bioactive molecules from one cell to another, causing the exchange of genetic information and reprogramming of the recipient cells. Moreover, extracellular vesicles may provide therapeutic cargo for a wide range of diseases and cancer therapy. Key Words: Mesenchymal Stem Cells, Extracellular vesicles, Exosome, Regenerative medicine

The protective effect of coenzyme Q10 and berberine on sperm parameters, with and without varicocelectomy in rats with surgically induced varicoceles

The current study aimed to investigate the protective effects of coenzyme Q10 (Co Q10) and berberine (BB) with and without varicocelectomy on sperm parameters in postoperative varicocele rats. For the current purpose, a total of 60 mature male Wistar rats were randomly divided into control (n = 6 rats), control-sham (n = 6 rats), and experimental (n = 6 rats) groups. The animals in the experimental groups were undergone experimental varicocele, and simple laparotomy was performed in control-sham group. The experimental group was subdivided into the following groups 60 days after varicocele (VCL) induction: non-treated VCL-induced rats (n = 6 rats), VCL-induced rats administered 100 mg (kg per day) BB (n = 6 rats), VCL-induced rats administered Co Q10 75 mg (kg per day) (n = 6 rats), VCL-induced rats administered 100 mg (kg per day) BB + Co Q10 75 mg (kg per day) (n = 6 rats), varicocelectomy rats (n = 6 rats), varicocelectomy rats administered 100 mg (kg per day) BB (n = 6 rats), varicocelectomy rats administered Co Q10 75 mg (kg per day) (n = 6 rats), varicocelectomy rats administered 100 mg (kg per day) BB + Co Q10 75 mg (kg per day) (n = 6 rats). Following 60 days, the animals were euthanized and sperm parameters were evaluated. Non-treated VCL-induced animals indicated a significant (P < 0.05) decrease in sperm parameters and a significant (P < 0.05) increase in sperm DNA damage compared to control and control-sham groups. Insignificant changes were found between control and control-sham groups. Meanwhile, each treatment group showed a remarkable (P < 0.05) increase in sperm parameters as well as a significant (P < 0.05) decrease in sperm DNA damage. Based on current results, BB and Co Q10 alone and/or together could improve sperm parameters and reduce sperm DNA damage in varicocele-induced rats compared to control and control-sham groups. Varicocelectomy alone will improve sperm parameters, but this recovery will be greater when combined with Co Q10 and BB. © 2018, Springer-Verlag London Ltd., part of Springer Nature

Evaluation of the serum sex hormones levels and alkaline phosphatase activity in rats� testis after administering of berberine in experimental varicocele

Current study was aimed to investigate the protective effect of berberine (BB) on the serum gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B (INHB), testosterone (T) and alkaline phosphatase (Alk-p) activity in the testis of experimental varicocele-induced animals. For the current objective, 30 mature-male Wistar rats were randomly divided into control (n = 6 rats), control-sham (n = 6 rats) and experimental groups (n = 18 rats). The animals in the experimental groups were undergone experimental varicocele and simple laparotomy was conducted in control-sham group. 60 days after varicocele (VCL) induction the experimental group subdivided into: non-treated VCL-induced and 50 mg/kg and 100 mg/kg BB-treated groups (intra-peritoneally). Following 60 days, the animals were euthanized and serum levels of testosterone and testicular activity of alkaline phosphatase were measured. Non-treated VCL-induced animals indicated a significant (P < 0.05) reduction in serum levels of T and INHB and a remarkable (P < 0.05) increase in GnRH, FSH, LH and Alk-p activity compared to control and control-sham groups. Insignificant changes were found between control and control-sham groups. Meanwhile, each BB administered group showed a remarkable (P < 0.05) increase in serum levels of T and INHB and a significant (P < 0.05) decrease in GnRH, FSH, LH and alkaline phosphatase activity in testis tissue. According to the current findings, BB by increasing serum levels of testosterone and INHB increases the testicular endocrine capacity and protects Leydig cell against inflammatory and oxidant injury of varicocele. In addition, BB by inhibiting GnRH, FSH, LH and alkaline phosphatase activity, regulate the levels of serum sex hormones in experimental varicocele and reduces varicocele-induced inflammatory reactions. © 2019, Institute of Korean Medicine, Kyung Hee University

Human leukocyte antigen class I (A, B) and class II (DRB1) allele and haplotype frequencies in Iranian patients with Buerger's disease

Objective: The aim of this study was to investigate the human leukocyte antigen (HLA) class I (HLA-A and HLA-B) and II (HLA-DRB1) allele and haplotype frequencies in a group of Iranian patients with Buerger's disease (BD) in comparison with a normal healthy control group. Methods: A total of 70 unrelated male patients and 100 healthy controls from Sina Hospital, Tehran, Iran, belonging to the same ethnic background, were enrolled in this case-control study. HLA-A, B, and DRB1 typing were performed by polymerase chain reaction with sequence-specific primers (PCR-SSP). Results: The results of this case-control study showed that the frequency of the HLA-A*03:01 (odds ratio (OR) = 2.88, P value (Pv) =.002), HLA-A*29:01 (OR = 15.31, Pv <.001), HLA-DRB1*04:02 (OR = 3.41, Pv <.001), and HLA-DRB1*16:01 (OR = 8.16, Pv <.001) was significantly higher in BD patients compared with healthy controls, whereas the frequency of the HLA-DRB1*01:01 (OR = 0.03, Pv <.001) was significantly lower in BD patients. The most frequent extended haplotypes in our patients were HLA-A*02:01-B*55:01-DRB1*04:03. Conclusion: This study is the first study evaluating an association between the HLA pattern and BD in the patients with BD from North West and North Iran. © 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Lt

Studies on combination of oxaliplatin and dendrosomal nanocurcumin on proliferation, apoptosis induction, and long non-coding RNA expression in ovarian cancer cells

Drug resistance remains a major challenge in the treatment of patients with ovarian cancer. Therefore, the development of new anticancer drugs is a clinical priority to develop more effective therapies. New approaches to improve clinical outcomes and limit the toxicity of anticancer drugs focus on chemoprevention. The aim of this study was to determine the effects of dendrosomal nanocurcumin (DNC) and oxaliplatin (Oxa) and their combination on cell death and apoptosis induction in human ovarian carcinoma cell lines analyzed by MTT assay and flow cytometry, respectively. The synergism effect of Oxa and DNC was analyzed using the equation derived from Chou and Talalay. In addition, real-time PCR was used to measure the effect of this combination on the expression levels of long non-coding RNAs with different expression in ovarian cancer and normal ovaries. Our data showed that the effect of DNC on cell death is more than curcumin alone in the same concentration. The greatest cell death effect was observed in combination of Oxa with DNC, while Oxa was added first, followed by DNC at 4 h interval (0/4 h). The findings indicated that DNC induced apoptosis significantly in both cell lines as compared to control groups; however, combination of both agents had no significant effect in apoptosis induction. In addition, combination of both agents significantly affects the relative expression of long non-coding RNAs investigated in the study as compared with mono therapy. © 2018, Springer Nature B.V

Monitoring the genomic stability of in vitro cultured rat bone-marrow-derived mesenchymal stem cells

Bone-marrow-derived mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation into multiple cell types. Accumulating preclinical and clinical evidence indicates that MSCs are good candidates to use as cell therapy in many degenerative diseases. For MSC clinical applications, an adequate number of cells are necessary so an extensive expansion is required. However, spontaneous immortalization and malignant transformation of MSCs after culture expansion have been reported in human and mouse, while very few data are present for rat MSCs (rMSCs). In this study, we monitored the chromosomal status of rMSCs at several passages in vitro, also testing the influence of four different cell culture conditions. We first used the conventional traditional cytogenetic techniques, in order to have the opportunity to observe even minor structural abnormalities and to identify low-degree mosaic conditions. Then, a more detailed genomic analysis was conducted by array comparative genomic hybridization. We demonstrated that, irrespective of culture conditions, rMSCs manifested a markedly aneuploid karyotype and a progressive chromosomal instability in all the passages we analyzed and that they are anything but stable during in vitro culture. Despite the fact that the risk of neoplastic transformation associated with this genomic instability needs to be further addressed and considering the apparent genomic stability reported for in vitro cultured human MSCs (hMSCs), our findings underline the fact that rMSCs may not in fact be a good model for effectively exploring the full clinical therapeutic potential of hMSCs

Effector CD4+ T Cell Expression Signatures and Immune-Mediated Disease Associated Genes

Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naïve CD4+ T cells of genes contained among immune–mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis

Tumor-Like Stem Cells Derived from Human Keloid Are Governed by the Inflammatory Niche Driven by IL-17/IL-6 Axis

Alterations in the stem cell niche are likely to contribute to tumorigenesis; however, the concept of niche promoted benign tumor growth remains to be explored. Here we use keloid, an exuberant fibroproliferative dermal growth unique to human skin, as a model to characterize benign tumor-like stem cells and delineate the role of their "pathological" niche in the development of the benign tumor.Subclonal assay, flow cytometric and multipotent differentiation analyses demonstrate that keloid contains a new population of stem cells, named keloid derived precursor cells (KPCs), which exhibit clonogenicity, self-renewal, distinct embryonic and mesenchymal stem cell surface markers, and multipotent differentiation. KPCs display elevated telomerase activity and an inherently upregulated proliferation capability as compared to their peripheral normal skin counterparts. A robust elevation of IL-6 and IL-17 expression in keloid is confirmed by cytokine array, western blot and ELISA analyses. The altered biological functions are tightly regulated by the inflammatory niche mediated by an autocrine/paracrine cytokine IL-17/IL-6 axis. Utilizing KPCs transplanted subcutaneously in immunocompromised mice we generate for the first time a human keloid-like tumor model that is driven by the in vivo inflammatory niche and allows testing of the anti-tumor therapeutic effect of antibodies targeting distinct niche components, specifically IL-6 and IL-17.These findings support our hypothesis that the altered niche in keloids, predominantly inflammatory, contributes to the acquirement of a benign tumor-like stem cell phenotype of KPCs characterized by the uncontrolled self-renewal and increased proliferation, supporting the rationale for in vivo modification of the "pathological" stem cell niche as a novel therapy for keloid and other mesenchymal benign tumors