MiR-182-5p, MiR-192-5p, and MiR-493-5p Constitute a Regulatory Network with CRISP3 in Seminal Plasma Fluid of Teratozoospermia Patients.

Numerous evidences suggested that microRNAs (miRs) could play an active and significant role during spermatogenesis. Cysteine-rich secretory protein (CRISP3) has a role in inflammatory response and is extremely over-expressed in adolescents with varicocele seminal plasma and modified semen analysis. Nowadays, the miRs expression's association with their target genes is well recognized. The aim of this study was evaluating the association of CRISP3 and four candidate miRs among teratozoospermia (TZ) infertile men. First, we have selected four miRs, miR-182-5p, miR-192-5p, miR-204-5p, and miR-493-5p bioinformatically. After that, RNA was extracted from semen samples of 21 TZ patients and 20 normozoospermia (Norm). Then, their expression levels were assessed using real-time polymerase chain reaction method. In the next step, we quantified the expression of two CRISP3 protein isoforms, targeted by these miRs, using western blotting. According to our results, up-regulation of miR-182-5p, miR-192-5p, and miR-493-5p was observed. MiR-182-5p, miR-192-5p, and miR-493-5p showed good AUC values which can be introduced as possible biomarkers of TZ. In addition, the expression level of the CRISP3 glycosylated (31 kDa) isoform was significantly lower in TZ patients than Norm ones. Notably, in TZ patients, there was a possibly positive correlation of glycosylated CRISP3 expression with normal sperm morphology. According to our results, CRISP3 protein can play a significant role in male infertility especially in maturation formation of spermatozoa. Also, deregulation of the studied miRs, miR-182-5p, miR-92-5p, and miR-493-5p, can suggest a regulatory network between these miRs and CRISP3 isoforms and suggest their regulatory roles in male infertility.

Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria.

Injury to podocytes is a principle cause of initiation and progression of both immune and non-immune mediated glomerular diseases that result in proteinuria and decreased function of the kidney. Current advances in regenerative medicine shed light on the therapeutic potential of cell-based strategies for treatment of such disorders. Thus, there is hope that generation and transplantation of podocytes from induced pluripotent stem cells (iPSCs), could potentially be used as a curative treatment for glomerulonephritis caused by podocytes injury and loss. Despite several reports on the generation of iPSC-derived podocytes, there are rare reports about successful use of these cells in animal models. In this study, we first generated a model of anti-podocyte antibody-induced heavy proteinuria that resembled human membranous nephropathy and was characterized by the presence of sub-epithelial immune deposits and podocytes loss. Thereafter, we showed that transplantation of functional iPSC-derived podocytes following podocytes depletion results in recruitment of iPSC-derived podocytes within the damaged glomerulus, and leads to attenuation of proteinuria and histological alterations. These results provided evidence that application of iPSCs-derived renal cells could be a possible therapeutic strategy to favorably influence glomerular diseases outcomes.

Intra-renal arterial injection of autologous bone marrow mesenchymal stromal cells ameliorates cisplatin-induced acute kidney injury in a rhesus Macaque mulatta monkey model.

BACKGROUND: Clinically, acute kidney injury (AKI) is a potentially devastating condition for which no specific therapy improves efficacy of the repair process. Bone marrow mesenchymal stromal cells (BM-MSCs) are proven to be beneficial for the renal repair process after AKI in different experimental rodent models, but their efficacy in large animals and humans remains unknown. This study aims to assess the effect of autologous rhesus Macaque mulatta monkey BM-MSC transplantation in cisplatin-induced AKI. METHODS: We chose a model of AKI induced by intravenous administration of 5 mg/kg cisplatin. BM-MSCs were transplanted through intra-arterial injection. The animals were followed for survival, biochemistry analysis and pathology. RESULTS: Transplantation of 5 × 10(6) cells/kg ameliorated renal function during the first week, as shown by significantly lower serum creatinine and urea values and higher urine creatinine and urea clearance without hyponatremia, hyperkalemia, proteinuria and polyuria up to 84 d compared with the vehicle and control groups. The superparamagnetic iron oxide nanoparticle-labeled cells were found in both the glomeruli and tubules. BM-MSCs markedly accelerated Foxp3+ T-regulatory cells in response to cisplatin-induced damage, as revealed by higher numbers of Foxp3+ cells within the tubuli of these monkeys compared with cisplatin-treated monkeys in the control and vehicle groups. CONCLUSIONS: These data demonstrate that BM-MSCs in this unique large-animal model of cisplatin-induced AKI exhibited recovery and protective properties.

Association of thrombophilia and polycystic ovarian syndrome in women with history of recurrent pregnancy loss.

PURPOSE: To evaluate the prevalence of thrombophilic disorders in polycystic ovarian syndrome (PCOS) women with history of recurrent pregnancy loss (RPL). MATERIALS AND METHODS: This study was carried out in 184 women with history of RPL, of which 92 of them were diagnosed with PCOS and 92 patients were without known PCOS. The prevalence of thrombophilic disorders was compared between the two mentioned groups. RESULTS: According to the findings, 70.7% of PCOS women with history of RPL had thrombophilic disorders. The prevalence of protein C deficiency was significantly higher in PCOS group compared to the non-PCOS group (21.7% vs. 10.9%, p = 0.04). There was a trend toward higher prevalence of protein S deficiency in PCOS group compared to the control group, but the difference did not reach statistical significance (23.9% vs. 13%, p = 0.05). The prevalence of other thrombophilic disorders such as antithrombin III deficiency, homocysteine elevation, antiphospholipid antibody and Factor V Leiden was comparable between groups. CONCLUSION: The prevalence of thrombophilic disorders was more common in PCOS women than the normal group. The protein C deficiency is associated with PCOS in women with history of RPL. There was a trend toward higher prevalence of protein S deficiency in PCOS women, which needs further study.

Generation of human induced pluripotent stem cells from a Bombay individual: moving towards "universal-donor" red blood cells.

Bombay phenotype is one of the rare phenotypes in the ABO blood group system that fails to express ABH antigens on red blood cells. Nonsense or missense mutations in fucosyltransfrase1 (FUT1) and fucosyltransfrase2 (FUT2) genes are known to create this phenotype. This blood group is compatible with all other blood groups as a donor, as it does not express the H antigen on the red blood cells. In this study, we describe the establishment of human induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of a Bombay blood-type individual by the ectopic expression of established transcription factors Klf4, Oct4, Sox2, and c-Myc. Sequence analyses of fibroblasts and iPSCs revealed a nonsense mutation 826C to T (276 Gln to Ter) in the FUT1 gene and a missense mutation 739G to A (247 Gly to Ser) in the FUT2 gene in the Bombay phenotype under study. The established iPSCs resemble human embryonic stem cells in morphology, passaging, surface and pluripotency markers, normal karyotype, gene expression, DNA methylation of critical pluripotency genes, and in-vitro differentiation. The directed differentiation of the iPSCs into hematopoietic lineage cells displayed increased expression of the hematopoietic lineage markers such as CD34, CD133, RUNX1, KDR, alpha-globulin, and gamma-globulin. Such specific stem cells provide an unprecedented opportunity to produce a universal blood group donor, in-vitro, thus enabling cellular replacement therapies, once the safety issue is resolved.

Calciotropic hormones, insulin resistance, and the polycystic ovary syndrome.

OBJECTIVE: To investigate whether abnormalities in serum concentrations of 1,25-dihydroxyvitamin D [1,25(OH)(2)D], 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), calcium, and phosphorus were associated with risk of polycystic ovary syndrome (PCOS) and obesity. The possible correlations of the calciotropic hormones with insulin resistance were also examined. DESIGN: Case-control study. SETTING: Department of Genetics, Royan Institute. PATIENT(S): Eighty-five women with PCOS and 115 control women were recruited. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum levels of glucose, insulin, total calcium, phosphorus, PTH, 25(OH)D, and 1,25(OH)(2)D were measured in all 200 subjects. RESULT(S): The presence of PCOS had age- and body mass index (BMI)-independent positive effects on serum phosphorus, PTH, 25(OH)D, and insulin concentrations as well as on insulin resistance. Furthermore, overweight/obese (BMI > or =25 kg/m(2)) women with PCOS had significantly decreased levels of 1,25(OH)(2)D and glucose compared with normal-weight (BMI <25 kg/m(2)) women with PCOS. In women with PCOS, phosphorus was correlated negatively with insulin and insulin resistance and positively with 1,25(OH)(2) D. In addition, in normal-weight patients, PTH correlated positively with insulin and insulin resistance. CONCLUSION(S): It is possible that elevated levels of phosphorus and PTH in women with PCOS, at least in part, through their effects on insulin levels and insulin resistance, are involved in pathogenesis of the syndrome.