Increased Cyclic Adenosine Monophosphate Responsive Element is Closely Associated with the Pathogenesis of Drug-resistant Epilepsy.

BACKGROUND: Drug-resistant epilepsy (DRE) is a refractory neurological disorder. There is ample evidence that suggest that γ-aminobutyric acid-a (GABAA) receptors could be one of the mechanisms responsible for the development of drug resistance in epilepsy. It is also known that the cAMP response element binding protein (CREB) plays a possible key role in the transcriptional regulation of GABAA. OBJECTIVE: This study explores the role of CREB in the development of DRE and the effect of CREB on GABA-related receptors in DRE. METHODS: The CREB expression was increased or decreased in the hippocampus of normal rats by lentiviral transfection, who then underwent the lithium-pilocarpine-induced epilepsy model. Phenobarbital (PB) sodium and carbamazepine (CBZ) were used to select a drug-resistant epileptic model. The expression levels of GABAA receptor α1, ß2, and γ2 subunits and CREB protein were measured in the rat hippocampus by western blot and fluorescent quantitative PCR. RESULTS: The frequency and duration of seizures increased in the overexpression group compared to that in the control group. In addition, the severity, frequency, and duration of seizures decreased in the group with decreased expression. The hippocampus analysis of the expression levels of the CREB protein and CREB mRNA yielded similar findings. Altering the CREB protein expression in the rat hippocampus could negatively regulate the expression and transcript levels of GABAA receptors α1, ß2, and γ2, suggesting that CREB may serve as a potential target for the development of treatment protocols and drugs for epilepsy. CONCLUSION: Our study shows that enhanced CREB expression promotes the development of DRE and negatively regulates GABAA receptor levels and that the inhibition of CREB expression may reduce the incidence of DRE.

Efficacy and safety of selegiline for the treatment of Parkinson's disease: A systematic review and meta-analysis.

Background: Drug efficacy generally varies with different durations. There is no systematic review analyzing the effect of selegiline for Parkinson's disease (PD) on different treatment duration. This study aims to analyze how the efficacy and safety of selegiline changes for PD over time. Methods: PubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure and Wanfang Database were systematically retrieved for randomized controlled trials (RCTs) and observational studies of selegiline for PD. The search period was from inception to January 18th, 2022. The efficacy outcomes were measured by the mean change from baseline in the total and sub Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD) and Webster Rating Scale (WRS) scores. The safety outcomes were measured by the proportion of participants having any adverse events overall and that in different system organ classes. Results: Among the 3,786 studies obtained, 27 RCTs and 11 observational studies met the inclusion criteria. Twenty-three studies reported an outcome which was also reported in at least one other study, and were included in meta-analyses. Compared with placebo, selegiline was found with a stronger reduction of total UPDRS score with increasing treatment duration [mean difference and 95% CIs in 1 month: -3.56 (-6.67, -0.45); 3 months: -3.32 (-3.75, -2.89); 6 months: -7.46 (-12.60, -2.32); 12 months: -5.07 (-6.74, -3.41); 48 months: -8.78 (-13.75, -3.80); 60 months: -11.06 (-16.19, -5.94)]. A similar trend was also found from the point estimates in UPDRS I, II, III, HAMD and WRS score. The results of observational studies on efficacy were not entirely consistent. As for safety, compared with placebo, selegiline had higher risk of incurring any adverse events [rate: 54.7% vs. 62.1%; odd ratio and 95% CIs: 1.58 (1.02, 2.44)], with the excess adverse events mainly manifested as neuropsychiatric disorders [26.7% vs. 31.6%; 1.36 (1.06, 1.75)] and no significant change over time. The statistically difference in overall adverse event between selegiline and active controls was not found. Conclusion: Selegiline was effective in improving total UPDRS score with increasing treatment duration, and had a higher risk of incurring adverse events, especially the adverse events in the neuropsychiatric system. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: PROSPERO CRD42021233145.

Evidence for the existence of CD34+ angiogenic stem cells in human first-trimester decidua and their therapeutic for ischaemic heart disease.

Stem cell transplantation is nearly available for clinical application in the treatment of ischaemic heart disease (IHD), where it may be joined traditional methods (intervention and surgery). The angiogenic ability of seed cells is essential for this applicability. The aim of this study was to reveal the presence of CD34+ angiogenic stem cells in human decidua at the first trimester and to use their strong angiogenic capacity in the treatment of IHD. In vitro, human decidual CD34+ (dCD34+ ) cells from the first trimester have strong proliferation and clonality abilities. After ruling out the possibility that they were vascular endothelial cells and mesenchymal stem cells (MSCs), dCD34+ cells were found to be able to form tube structures after differentiation. Their angiogenic capacity was obviously superior to that of bone marrow mesenchymal stem cells (BMSCs). At the same time, these cells had immunogenicity similar to that of BMSCs. Following induction of myocardial infarction (MI) in adult rats, infarct size decreased and cardiac function was significantly enhanced after dCD34+ cell transplantation. The survival rate of cells increased, and more neovasculature was found following dCD34+ cell transplantation. Therefore, this study confirms the existence of CD34+ stem cells with strong angiogenic ability in human decidua from the first trimester, which can provide a new option for cell-based therapies for ischaemic diseases, especially IHD.

SIRT3 Transfection of Aged Human Bone Marrow-Derived Mesenchymal Stem Cells Improves Cell Therapy-Mediated Myocardial Repair.

Sirtuin 3 (SIRT3) is a deacetylase important for antioxidant protection, cell longevity, and aging. We hypothesized that SIRT3 improve oxidative resistance of aged cells and improve cell therapy in aged patients. In vitro, the proliferation and oxidative resistance of human mesenchymal stem cells (hMSCs) significantly declined with age. The expression and activity of antioxidant enzymes, including catalase (CAT) and manganese superoxide dismutase (MnSOD), increased after transfection of SIRT3 in hMSCs from older donors (O-hMSCs). The protein level of Forkhead box O3a (FOXO3a) in nucleus increased after SIRT3 overexpression. The antioxidant capacity of O-hMSCs increased after SIRT3 overexpression. 3-Amino-1,2,4-triazole (3-AT, CAT inhibitor) or diethyldithiocarbamate (DETC, SOD inhibitor) that was used to inhibit CAT or SOD activity significantly blocked the antioxidant function of SIRT3. When two inhibitors were used together, the antioxidant function of SIRT3 almost disappeared. Following myocardial infarction and intramyocardial injections of O-hMSCs in rats in vivo, the survival rate of O-hMSCs increased by SIRT3 transfection. The cardiac function of rats was improved after SIRT3-overexpressed O-hMSC transplantation. The infarct size, collagen content, and expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 decreased. Besides, the protein level of vascular endothelial growth factor A and vascular density increased after cell transplantation with SIRT3-modified O-hMSCs. These results indicate that damage resistance of hMSCs decline with age and SIRT3 might protect O-hMSCs against oxidative damage by activating CAT and MnSOD through transferring FOXO3a into nucleus. Meanwhile, the therapeutic effect of aged hMSC transplantation can be improved by SIRT3 overexpression.

Comparison of vaginal and abdominal hysterectomy:A prospective non-randomized trial.

OBJECTIVE: To compare outcomes of vaginal and abdominal hysterectomy procedures in women with benign gynaecological diseases. METHODS: This was a prospective study of outcomes of consecutive patients who underwent total vaginal hysterectomy (VH) or abdominal hysterectomy (AH) for benign gynaecological diseases. Patient characteristics before, during, and after the operations were reviewed. Patients were followed up for three months to evaluate postoperative complications. RESULTS: This study included a total of 313 patients. 143 patients underwent AH and 170 patients underwent VH. Baseline characteristics were similar between the two groups. There were no intraoperative complications in either group. Operation time, intraoperative blood loss, first postoperative flatus time, time to out-of-bed activity, mean maximum postoperative body temperature, and duration of fever were all significantly shorter and less severe in the VH group compared with the AH group. In addition, vaginal length in the VH group was significantly shorter than in the AH group. CONCLUSIONS: Vaginal hysterectomy has advantages over AH in the treatment of benign gynaecological diseases, providing greater efficacy and safety with minimal invasiveness.