ABSTRACT
Bone marrow-derived neural stem cells (BM-NSCs) have shed light on novel therapeutic approaches for PD with the potential to halt or even reverse disease progression. Various strategies have been developed to promote therapeutic efficacy via optimizing implanted cells and the microenvironment of transplantation in the central nervous system (CNS). This current study further proved that the combination of fasudil, a Rho-kinase inhibitor, and BM-NSCs exhibited a synergetic effect on restoring neuron loss in the MPTP-PD mice model. It simultaneously unveiled cellular mechanisms underlying synergistic neuron-protection effects of fasudil and BM-NSCs, which included promoting the proliferation, and migration of endogenous NSCs, and contributing to microglia shift into the M2 phenotype. Corresponding molecular mechanisms were observed, including the inhibition of inflammatory responses, the elevation of neurotrophic factors, and the induction of WNT/ß-catenin and PI3K/Akt/mTOR signaling pathways. Our study provides evidence for the co-intervention of BM-NSCs and fasudil as a promising therapeutic method with enhanced efficacy in treating neurodegenerative diseases.
Subject(s)
Neural Stem Cells , Parkinson Disease , Mice , Animals , Parkinson Disease/metabolism , Bone Marrow , Phosphatidylinositol 3-Kinases/metabolism , Neurons , Neural Stem Cells/metabolism , Bone Marrow CellsABSTRACT
Parkinson's disease (PD) is the second most common neurodegenerative disease with a fast-growing prevalence. Developing disease-modifying therapies for PD remains an enormous challenge. Current drug treatment will lose efficacy and bring about severe side effects as the disease progresses. Extracts from Ginkgo biloba folium (GBE) have been shown neuroprotective in PD models. However, the complex GBE extracts intertwingled with complicated PD targets hinder further drug development. In this study, we have pioneered using single-nuclei RNA sequencing data in network pharmacology analysis. Furthermore, high-throughput screening for potent drug-target interaction (DTI) was conducted with a deep learning algorithm, DeepPurpose. The strongest DTIs between ginkgolides and MAPK14 were further validated by molecular docking. This work should help advance the network pharmacology analysis procedure to tackle the limitation of conventional research. Meanwhile, these results should contribute to a better understanding of the complicated mechanisms of GBE in treating PD and lay the theoretical ground for future drug development in PD.
ABSTRACT
[This corrects the article DOI: 10.3389/fphar.2022.1007556.].
ABSTRACT
<p><b>OBJECTIVE</b>To compare the safety, feasibility, and efficacy of a completely nonfluoroscopic approach to radiofrequency catheter ablation (RFCA) using CARTO3 and ablation with conventional fluoroscopic guidance for treatment of idiopathic premature ventricular contractions from the aortic sinus cusp (ASC-PVCs).</p><p><b>METHODS</b>From April 2013 to October 2015, we prospectively enrolled 52 consecutive patients with ASC-PVCs scheduled for either CARTO3 mapping-guided zero-fluoroscopy ablation (group A, n=23) or conventional fluoroscopic ablation (group B, n=29). The success rates, rates of complications, rates of recurrences, number of radiofrequency applications, procedure time, mapping time and fluoroscopy time were compared between the 2 groups.</p><p><b>RESULTS</b>s No significant differences were found in the success rates between the 2 groups [22/23 (96%) vs 24/29 (83%), P=0.21]. No major complications occurred during the procedures in either group. There was no significant difference with regard to the procedure time between the two groups (79.6∓8.8 vs 77.4∓7.2 min, P=0.332). The procedure was completed without any fluoroscopy use in group A, while the mean fluoroscopy time in group B was 23.1∓6.0 min. Group A showed a shorter mapping time than group B (4.3∓1.7 vs 7.8∓2.6 min, P<0.01) with significantly fewer radiofrequency applications (4.8∓1.1 vs 7.9∓3.2, P<0.01). The recurrence rates were comparable between the two groups over a follow-up period of 5 to 20 months.</p><p><b>CONCLUSION</b>Compared with the conventional fluoroscopic technique, the zero-fluoroscopy approach can shorten the total procedure time and the ablation time with significantly reduced RF applications to eliminate ionizing radiation exposure in RFCA. RFCA guided by CARTO3 system without fluoroscopy is feasible, safe, and effective for treatment of ASC-PVCs.</p>
Subject(s)
Humans , Catheter Ablation , Fluoroscopy , Radio Waves , Recurrence , Sinus of Valsalva , Treatment Outcome , Ventricular Premature Complexes , General SurgeryABSTRACT
<p><b>OBJECTIVE</b>To investigate whether Tpeak-Tend interval (Tp-e) and Tp-e/QT ratio are associated with malignant ventricular arrhythmia in patients with implantable cardioverter-defibrillator (ICD) for primary prevention.</p><p><b>METHODS</b>A cohort of 68 consecutive patients with chronic heart failure undergoing standard ICD for primary prevention indications (NYHA function class II-III, left ventricular ejection fraction ≤35%, systolic cardiomyopathy without prior malignant ventricular arrhythmia) were enrolled in this study. The patients were followed up for 18-48 months and were divided into high-risk group and low-risk group according to the occurrence of the endpoint events of sudden cardiac death (SCD), ventricular tachycardia (VT), or ventricular fibrillation (VF). Electrocardiographic and echocardiographic characteristics, Tp-e, and Tp-e/QT ratio were analyzed in all cases before ICD implantation.</p><p><b>RESULTS</b>During the follow-up, ICD shock for sustained ventricular tachycardia or ventricular fibrillation occurred in 11 patients; nonsustained ventricular tachycardia (NSVT) that did not require therapy was detected by ICD in 7 patients (high-risk group, 18 cases). ICD did not detect ventricular tachycardia or ventricular fibrillation in 50 patients (low-rsk group). Compared with the low-rsik group, the high-risk group had an increased Tp-e/QT ratio (0.27±0.04 vs 0.22±0.05 P<0.01) and an increased Tp-e (105±15 vs 90±17 ms P<0.01). ROC analysis revealed that a Tp-e/QT ratio ≥0.255 had a sensitivity of 72.2% and a specificity of 65.9%, and a Tp-e ≥103 ms had a sensitivity of 66.7% and a specificity of 67.9% for predicting VT and VF in these patients.</p><p><b>CONCLUSION</b>Increased Tp-e and Tp-e/QT ratio are associated with increased risks of ventricular arrhythmias in patients with ICD for primary prevention.</p>
Subject(s)
Humans , Death, Sudden, Cardiac , Defibrillators, Implantable , Electrocardiography , Heart Failure , Therapeutics , Primary Prevention , ROC Curve , Tachycardia, Ventricular , Ventricular Fibrillation , Ventricular Function, LeftABSTRACT
<p><b>OBJECTIVE</b>To elucidate the molecular and electrophysiological mechanisms of Brugada syndrome through functional analysis of a novel SCN5A gene mutation G1712C.</p><p><b>METHODS</b>A recombinant plasmid pRc<CMV-hH1 containing the mutant human cardiac sodium channel α subunit (hH1) cDNA was constructed using in vitro PCR-based site-directed mutagenesis technique. LipofectamineTM 3000 was used to transfect the plasmid DNA into HEK293 cell line to induce stable expression of Nachannel β1-subunit, and the positive colonies were selected by screening with G418.The standard liposome method was used to transiently transfect HEK293 cells with either the wild-type or mutant Nachannel subunits (hH1 and mhH1, respectively), and the macroscopic Nacurrents were recorded using whole-cell patch-clamp technique. Data acquisition and analysis, generation of voltage commands and curve fitting were accomplished with EPC-10, PatchMaster and IGOR Pro 6.0.</p><p><b>RESULTS</b>An HEK293 cell line that stably expressed Nachannel β1-subunit was successfully established. After transient transfection with the WT subunit, large Nacurrents were recorded from the stable β1-cell line. Transient transfection with the G1712C subunit, however, did not elicit a Nacurrent in the cells.</p><p><b>CONCLUSION</b>Compared with normal Nachannel, the wild-type channel exhibits a similar sodium current. The characteristic kinetics of sodium channel of WT-hH1 was identical to that in normal cardiac muscle cell, and the missense mutation (G1712C) in the P-loop region of the domain IV may have caused the failure of sodium channel expression.</p>
Subject(s)
Humans , Brugada Syndrome , Genetics , Genotype , HEK293 Cells , Mutagenesis, Site-Directed , Mutation , Genetics , Patch-Clamp Techniques , Polymerase Chain Reaction , TransfectionABSTRACT
To study the liver histopathological features that are distinctive between chronic hepatitis B virus (HBV) infection patients who have normal serum alanine aminotransferase (ALT)/asparatate aminotransferase (AST) and those with mildly elevated serum ALT/AST. One-hundred-and-thrity-four chronic HBV infection patients with normal serum ALT/AST and 165 chronic HBV infection patients with mildly elevated serum ALT/AST were included in the study. Liver biopsies were performed and used to assess the histological changes by hematoxylin-eosin and reticular fiber staining; mild to severe scoring for inflammation was made as grade G0-G4 and for fibrosis stage as S0-S4. HBV DNA levels were detected by fluorescent quantitative PCR. HBV serological markers were examined by chemiluminescence. The mildly elevated serum ALT/AST group had more male patients than the normal serum ALT/AST group. In the normal serum ALT/AST group, 50.0% (67/134) of the patients had moderate histological changes and only 3.0% (4/134) had severe changes (G3-4 and/or S3-4). In the mildly elevated ALT/AST group, 65.7% (174/265) of patients had moderate histological changes and 16.2% (43/265) had severe changes (G3-4 and/or S3-4). Hepatic inflammation and fibrosis were significantly more severe in the mildly elevated serum ALT/AST group than in the normal ALT/AST group (x2 = 26.386, P less than 0.01; x2 = 15.299, P less than 0.01). In the normal ALT/AST group, the severity of inflammation and fibrosis were positively correlated with age (rs = 0.620, P less than 0.01; rs = 0.347, P less than 0.01). In the mildly elevated ALT/AST group, the severity of inflammation and fibrosis were negatively correlated with age (rs = -0.807, P less than 0.01; rs = -0.557, P less than 0.01). In both groups, the severity of inflammation and fibrosis were negatively correlated with HBV DNA levels (rs = -0.215, P less than 0.01, rs = -0.527, P less than 0.01, rs = -0.951, P less than 0.01; rs = -0.715, P less than 0.01) and were not positively correlated with HBeAg. The majority of the chronic HBV infection patients with normal serum ALT/AST and those with mildly elevated serum ALT/AST had moderate liver pathological changes. All patients with low HBV DNA levels were closely followed-up, regardless of HBeAg-positive status.
Subject(s)
Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , Age Factors , Alanine Transaminase , Blood , Aspartate Aminotransferases , Blood , Biopsy, Needle , DNA, Viral , Blood , Fatty Liver , Pathology , Virology , Hepatitis B e Antigens , Blood , Hepatitis B virus , Genetics , Hepatitis B, Chronic , Blood , Pathology , Virology , Liver , Pathology , Virology , Retrospective Studies , Viral LoadABSTRACT
Objective: To investigate the relation of diabetic encephalopathy with oxidative stress and hippocampus expression of inducible nitric oxide synthase(iNOS) in rats and to study the therapeutic effects of curcumin. Methods: Diabetes mellitus was induced by injection of Streptozotocin in rats. The experiment animals were randomly divided into control group, diabetic group, diabetes plus curcumin group and control plus curcumin group; animals in the latter two groups received 60 mg·kg-1·d-1 curcumin treatment. Superoxide dismutase(SOD), catalase(CAT), malondialdehyde(MDA) and nitric oxide (NO) in the hippocampal tissues were measured 12 weeks after treatment. The expression of iNOS mRNA and the mean optical density (MOD) of immunoreactive neurons were evaluated by RT-PCR and immunohistochemistry method, respectively. Results: Compared with the control group, diabetic group had significantly lower activities of SOD and CAT, higher contents of NO and MDA, and increased expression of iNOS mRNA and protein in the hippocampal tissues (P<0.01). Compared with the diabetic group, diabetic plus curcumin group had significantly higher activities of SOD and CAT, lower contents of NO and MDA and decreased expression of iNOS mRNA and the MOD of immunoreactive neurons in hippocampus (P<0.01). Conclusion: Diabetic encephalopathy is associated with oxidative stress and increased expression of iNOS; curcumin may protect diabetic encephalopathy by inhibiting oxidative stress and down-regulating the iNOS expression.