Correction: Wang et al. Microarray Profile of Long Noncoding RNA and Messenger RNA Expression in a Model of Alzheimer's Disease. Life 2020, 10, 64.

We have updated the email addresses of Li Zeng and Hailun Jiang as the two authors' previous email addresses are no longer in use [...].

The mechanistic effects of acupuncture in rodent neurodegenerative disease models: a literature review.

Neurodegenerative diseases refer to a battery of medical conditions that affect the survival and function of neurons in the brain, which are mainly presented with progressive loss of cognitive and/or motor function. Acupuncture showed benign effects in improving neurological deficits, especially on movement and cognitive function impairment. Here, we reviewed the therapeutic mechanisms of acupuncture at the neural circuit level in movement and cognition disorders, summarizing the influence of acupuncture in the dopaminergic system, glutamatergic system, γ-amino butyric acid-ergic (GABAergic) system, serotonergic system, cholinergic system, and glial cells at the circuit and synaptic levels. These findings can provide targets for clinical treatment and perspectives for further studies.

The Prescription trends and dosing appropriateness analysis of novel oral anticoagulants in ischemic stroke patients: a retrospective study of 9 cities in China.

Background: Novel oral anticoagulants (NOACs) have been recommended by guidelines as the first-line drugs for preventing cardiogenic stroke. We aimed to provide an overview of the prescription trends and dosing appropriateness of NOACs in China. Methods: We conducted a retrospective analysis of NOAC prescriptions using the Hospital Prescription Analysis Cooperation Project data from 2016 to 2022. Various patient features, such as gender, age, city, year, source, department visited, original diagnosis, dosing, cost, and insurance type, were collected and analyzed to examine the trends and dosing appropriateness of NOAC usage in ischemic stroke patients. Results: 62,014 NOAC prescriptions were analyzed, including 16,602 for dabigatran, 45,253 for rivaroxaban, and 159 for apixaban. 85.14% of the patients were aged 65 or above, and tertiary hospitals accounted for 95.97% of NOAC prescriptions. NOAC prescriptions rose from 1828 in 2016 to 13,998 in 2021 but dropped to 13,166 in 2022. The percentage of annual prescriptions for NOACs among stroke patients has increased from 0.05% in 2016 to 0.37% in 2022. Total drug cost increased from ¥704541.18 in 2016 to ¥4128648.44 in 2021, then decreased to ¥1680109.14 in 2022. Prescriptions were divided into 48,321 appropriate and 11,262 inappropriate dosing groups, showing significant differences in medications, age, year, city type, hospital level, source, insurance type, and department visited (all p < 0.001). The median drug cost for inappropriate dosing was higher than for appropriate dosing (¥55.20 VS ¥83.80). The top comorbidities in ischemic stroke patients were atrial fibrillation (35.30%), hypertension (32.75%), and coronary heart disease (16.48%). Conclusion: The application of NOACs in the Chinese population is increasing. Our findings highlight the frequent deviation from labeled dosing of NOACs in clinical practice. Continued efforts are necessary to promote the appropriate use of NOACs according to the standard dosage in the drug insert.

Acupuncture for insomnia symptoms in hypertensive patients: a systematic review and meta-analysis.

Purpose: In the realm of pain management, traditional Chinese medicine, specifically acupuncture, has garnered increasing attention. This meta-analysis pioneers the evaluation of acupuncture's effectiveness in treating insomnia among hypertensive patients. Methods: We conducted a comprehensive search across several databases-PubMed, Web of Science, Cochrane Library, WANFANG, China National Knowledge Infrastructure (CNKI), Sinomed, and the Chinese Journal of Science and Technology (VIP). Additionally, forward and backward articles of studies published from the inception of these databases until 10 September 2023, were reviewed. This systematic review and meta-analysis included all randomized controlled trials (RCTs) focusing on acupuncture for insomnia in hypertensive patients, without imposing language or date restrictions. We rigorously assessed all outcome measures reported in these trials. The evidence was synthesized by calculating the difference between mean differences (MD) in symptom change. The quality of the evidence was determined using the Cochrane Risk of Bias tool. This study is registered with PROSPERO under number CRD42023461760. Results: Our analysis included 16 RCTs, comprising 1,309 patients. The findings revealed that acupuncture was significantly more effective than the control group in reducing insomnia symptoms, as indicated by a greater decrease in the PSQI score (MD = -3.1, 95% CI [-3.77 to -2.62], p < 0.00001). Additionally, improvements in both systolic and diastolic blood pressure were more pronounced in the acupuncture group compared to the control group (SBP: MD = -10.31, 95% CI [-16.98 to -3.64], p = 0.002; DBP: MD = -5.71, 95% CI [-8.19 to -3.23], p < 0.00001). These results suggest that acupuncture not only improves sleep quality but also lowers blood pressure in patients suffering from hypertension and insomnia. Further research is warranted to elucidate optimal acupuncture points and the duration of treatment for maximized therapeutic effect.Systematic review registration:https://www.crd.york.ac.uk/prospero, CRD42023461760.

Corrigendum: Tilianin extracted from Dracocephalum moldavica L. induces intrinsic apoptosis and drives inflammatory microenvironment response on pharyngeal squamous carcinoma cells via regulating TLR4 signaling pathways.

[This corrects the article DOI: 10.3389/fphar.2020.00205.].

Erratum: Implications of miR-148a-3p/p35/PTEN signaling in tau hyperphosphorylation and autoregulatory feedforward of Akt/CREB in Alzheimer's disease.

[This corrects the article DOI: 10.1016/j.omtn.2021.11.019.].

Application of diffusion tensor imaging in the diagnosis of post-stroke aphasia: a meta-analysis and systematic review.

Introduction: Diffusion Tensor Imaging (DTI) indicators of different white matter (WM) fibers and brain region lesions for post-stroke aphasia (PSA) are inconsistent in existing studies. Our study examines the consistency and differences between PSA tests performed with DTI. In addition, obtaining consistent and independent conclusions between studies was made possible by utilizing DTI in PSA assessment. Methods: In order to gather relevant studies using DTI for diagnosing PSA, we searched the Web of Science, PubMed, Embase, and CNKI databases. Based on the screening and evaluation of the included studies, the meta-analysis was used to conduct a quantitative analysis. Narrative descriptions were provided for studies that met the inclusion criteria but lacked data. Results: First, we reported on the left hemisphere. The meta-analysis showed that fractional anisotropy (FA) of the arcuate fasciculus (AF) and superior longitudinal fasciculus (SLF), inferior frontal-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), and uncinate fasciculus (UF) were decreased in the PSA group in comparison with the healthy controls (p < 0.00001). However, in the comparison of axial diffusivity (AD), there was no statistically significant difference in white matter fiber tracts in the dual-stream language model of the PSA group. Elevated radial diffusivity (RD) was seen only in the IFOF and ILF (PIFOF = 0.01; PILF = 0.05). In the classic Broca's area, the FA of the PSA group was decreased (p < 0.00001) while the apparent diffusion coefficient was elevated (p = 0.03). Secondly, we evaluated the white matter fiber tracts in the dual-stream language model of the right hemisphere. The FA of the PSA group was decreased only in the IFOF (p = 0.001). AD was elevated in the AF and UF (PAF < 0.00001; PUF = 0.009). RD was elevated in the AF and UF (PAF = 0.01; PUF = 0.003). The other fiber tracts did not undergo similar alterations. Conclusion: In conclusion, DTI is vital for diagnosing PSA because it detects WM changes effectively, but it still has some limitations. Due to a lack of relevant language scales and clinical manifestations, diagnosing and differentiating PSA independently remain challenging. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=365897.

Knowledge Mapping of Inflammasome and Pyroptosis in Stroke: A Bibliometric Analysis (2007-2023).

BACKGROUND: Stroke is a major contributor to disability and death worldwide. Studies have demonstrated that inflammasome/pyroptosis and its mediated inflammatory response are important factors aggravating brain injury after stroke. We aimed to investigate and map the knowledge structure and global trends on inflam- masome/pyroptosis in stroke. METHODS: All relevant documents were obtained from the Web of Science on 5 June 2023. Bibliometric visualization diagrams were created using VOSviewer and CiteSpace. Excel was used for statistical analysis and drawing graphs. RESULTS: A total of 1106 publications were included, with more articles published each year, especially since 2014. China (740 papers), Zhejiang University (57 papers), Wang J (25 papers), and the Journal of Neuroinflammation (45 papers) were the most productive countries, institutions, authors, and journals, respectively. The United States was the country with highest centrality (0.56) and total link strength (171), and all of the top 10 institutions were in China. China and the U.S. cooperated closely. The centralities of the top 10 authors were all lower than 0.01; no leader has yet emerged in this field. "NLRP3 inflammasome" ranked first with 447 occurrences among 2136 keywords, of which 56 terms appeared more than 10 times when categorized into four clusters: cluster 1 (inflammation), cluster 2 (pyroptosis), cluster 3 (NLRP3 inflammasome), and cluster 4 (neuroinflammation). The studies focused on the mechanisms of inflammasome/pyroptosis in stroke were mainly limited to cell and animal experiments. CONCLUSION: Interest in inflammasome/pyroptosis in stroke is progressively increasing. The NLRP3 inflammasome is the most extensively studied and has been a research hotspot. The mechanisms of cell death in stroke are complex and future studies are needed to strengthen the clinical research on the relationship between pyroptosis-related processes and stroke, determine at which stage NLRP3 inflammasome activation, and clarify the detailed mechanism of NLRP3 in stroke.

Assessment of corticospinal tract remodeling based on diffusion tensor imaging in the treatment of motor dysfunction after ischemic stroke by acupuncture: A meta-analysis.

BACKGROUND: To investigate the efficacy of acupuncture in improving motor dysfunction after ischemic stroke (IS) and to investigate the effect of acupuncture on corticospinal tract (CST) remodeling using diffusion tensor imaging. METHODS: Published literature on the effect of acupuncture on CST remodeling after IS using diffusion tensor imaging in the form of randomized controlled trials (RCTs) were systematically retrieved and screened from Cochrane Library, Web of Science, PubMed, Embase, CNKI, CBM, VIP, and Wanfang databases from inception to December 2022. The methodological quality of the included studies was critically and independently evaluated by 2 reviewers using the Cochrane Risk of Bias Assessment Tool for RCTs. The correlated data were extracted using the pre-designed form, and all analyses were performed using Reviewer Manager version 5.4. RESULTS: Eleven eligible RCTs involving 459 patients were eventually included. The combined evidence results showed that the acupuncture group significantly improved patients' National Institute of Health stroke scale, Fugl-Meyer Assessment Scale, and Barthel index compared with conventional medical treatment. The acupuncture group significantly promoted remodeling of the CST, as reflected by an increase in fractional anisotropy (FA) throughout the CST [MD = 0.04, 95% CI (0.02, 0.07), P = .001], and in addition, subgroup analysis showed that the acupuncture group significantly improved FA in the infarct area compared with conventional medical treatment at around 4 weeks [MD = 0.04, 95% CI (0.02, 0.06), P = .0002] and FA of the affected cerebral peduncle [MD = 0.03, 95% CI (0.00, 0.07), P = .02]. Also, compared with conventional medical treatment, the acupuncture group significantly increased average diffusion coefficient of the affected cerebral peduncle [MD = -0.21, 95% CI (-0.28, -0.13), P < .00001]. CONCLUSION: The results of the meta-analysis suggest that acupuncture therapy can improve the clinical manifestations of motor dysfunction in patients after IS and advance a possibly beneficial effect on CST remodeling. However, due to the number and quality of eligible studies, these findings need to be further validated in more standardized, rigorous, high-quality clinical trials.

Prospective observational studies on nutrition intake and the incidence of cognitive impairment in middle-aged and older adults: A protocol for systematic review and meta-analysis.

INTRODUCTION: According to several studies, a specific dietary pattern can reduce the risk of dementia and cognitive impairment. However, the robustness of these results has not been tested. The study intends to investigate the association between nutrition intake and cognitive impairment in middle-aged and older adults (≥45-years) and provide reliable, evidence-based references for healthcare decision-makers, researchers, and policymakers. REVIEW QUESTION: Are the dietary characteristics of community-dwelling adults (≥45-years) associated with the occurrence of cognitive impairment? OBJECTIVES: The primary objective of this protocol is to synthesize the longitudinal observational evidence on the relationship between nutrition intake patterns and the incidence of cognitive impairment in middle-aged and older adults (≥45-years), and to provide detailed dietary recommendations for the prevention of cognitive impairment in this population. METHODS AND ANALYSIS: Cohort studies conducted among adults (≥45-years) will be included. The following electronic databases will be searched for relevant records published by July 2023, with a restriction on language to English: Pubmed, Medline, Embase, Web of science, Cochrane Library. The studies will be selected, the data will be extracted, and the bias risk will be assessed by two independent investigators. The Meta-analysis of Observational Studies in Epidemiology guidelines will be followed to summarize observational studies, and the protocol will adhere to the recommendations from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. Endnote X9 will be used to manage data screening. We will use Review Manager 5.4 and Stata 16.0 to conduct data analysis, and a random-effects model will be applied to pool clinically homogenous studies. The results will be presented based on the form of nutrition intake. For assessing publication bias, Egger's test and visual inspection of funnel plots will be utilized. ETHICS AND DISSEMINATION: As this study does not involve primary data, ethical approval is not required. The final report will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: A registration number of DOI 10.17605/OSF.IO/NAKC3 was assigned to it on October 15, 2022 on Prospero.

Advances and applications of fluids biomarkers in diagnosis and therapeutic targets of Alzheimer's disease.

AIMS: Alzheimer's disease (AD) is a neurodegenerative disease with challenging early diagnosis and effective treatments due to its complex pathogenesis. AD patients are often diagnosed after the appearance of the typical symptoms, thereby delaying the best opportunity for effective measures. Biomarkers could be the key to resolving the challenge. This review aims to provide an overview of application and potential value of AD biomarkers in fluids, including cerebrospinal fluid, blood, and saliva, in diagnosis and treatment. METHODS: A comprehensive search of the relevant literature was conducted to summarize potential biomarkers for AD in fluids. The paper further explored the biomarkers' utility in disease diagnosis and drug target development. RESULTS: Research on biomarkers mainly focused on amyloid-ß (Aß) plaques, Tau protein abnormal phosphorylation, axon damage, synaptic dysfunction, inflammation, and related hypotheses associated with AD mechanisms. Aß42 , total Tau (t-Tau), and phosphorylated Tau (p-Tau), have been endorsed for their diagnostic and predictive capability. However, other biomarkers remain controversial. Drugs targeting Aß have shown some efficacy and those that target BACE1 and Tau are still undergoing development. CONCLUSION: Fluid biomarkers hold considerable potential in the diagnosis and drug development of AD. However, improvements in sensitivity and specificity, and approaches for managing sample impurities, need to be addressed for better diagnosis.

Acupuncture treatment for post-stroke depression: Intestinal microbiota and its role.

Stroke-induced depression is a common complication and an important risk factor for disability. Besides psychiatric symptoms, depressed patients may also exhibit a variety of gastrointestinal symptoms, and even take gastrointestinal symptoms as the primary reason for medical treatment. It is well documented that stress may disrupt the balance of the gut microbiome in patients suffering from post-stroke depression (PSD), and that disruption of the gut microbiome is closely related to the severity of the condition in depressed patients. Therefore, maintaining the balance of intestinal microbiota can be the focus of research on the mechanism of acupuncture in the treatment of PSD. Furthermore, stroke can be effectively treated with acupuncture at all stages and it may act as a special microecological regulator by regulating intestinal microbiota as well. In this article, we reviewed the studies on changing intestinal microbiota after acupuncture treatment and examined the existing problems and development prospects of acupuncture, microbiome, and poststroke depression, in order to provide new ideas for future acupuncture research.

Acupuncture for the treatment of thalamencephalic and mesencephalic injury secondary to electrical trauma: A case report.

In a case of thalamencephalic and mesencephalic injury secondary to electrical trauma, a 29-year-old patient has been receiving manual acupuncture for 17 months in National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion. As a result of treatment, the patient's self-care ability and quality of life have greatly improved. In order to fully understand how acupuncture can benefit neurological sequelae resulting from electrical trauma, further research is needed. Additionally, there should be consideration given to the promotion of acupuncture therapy in the neurological sequelae of electric shock.

Transcutaneous electrical acupoint stimulation for the prevention of perioperative neurocognitive disorders in geriatric patients: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To evaluate whether transcutaneous electrical acupoint stimulation (TEAS) decreases rates of perioperative neurocognitive disorders (PND) when used as an adjuvant method during perioperative period in geriatric patients since the new definition was released in 2018. METHODS: Six databases [Chinese National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals, WanFang Database, PubMed, EMBASE, and Cochrane Library] were systematically searched. Data analysis was performed using RevMan 5.4.1 software (Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2020). Risk ratios (RR) with 95% confidence interval were calculated using a random effects model. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: 13 randomized clinical trials (999 patients) in total were included. TEAS had positive effects on preventing the incidence of PND (RR: 0.43; 0.31, 0.61; P < .001; low certainty) [postoperative delirium within 7 days (RR: 0.39; 0.26, 0.59; P < .001), delayed neurocognitive recovery within 3 months (RR: 0.51; 0.33, 0.78; P = .002)]. TEAS could also improve the scores of the confusion assessment method (CAM) (Mean difference: -1.30; -2.14, -0.46; P = .003; low certainty). Limited evidence suggested that TEAS could reduce the serum levels of biochemical indicator (S100ß) (SMD = -1.08, -1.67, -0.49, P < .001; I2  = 83%; very low certainty) as well as anesthetic requirements (remifentanil) (SMD: -1.58; -2.54, -0.63; P = .001; I2  = 87%; very low certainty). Subgroup analysis indicated that different protocols of TEAS had significant pooled benefits (TEAS used only in surgery and in combination with postoperative intervention) (RR: 0.45; 0.31, 0.63; P < .001). Acupoint combination (LI4 and PC6) in the TEAS group had more significantly advantages (RR: 0.34; 0.17, 0.67; P = .002). TEAS group had a lower incidence of PND in different surgery type (orthopedic surgery and abdominal surgery) (RR: 0.43; 0.30, 0.60; P < .001), as well as with different anesthetic modality (intravenous anesthesia and intravenous and inhalational combined anesthesia) (RR: 0.38; 0.23, 0.61; P < .001). CONCLUSION: In terms of clinical effectiveness, TEAS appeared to be beneficial for prophylaxis of PND during a relatively recent period, noting the limitations of the current evidence.

Efficacy of acupuncture and moxibustion therapy for simple obesity in adults: A meta-analysis of randomized controlled trials.

BACKGROUND: To evaluate the clinical efficacy of acupuncture and moxibustion therapy compared to non-acupuncture therapy in the treatment of simple obesity in adult. METHODS: Randomized clinical trials concerning acupuncture and moxibustion therapy as a treatment of simple adult obesity were searched in the following Chinese and English databases: Chinese National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang Database, Chinese Biomedical Literature Database, PubMed, Web of Science, Embase, Medline and Cochrane Library. Two researchers independently screened suitable literature according to inclusion and exclusion criteria, extracted data, and evaluated the quality of included studies using the Jadad score scale. After that, data analysis was performed using RevMan 5.4.1 software, Stata 17.0 software and SPSS 25.0 software. RESULTS: A total of 14 studies involving 1116 adults with simple obesity were included in the meta-analysis. Results revealed that BMI, body weight, waist circumference, total effective rate, triglyceride in the acupuncture group were superior to those in the non-acupuncture group, while there was no statistical difference in improving low density lipoprotein, high density lipoprotein and total cholesterol. As to the selection of acupoints, the acupoints of the stomach meridian of Foot Yangming have the highest frequency of use, with a frequency of 30 times, accounting for 35%. The acupoints can be divided into three clusters: the first category: RN9-SP9-SP6-RN4; the second category: ST40-RN6-SP15-ST36; the third category: ST25-RN12. CONCLUSION: Acupuncture and moxibustion is effective in treating adult simple obesity; however, due to the low score of the included studies, we still expect the results of higher-quality literature to provide a higher-level evidence-based basis for clinical decision-making. Furthermore, for the treatment of adult simple obesity, acupoints analysis revealed that Tianshu (ST25), Zhongwan (RN12), Zusanli (ST36), Fenglong (ST40) and Qihai (RN6) can form the basis for the treatment of simple obesity in adult.

Manual Acupuncture or Combination of Rehabilitation Therapy to Treat Poststroke Dysphagia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Backgroundand Objective. Poststroke dysphagia is one of the most common stroke complications with high morbidity and long course, while acupuncture treatment is easily accepted by patients due to its reliability, feasibility, simple operation, low price, and quick effect. Our objective was to evaluate the efficacy of manual acupuncture in poststroke dysphagia patients. Methods. Databases including Medline, Web of Science, PubMed, Cochrane Library databases, EMBASE, CNKI (China National Knowledge Infrastructure), WanFang (WanFang Database), and VIP (Chongqing VIP) were searched from inception until Aug 19, 2022. Data were analyzed using Revman 5.3, Stata 14.0, and TSA 0.9.5.10 Beta software. Evidence quality evaluation was performed by using GRADE profiler 3.6. Results. A total of 33 randomized control trials (RCTs) enrolled 2680 patients. Meta-analysis results revealed that compared to rehabilitation, acupuncture decreased water swallow test (WST) and standard swallowing assessment (SSA) scores. Meanwhile, in contrast to rehabilitation alone, integration of acupuncture with rehabilitation effectively decreased WST and SSA scores; improved swallowing scores of videofluoroscopic swallowing study (VFSS), swallowing scores of Fujishima Ichiro, Barthel index (BI), and swallowing quality of life questionnaire (SWAL-QOL); reduced the aspiration rates as well as aspiration pneumonia; and shortened the duration of empty swallowing and the duration of 5 mL water swallowing. Pooled analysis did not reveal any significant differences in dysphagia outcome severity scores (DOSS) (p=0.15 > 0.05p) between the acupuncture group combined with rehabilitation group and the rehabilitation group alone. After the risk-of-bias assessment, these studies were not of low quality, except in terms of allocation concealment and blindness. Evidence quality evaluation showed that allocation concealment and blindness led to a downgrade and primary outcomes' evaluation of acupuncture combined with rehabilitation were ranked as moderate-quality evidence while acupuncture alone was ranked as low-quality. Conclusion. This meta-analysis provided positive pieces of evidences that acupuncture and acupuncture combined with rehabilitation were better than using rehabilitation alone in the treatment of poststroke dysphagia.

Discovery of highly potent DENV NS2B-NS3 covalent inhibitors containing a phenoxymethylphenyl residue.

Dengue virus (DENV) has developed rapidly in the past few decades and has been becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of relevant proteins makes it the most promising target for anti-DENV drug discovery, although none of NS2B-NS3 inhibitors have been approved for the market so far. In this study, potent NS2B-NS3 covalent inhibitors were discovered via chemical modification of a published covalent inhibitor WSL-01 (IC50 = 129 nM), yielding promising analogs WSL-75 and WSL-84 (IC50 = 24.8 nM and IC50 = 32.89 nM, respectively) with more than 10-fold increased enzymatic activities compared to the lead compound, and no evident cellular toxicity was observed. Further comprehensive structure-activity relationship analysis through covalent docking and molecular dynamics simulation provides informative understanding of the binding modes of covalent inhibitors targeting NS2B-NS3, which would be beneficial for novel NS2B-NS3 inhibitory development.

Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction.

BACKGROUND: Mutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacterized. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies. METHODS: The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autosomal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart. RESULTS: A novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segregated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other potential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haploinsufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate production, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired autophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes. CONCLUSIONS: The TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin's roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

miR-23b-3p rescues cognition in Alzheimer's disease by reducing tau phosphorylation and apoptosis via GSK-3ß signaling pathways.

Dysregulated microRNA (miRNA) expression in the brain can contribute to cognitive dysfunction and aberrant tau hyperphosphorylation in Alzheimer's disease (AD). Several studies have reported a role for microRNA-23b-3p (miR-23b-3p) in various neurologic disorders; however, its involvement in cognition-related functions remains unclear. In the present study, we investigated the potential therapeutic effects and mechanisms of miR-23b-3p in AD. miRNA profiles in the cortex of amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mice (APP/PS1 mice) demonstrated that miR-23b-3p was reduced. This decrease was verified in APPswe cells, SAMP8 mouse brains, and plasma from AD patients. Furthermore, glycogen synthase kinase-3ß (GSK-3ß), a major tau kinase implicated in tau pathology, was identified as a target of miR-23b-3p. Functional in vivo studies demonstrated that intracerebroventricular delivery of miR-23b-3p in APP/PS1 mice ameliorated cognitive deficits, histopathological changes, and tau phosphorylation immunoreactivity at several sites by inhibiting GSK-3ß expression and activation. Similarly, the upregulation of miR-23b-3p in APPswe cells inhibited GSK-3ß-mediated tau hyperphosphorylation, Aß1-42 generation, and neuronal apoptosis, resulting in the suppression of the GSK-3ß/p-tau and Bax/caspase-3 pathways. Collectively, our findings strongly support the hypothesis that miR-23b-3p plays a neuroprotective role in AD, thereby identifying miR-23b-3p as a promising therapeutic target for AD.

Identification and In Silico Binding Study of a Highly Potent DENV NS2B-NS3 Covalent Inhibitor.

Dengue virus (DENV), an arthropod-borne flavivirus, has developed rapidly in the past few decades and becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of viral proteins makes it the most promising target for anti-DENV drug discovery. In the current work, a potent NS2B-NS3 covalent inhibitor 23 (IC50 = 6.0 nM, k inac/K i = 1581 M-1 s-1) was discovered through the chemical modification of a published covalent inhibitor 1 (IC50 = 500 nM, k inac/K i = 156.1 M-1 s-1), followed by in vitro assay. Further comprehensive structure-activity relationship analysis through covalent docking and molecular dynamics simulation provides informative understanding of the binding modes of covalent inhibitors targeting NS2B-NS3.