Mesenchymal stem cells (MSCs) are promising tools for the treatment of diseases such as infarcted myocardia and strokes because of their ability to promote endogenous angiogenesis and neurogenesis ...via a variety of secreted factors. MSCs found in the Wharton's jelly of the human umbilical cord are easily obtained and are capable of transplantation without rejection. We isolated MSCs from Wharton's jelly and bone marrow (WJ-MSCs and BM-MSCs, respectively) and compared their secretomes. It was found that WJ-MSCs expressed more genes, especially secreted factors, involved in angiogenesis and neurogenesis. Functional validation showed that WJ-MSCs induced better neural differentiation and neural cell migration via a paracrine mechanism. Moreover, WJ-MSCs afforded better neuroprotection efficacy because they preferentially enhanced neuronal growth and reduced cell apoptotic death of primary cortical cells in an oxygen-glucose deprivation (OGD) culture model that mimics the acute ischemic stroke situation in humans. In terms of angiogenesis, WJ-MSCs induced better microvasculature formation and cell migration on co-cultured endothelial cells. Our results suggest that WJ-MSC, because of a unique secretome, is a better MSC source to promote in vivo neurorestoration and endothelium repair. This study provides a basis for the development of cell-based therapy and carrying out of follow-up mechanistic studies related to MSC biology.
Dysfunction and reduction of circulating endothelial progenitor cell (EPC) is correlated with the onset of cardiovascular disorders including coronary artery disease (CAD). VEGF is a known mitogen ...for EPC to migrate out of bone marrow to possess angiogenic activities, and the plasma levels of VEGF are inversely correlated to the progression of CAD. Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. However, how miRNAs and VEGF cooperate to regulate CAD progression is still unclear. Through the small RNA sequencing (smRNA-seq), we deciphered the miRNome patterns of EPCs with different angiogenic activities, hypothesizing that miRNAs targeting VEGF must be more abundant in EPCs with lower angiogenic activities. Candidates of anti-VEGF miRNAs, including miR-361-5p and miR-484, were enriched in not only diseased EPCs but also the plasma of CAD patients. However, we found out only miR-361-5p, but not miR-484, was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-361-5p to the 3'-UTR of VEGF mRNA. Knock down of miR-361-5p not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but further promoted blood flow recovery in ischemic limbs of mice. Collectively, we discovered a miR-361-5p/VEGF-dependent regulation that could help to develop new therapeutic modalities not only for ischemia-related diseases but also for tumor angiogenesis.
Functional impairment of endothelial colony-forming cells (ECFCs), a specific cell lineage of endothelial progenitor cells (EPCs) is highly associated with the severity of coronary artery disease ...(CAD), the most common type of cardiovascular disease (CVD). Emerging evidence show that circulating microRNAs (miRNAs) in CAD patients' body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq), we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson's correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis-related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b-5p up-regulation compared to healthy control. Knockdown of miR-146a-5p or miR-146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3'-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases.
Diabetes is a risk factor for Alzheimer's disease (AD), a chronic neurodegenerative disease. We and others have shown prediabetes, including hyperglycemia and obesity induced by high fat and high ...sucrose diets, is associated with exacerbated amyloid beta (Aβ) accumulation and cognitive impairment in AD transgenic mice. However, whether hyperglycemia reduce glial clearance of oligomeric amyloid-β (oAβ), the most neurotoxic Aβ aggregate, remains unclear. Mixed glial cultures simulating the coexistence of astrocytes and microglia in the neural microenvironment were established to investigate glial clearance of oAβ under normoglycemia and chronic hyperglycemia. Ramified microglia and low IL-1β release were observed in mixed glia cultures. In contrast, amoeboid-like microglia and higher IL-1β release were observed in primary microglia cultures. APPswe/PS1dE9 transgenic mice are a commonly used AD mouse model. Microglia close to senile plaques in APPswe/PS1dE9 transgenic mice exposed to normoglycemia or chronic hyperglycemia exhibited an amoeboid-like morphology; other microglia were ramified. Therefore, mixed glia cultures reproduce the in vivo ramified microglial morphology. To investigate the impact of sustained high-glucose conditions on glial oAβ clearance, mixed glia were cultured in media containing 5.5 mM glucose (normal glucose, NG) or 25 mM glucose (high glucose, HG) for 16 days. Compared to NG, HG reduced the steady-state level of oAβ puncta internalized by microglia and astrocytes and decreased oAβ degradation kinetics. Furthermore, the lysosomal acidification and lysosomal hydrolysis activity of microglia and astrocytes were lower in HG with and without oAβ treatment than NG. Moreover, HG reduced mitochondrial membrane potential and ATP levels in mixed glia, which can lead to reduced lysosomal function. Overall, continuous high glucose reduces microglial and astrocytic ATP production and lysosome activity which may lead to decreased glial oAβ degradation. Our study reveals diabetes-induced hyperglycemia hinders glial oAβ clearance and contributes to oAβ accumulation in AD pathogenesis.
Uncertainty in illness is regarded as a source of stress in many chronic diseases and is negatively related to health-related quality of life (HRQoL). However, studies on the relationship between ...uncertainty and HRQoL in patients with heart failure are limited. This study used Mishel's theory of uncertainty in illness to investigate the mediating role of uncertainty in illness and depressive symptoms between symptom distress and HRQoL in patients with heart failure. This study used a cross-sectional correlation design. Participants were recruited by convenience sampling from outpatient services and medical wards of cardiology departments of a medical center in northern Taiwan. Data were collected for uncertainty, depressive symptoms, symptoms distress of heart failure, and HRQoL using self-report questionnaires. Demographics and clinical characteristics were analyzed with descriptive statistics. The mutual effects of disease characteristics, symptom distress, uncertainty in illness, depressive symptoms and HRQoL, as well as the overall model fitness, were analyzed by with structural equation modeling. We collected 147 qualified questionnaires. The mean score for the Mishel Uncertainty in Illness Scale for patients with heart failure was 73.5 (SD = 18.55); 65.3% of participants had a score of ≧13 on the Beck Depressive Inventory-II, indicating mild depression. Uncertainty, depressive symptoms, and HRQoL were directly related to symptom distress. Symptom distress and depressive symptoms were both mediators between uncertainty and depressive symptoms. Depressive symptoms also mediated emotional support and HRQoL. Uncertainty and depressive symptoms were important factors in the pathway between symptom distress and HRQoL for heart failure patients. We suggest providing heart failure patients with tailored interventions for effective self-management of symptoms based on Mishel's theory of uncertainty in illness, which could help control disease symptoms, alleviate uncertainty and depression as well as improve HRQoL.
Background
Atrial fibrillation (AF) is related to a variety of chronic diseases and life-threatening complications. It is estimated that by 2050, there will be 72 million patients with AF in Asia, of ...which 2.9 million will have AF-associated stroke. AF has become a major issue for health care systems.
Objective
We aimed to evaluate the effects of a web-based integrated management program on improving coping strategies, medication adherence, and health-related quality of life (HRQoL) in patients with AF, and to detect the effect on decreasing readmission events.
Methods
The parallel-group, single-blind, prospective randomized controlled trial recruited patients with AF from a medical center in northern Taiwan and divided them randomly into intervention and control groups. Patients in the intervention group received the web-based integrated management program, whereas those in the control group received usual care. The measurement tools included the Brief Coping Orientation to Problems Experienced (COPE) scale, Medication Adherence Rating Scale (MARS), the three-level version of the EuroQoL five-dimension self-report questionnaire (EQ-5D-3L), and readmission events 2 years after initiating the intervention. Data were collected at 4 instances (baseline, 1 month, 3 months, and 6 months after initiating the intervention), and analyzed with generalized estimating equations (GEEs).
Results
A total of 231 patients were recruited and allocated into an intervention (n=115) or control (n=116) group. The mean age of participants was 73.08 (SD 11.71) years. Most participants were diagnosed with paroxysmal AF (171/231, 74%), and the most frequent comorbidity was hypertension (162/231, 70.1%). Compared with the control group, the intervention group showed significantly greater improvement in approach coping strategies, medication adherence, and HRQoL at 1, 3, and 6 months (all P<.05). In addition, the intervention group showed significantly fewer readmission events within 2 years (OR 0.406, P=.03), compared with the control group.
Conclusions
The web-based integrated management program can significantly improve patients' coping strategy and medication adherence. Therefore, it can empower patients to maintain disease stability, which is a major factor in improving their HRQoL and reducing readmission events within 2 years.
Trial Registration
ClinicalTrials.gov NCT04813094; https://clinicaltrials.gov/ct2/show/NCT04813094.
The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. ...Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the
mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.
This study evaluated the association between ischaemic stroke (IS) and heart failure (HF) in the absence of atrial fibrillation (AF) or atrial flutter (AFL) using a population-based nation-wide ...cohort database.
Newly diagnosed patients with HF without previous stroke and acute myocardial infarction (AMI) were enrolled. Based on the propensity scores matching age, sex and all comorbidities, our studies comprised 12 179 patients with HF and 12 179 patients without HF. Cox proportion hazard regression models and competing-risk regression models were used to evaluate the risk of IS among patients with HF without AF or AFL.
In the multivariable analysis, older age (adjusted HR (95% CI)=1.05 (1.04 to 1.05)), male sex (adjusted HR (95% CI)=1.36 (1.24 to 1.50)), diabetes (adjusted HR (95% CI)=2.22 (1.97 to 2.49)) and hypertension (adjusted HR (95% CI)=1.60 (1.41 to 1.82)) were markedly associated with IS in patients with HF. The HF group had a markedly higher risk of IS than did the non-HF group (subdistribution HR (SHR)=1.51, 95% CI: 1.37 to 1.66) and AMI (SHR=3.40, 95% CI: 2.71 to 4.28). Additionally, according to the Kaplan-Meier analysis, patients with HF were at a significantly higher risk of cumulative incidence of IS and AMI than did patients with non-HF (p value of log-rank test <0.001).
This study indicated that HF is a strong independent risk factor for IS, even in the absence of AF or AFL. Clinical physicians should investigate IS through routine screening and careful monitoring of patients with HF.
Delayed diagnosis or misdiagnosis of acute myocardial infarction (AMI) is not unusual in daily practice. Since a 12-lead electrocardiogram (ECG) is crucial for the detection of AMI, a systematic ...algorithm to strengthen ECG interpretation may have important implications for improving diagnosis.
We aimed to develop a deep learning model (DLM) as a diagnostic support tool based on a 12-lead electrocardiogram.
This retrospective cohort study included 1,051/697 ECGs from 737/287 coronary angiogram (CAG)-validated STEMI/NSTEMI patients and 140,336 ECGs from 76,775 non-AMI patients at the emergency department. The DLM was trained and validated in 80% and 20% of these ECGs. A human-machine competition was conducted. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the performance of the DLM.
The AUC of the DLM for STEMI detection was 0.976 in the human-machine competition, which was significantly better than that of the best physicians. Furthermore, the DLM independently demonstrated sufficient diagnostic capacity for STEMI detection (AUC=0.997; sensitivity, 98.4%; specificity, 96.9%). Regarding NSTEMI detection, the AUC of the combined DLM and conventional cardiac troponin I (cTnI) increased to 0.978, which was better than that of either the DLM (0.877) or cTnI (0.950).
The DLM may serve as a timely, objective and precise diagnostic decision support tool to assist emergency medical system-based networks and frontline physicians in detecting AMI and subsequently initiating reperfusion therapy.
Lifestyle modification is an essential component of prevention and management of hypertension. Existing instruments in Taiwan focus on assessing lifestyle modifications by evaluating medication ...adherence or confidence in controlling blood pressure. However, other self-care activities, such as diet, physical activity, weight management, smoking, and alcohol consumption are also important. The Hypertension Self-Care Activity Level Effects (H-SCALE) is one such instrument, but there are no similar tools available in Taiwan.
This study aimed to translate the H-SCALE into Chinese and test its validity, and reliability in a sample of adults with hypertension.
The English version of the 31-item H-SCALE was translated into Chinese using the forward-backward method. The content validity index (CVI) of the translated scale was determined by five experts in hypertension. Item analysis was conducted with a pilot sample of 20 patients with hypertension. Cronbach's α was used to establish the internal consistency reliability for the Chinese version of the H-SCALE (H-SCALE-C). Exploratory factor analysis (EFA) explored the structure of the H-SCALE-C. Additionally, construct validity was examined with confirmatory factor analysis (CFA). Patients with hypertension were recruited by convenience sampling from a cardiovascular outpatient clinic of a medical center in northern Taiwan. A total of 318 patients met the inclusion criteria and participated in factor analysis in the study.
Pilot testing of the scale items indicated most patients could not accurately estimate the number of days of alcohol consumption for the previous week. Therefore, three alcohol-related items were removed. The adaptation resulted in a 28-item H-SCALE-C. EFA revealed a 4-factor solution with 13 items that explained 63.93% of the total variance. CFA indicated a good fit for a 4-factor model and construct validity was acceptable. Internal consistency reliability was acceptable (Cronbach's alpha for the four subscales ranged from 0.65 to 0.94). Convergent validity was acceptable, and discriminant validity was significant.
The H-SCALE-C is a valid, reliable tool for promptly assessing life-style activities for patients with hypertension in Taiwan. The instrument is suitable for assisting healthcare providers in evaluating self-care activities, which could be used to facilitate lifestyle modifications for patients with hypertension.
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