Inflammation-Targeted Nanomedicines Alleviate Oxidative Stress and Reprogram Macrophages Polarization for Myocardial Infarction Treatment.

Myocardial infarction (MI) is a critical global health challenge, with current treatments limited by the complex MI microenvironment, particularly the excessive oxidative stress and intense inflammatory responses that exacerbate cardiac dysfunction and MI progression. Herein, a mannan-based nanomedicine, Que@MOF/Man, is developed to target the inflammatory infarcted heart and deliver the antioxidative and anti-inflammatory agent quercetin (Que), thereby facilitating a beneficial myocardial microenvironment for cardiac repair. The presence of mannan on the nanoparticle surface enables selective internalization by macrophages rather than cardiomyocytes. Que@MOF/Man effectively neutralizes reactive oxygen species in macrophages to reduce oxidative stress and promote their differentiation into a reparative phenotype, reconciling the inflammatory response and enhancing cardiomyocyte survival through intercellular communication. Owing to the recruitment of macrophages into inflamed myocardium post-MI, in vivo, administration of Que@MOF/Man in MI rats revealed the specific distribution into the injured myocardium compared to free Que. Furthermore, Que@MOF/Man exhibited favorable results in resolving inflammation and protecting cardiomyocytes, thereby preventing further myocardial remodeling and improving cardiac function in MI rats. These findings collectively validate the rational design of an inflammation-targeted delivery strategy to mitigate oxidative stress and modulate the inflammation response in the injured heart, presenting a therapeutic avenue for MI treatment.

Longer-Term Effects of Cardiac Telerehabilitation on Patients With Coronary Artery Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Cardiac telerehabilitation offers a flexible and accessible model for patients with coronary artery disease (CAD), effectively transforming the traditional cardiac rehabilitation (CR) approach. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the long-term effectiveness of cardiac telerehabilitation. METHODS: We searched randomized controlled trials (RCTs) in 7 electronic databases: PubMed, Web of Science, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the China National Knowledge Infrastructure, and WANFANG. The primary outcome focused on cardiopulmonary fitness. For secondary outcomes, we examined cardiovascular risk factors (blood pressure, BMI, and serum lipids), psychological scales of depression and anxiety, quality of life (QoL), cardiac telerehabilitation adherence, and adverse events. RESULTS: In total, 10 RCTs fulfilled the predefined criteria, which were reviewed in our meta-analysis. The results showed that after cardiac telerehabilitation, there was a significant difference in the improvement in long-term peak oxygen uptake compared to center-based CR (mean difference [MD] 1.61, 95% CI 0.38-2.85, P=.01), particularly after 6-month rehabilitation training (MD 1.87, 95% CI 0.34-3.39, P=.02). The pooled effect size of the meta-analysis indicated that there were no significant differences in the reduction in cardiovascular risk factor control. There was also no practical demonstration of anxiety scores or depression scores. However, cardiac telerehabilitation demonstrated an improvement in the long-term QoL of patients (MD 0.92, 95% CI 0.06-1.78, P=.04). In addition, the study reported a high completion rate (80%) for cardiac telerehabilitation interventions. The incidence of adverse events was also low during long-term follow-up. CONCLUSIONS: Cardiac telerehabilitation proves to be more effective in improving cardiopulmonary fitness and QoL during the long-term follow-up for patients with CAD. Our study highlights monitoring-enabled and patient-centered telerehabilitation programs, which play a vital role in the recovery and development of CAD and in the long-term prognosis of patients.

Pulsed Electromagnetic Fields Combined With Adipose-Derived Stem Cells Protect Ischemic Myocardium by Regulating miR-20a-5p/E2F1/p73 Signaling.

Myocardial infarction (MI) is a serious threat to human health. Although monotherapy with pulsed electromagnetic fields (PEMFs) or adipose-derived stem cells (ADSCs) has been reported to have positive effect on the treatment of MI, a satisfactory outcome has not yet been achieved. In recent years, combination therapy has attracted widespread interest. Herein, we explored the synergistic therapeutic effect of combination therapy with PEMFs and ADSCs on MI and found that the combination of PEMFs and ADSCs effectively reduced infarct size, inhibited cardiomyocyte apoptosis and protected the cardiac function in mice with MI. In addition, bioinformatics analysis and RT-qPCR showed that the combination therapy could affect apoptosis by regulating the expression of miR-20a-5p. A dual-luciferase reporter gene assay also confirmed that the miR-20a-5p could target E2F transcription factor 1 (E2F1) and inhibit cardiomyocyte apoptosis by regulating the E2F1/p73 signaling pathway. Therefore, our study systematically demonstrated the effectiveness of combination therapy on the inhibition of cardiomyocyte apoptosis by regulating the miR-20a-5p/E2F1/p73 signaling pathway in mice with MI. Thus, our study underscored the effectiveness of the combination of PEMFs and ADSCs and identified miR-20a-5p as a promising therapeutic target for the treatment of MI in the future.

Effects of shear stress on vascular endothelial functions in atherosclerosis and potential therapeutic approaches.

Different blood flow patterns in the arteries can alter the adaptive phenotype of vascular endothelial cells (ECs), thereby affecting the functions of ECs and are directly associated with the occurrence of lesions in the early stages of atherosclerosis (AS). Atherosclerotic plaques are commonly found at curved or bifurcated arteries, where the blood flow pattern is dominated by oscillating shear stress (OSS). OSS can induce ECs to transform into pro-inflammatory phenotypes, increase cellular inflammation, oxidative stress response, mitochondrial dysfunction, metabolic abnormalities and endothelial permeability, thereby promoting the progression of AS. On the other hand, the straight artery has a stable laminar shear stress (LSS), which promotes the transformation of ECs into an anti-inflammatory phenotype, improves endothelial cell function, thereby inhibits atherosclerotic progression. ECs have the ability to actively sense, integrate, and convert mechanical stimuli by shear stress into biochemical signals that further induces intracellular changes (such as the opening and closing of ion channels, activation and transcription of signaling pathways). Here we not only outline the relationship between functions of vascular ECs and different forms of fluid shear stress in AS, but also aim to provide new solutions for potential atherosclerotic therapies targeting intracellular mechanical transductions.

Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway.

Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway.

CD44 promotes angiogenesis in myocardial infarction through regulating plasma exosome uptake and further enhancing FGFR2 signaling transduction.

BACKGROUND: Since angiogenesis occurs as the pathological process following myocardial infarction to alleviate ischemia, therapeutic angiogenesis has been proposed to be a cardioprotective strategy. CD44 has been implicated in endothelial cell functions and its role has been well established in angiogenesis for years. Although recent studies indicate the close correlation between CD44 and exosome, as well as the two being implicated in myocardial ischemia pathological processes, the effect and the underlying mechanism of CD44 and its regulated plasma exosome in pathological angiogenesis post-myocardial infarction have not been fully elucidated. METHODS: In this study, we used CD44 knockout mice to study the in vivo impacts of CD44 on ischemic angiogenesis in myocardial infarction. Mouse cardiac function was measured by echocardiography, histological changes were observed by Evans Blue and TTC-double staining and Masson's trichrome staining, and molecular changes were detected by immunofluorescence. In the in vitro study, CD44 knockout HUVECs were generated and CD44 inhibitor was used to study the mechanism of CD44 on angiogenesis. We performed the immunoprecipitation, proximity ligation assay, and super-resolution imaging to study the mechanistic regulation of FGFR2 signaling transduction by CD44. Importantly, we also isolated plasma exosomes from myocardial infarction model mice and studied the effect of plasma exosomes on the activation of the FGFR2 signaling pathway and the related phenotypic alterations, including exosomes uptake and angiogenic function in primary mouse microvascular endothelial cells, and further discovered the regulation mechanism of exosomal miRNAs. RESULTS: We observed that the expression of CD44 in the border zone of the infarcted heart was tightly related to pathological angiogenesis following myocardial ischemia. The depletion of CD44 impaired angiogenesis and impacts biogenesis and proangiogenic function of plasma exosomes. Subsequently, we found that CD44 mediated the activation of the FGFR2 signaling pathway as well as the caveolin 1-dependent uptake of exosomes in vascular endothelial cells. Most importantly, the proangiogenic therapeutic effect of plasma exosomal miRNAs depended upon the participation of CD44/FGFR2 signaling transduction in vascular endothelial cells. CONCLUSION: CD44 and its regulated plasma exosomes have crucial potent angiogenic activity. Our studies elucidate that CD44 plays a key role in plasma exosomal miRNA-enhanced angiogenic FGFR2 singling transduction and ischemic angiogenesis in the early stage of myocardial infarction.

The Networks of Noncoding RNAs and Their Direct Molecular Targets in Myocardial Infarction.

Noncoding RNAs are closely related to the development of myocardial infarction (MI), and their specific roles in MI are still being carefully studied. Researchers can select the literature they are interested in according to their own wishes in traditional reviews, which results in a certain amount of selection bias. A data-driven approach was used to organize this review to understand the ncRNAs in MI in the past five years. Here, we reveal important networks of interactions between noncoding RNAs and their direct targets. Our review gives an unbiased description of the role of noncoding RNAs in MI. Key information, such as carrier selection, treatment time window, treatment dose and possible side effects of ncRNA therapy, needs to be further determined. In short, the interactions between coding and noncoding genes play indispensable roles in the occurrence and development of MI and still deserve great attention from researchers in this field. The rational application of ncRNAs is expected to become a target for the treatment of MI.

Signaling pathways and targeted therapy for myocardial infarction.

Although the treatment of myocardial infarction (MI) has improved considerably, it is still a worldwide disease with high morbidity and high mortality. Whilst there is still a long way to go for discovering ideal treatments, therapeutic strategies committed to cardioprotection and cardiac repair following cardiac ischemia are emerging. Evidence of pathological characteristics in MI illustrates cell signaling pathways that participate in the survival, proliferation, apoptosis, autophagy of cardiomyocytes, endothelial cells, fibroblasts, monocytes, and stem cells. These signaling pathways include the key players in inflammation response, e.g., NLRP3/caspase-1 and TLR4/MyD88/NF-κB; the crucial mediators in oxidative stress and apoptosis, for instance, Notch, Hippo/YAP, RhoA/ROCK, Nrf2/HO-1, and Sonic hedgehog; the controller of myocardial fibrosis such as TGF-ß/SMADs and Wnt/ß-catenin; and the main regulator of angiogenesis, PI3K/Akt, MAPK, JAK/STAT, Sonic hedgehog, etc. Since signaling pathways play an important role in administering the process of MI, aiming at targeting these aberrant signaling pathways and improving the pathological manifestations in MI is indispensable and promising. Hence, drug therapy, gene therapy, protein therapy, cell therapy, and exosome therapy have been emerging and are known as novel therapies. In this review, we summarize the therapeutic strategies for MI by regulating these associated pathways, which contribute to inhibiting cardiomyocytes death, attenuating inflammation, enhancing angiogenesis, etc. so as to repair and re-functionalize damaged hearts.

Efficacy of pulsed electromagnetic field on pain and physical function in patients with low back pain: A systematic review and meta-analysis.

OBJECTIVE: To assess the effectiveness of pulsed electromagnetic field (PEMF) on pain and physical function in patients with low back pain. DATA SOURCES: A search of PubMed, Embase, Cochrane Library, and Web of Science was conducted up to December 2021. METHODS: We included randomized controlled trials that investigated the effectiveness of PEMF in patients with low back pain. The primary outcome was pain intensity and the secondary outcome was physical function, both were evaluated by assessment scales. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated for the summary statistics analysis. The registration number of this systematic review in PROSPERO is CRD42020213829. RESULTS: Fourteen trials involving 618 participants were included. The PEMF treatment showed more significant pain alleviation than placebo or other therapy alone in patients with low back pain (SMD = -1.01, 95% CI -1.42 to -0.6, P < 0.001, I2 = 31%; SMD = -0.36, 95% CI -0.62 to -0.11, P = 0.005, I2 = 37%, respectively.) In addition, a significant difference in pain alleviation was observed in patients with chronic low back pain (SMD = -0.6, 95%CI - 0.94 to -0.25, p < 0.001, I2 = 67%), whereas no significant difference was observed in patients with acute low back pain (SMD = -0.46, 95%CI - 0.99 to 0.07, p = 0.09, I2 = 0%). PEMF did not improve physical function compared with the control treatment (SMD = -0.45, 95% CI - 0.98 to 0.07, p = 0.09, I2 = 86%). CONCLUSION: PEMF is beneficial for alleviating pain in patients with chronic low back pain despite having no advantage in improving physical function.

MiR-125 Family in Cardiovascular and Cerebrovascular Diseases.

Cardiovascular and cerebrovascular diseases are a serious threaten to the health of modern people. Understanding the mechanism of occurrence and development of cardiovascular and cerebrovascular diseases, as well as reasonable prevention and treatment of them, is a huge challenge that we are currently facing. The miR-125 family consists of hsa-miR-125a, hsa-miR-125b-1 and hsa-miR-125b-2. It is a kind of miRNA family that is highly conserved among different species. A large amount of literature shows that the lack of miR-125 can cause abnormal development of the cardiovascular system in the embryonic period. At the same time, the miR-125 family participates in the occurrence and development of a variety of cardiovascular and cerebrovascular diseases, including myocardial ischemia, atherosclerosis, ischemia-reperfusion injury, ischemic stroke, and heart failure directly or indirectly. In this article, we summarized the role of the miR-125 family in the development and maturation of cardiovascular system, the occurrence and development of cardiovascular and cerebrovascular diseases, and its important value in the current fiery stem cell therapy. In addition, we presented this in the form of table and diagrams. We also discussed the difficulties and challenges faced by the miR-125 family in clinical applications.