Correction to: Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury.

The original version of this article unfortunately contained a mistake.

Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury.

Extracellular vesicles (EVs) serve an important function as mediators of intercellular communication. Exercise is protective for the heart, although the signaling mechanisms that mediate this cardioprotection have not been fully elucidated. Here using nano-flow cytometry, we found a rapid increase in plasma EVs in human subjects undergoing exercise stress testing. We subsequently identified that serum EVs were increased by ~1.85-fold in mice after 3-week swimming. Intramyocardial injection of equivalent quantities of EVs from exercised mice and non-exercised controls provided similar protective effects against acute ischemia/reperfusion (I/R) injury in mice. However, injection of exercise-induced EVs in a quantity equivalent to the increase seen with exercise (1.85 swim group) significantly enhanced the protective effect. Similarly, treatment with exercise-induced increased EVs provided additional anti-apoptotic effect in H2O2-treated H9C2 cardiomyocytes mediated by the activation of ERK1/2 and HSP27 signaling. Finally, by treating H9C2 cells with insulin-like growth factor-1 to mimic exercise stimulus in vitro, we found an increased release of EVs from cardiomyocytes associated with ALIX and RAB35 activation. Collectively, our results show that exercise-induced increase in circulating EVs enhances the protective effects of endogenous EVs against cardiac I/R injury. Exercise-derived EVs might serve as a potent therapy for myocardial injury in the future.

miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2.

Cardiac dysfunction with sepsis is a major cause of death in intensive care units. Several lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting sepsis, though direct evidence of their functional roles in septic cardiac dysfunction is still lacking. In this study, C57BL/6 mice were exposed to lipopolysaccharide (LPS) to induce sepsis-associated cardiac dysfunction, as evidenced by reduced fractional shortening (FS) and ejection fraction (EF) and detrimental changes in cardiac contractility, inflammation, and energy metabolism. Microarray analysis and qRT-PCRs revealed that miR-21-3p was significantly induced in heart samples challenged with LPS. Impressively, pharmacological inhibition of miR-21-3p using antagomiR was able to preserve FS and EF and prevent mitochondria ultrastructural damage and autophagy in LPS-treated mice, while forced expression of miR-21-3p using agomiR aggravated that. Besides that, miR-21-3p antagomiR improved the survival of mice treated with LPS. Meanwhile, our data showed that SH3 domain-containing protein 2 (SORBS2) was inversely correlated with miR-21-3p expression level in mice hearts, and was repressed in hearts challenged with LPS, suggesting SORBS2 as a target gene of miR-21-3p. Additionally, plasma miR-21-3p was markedly elevated in septic patients with cardiac dysfunction as compared to septic patients without cardiac dysfunction. The ROC curve showed that plasma miR-21-3p could be a specific predictor of septic patients developing cardiac dysfunction with an area under the curve of 0.939. Collectively, the present study provides strong evidence that miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2. Inhibition of miR-21-3p might be a protective strategy to treat sepsis-induced cardiac dysfunction.

Biodegradable hollowed mesoporous SeO2 nanoplatform loaded with indocyanine green for simultaneous NIR II fluorescence imaging and synergistic breast carcinoma therapy.

Contrast agents in the second window of the near-infrared region (NIR II, 1000-1700 nm) have several advantages and indocyanine green (ICG), which emits NIR II fluorescence, is clinically approved and its use has been widely investigated for in vivo imaging, specifically for delineating tumor outlines; however, insufficient tumor targeting and rapid physiological metabolism of free ICG has substantially impeded its further clinical application. Here, we constructed novel hollowed mesoporous selenium oxide nanocarriers for precise ICG delivery. After surface modification with the active tumor targeting amino acid motif, RGD (hmSeO2@ICG-RGD), the nanocarriers were preferentially targeted toward tumor cells and subsequently degraded for ICG and Se-based nanogranule release under tumor tissue extracellular pH conditions (pH 6.5). The released ICG acted as an NIR II contrast agent, highlighting tumor tissue, after intravenous administration of hmSeO2@ICG-RGD into mammary tumor-bearing mice. Importantly, the photothermal effect of ICG improved reactive oxygen species production from SeO2 nanogranules, inducing oxidative therapy. The synergistic therapeutic effects of hyperthermia and increased oxidative stress on 808 nm laser exposure induced significant tumor cell killing. Thus, our nanoplatform can generate a high-performance diagnostic and therapeutic nanoagent that facilitates in vivo tumor outline discrimination and tumor ablation.

Combination of bacterial-targeted delivery of gold-based AIEgen radiosensitizer for fluorescence-image-guided enhanced radio-immunotherapy against advanced cancer.

Aggregation-Induced Emission luminogen (AIEgen) possess great potential in enhancing bioimaging-guided radiotherapeutic effects and radioimmunotherapy to improve the therapeutic effects of the tumor with good biosafety. Bacteria as a natural carrier have demonstrated great advantages in tumor targeted delivery and penetration to tumor. Herein, we construct a delivery platform that Salmonella VNP20009 act as an activated bacteria vector loaded the as-prepared novel AIEgen (TBTP-Au, VNP@TBTP-Au), which showed excellent radio-immunotherapy. VNP@TBTP-Au could target and retain AIEgen at the tumor site and deliver it into tumor cells specially, upon X-ray irradiation, much ROS was generated to induce immunogenic cell death via cGAS-STING signaling pathway to evoke immune response, thus achieving efficient radioimmunotherapy of the primary tumor with good biosafety. More importantly, the radioimmunotherapy with VNP@TBTP-Au formatted good abscopal effect that was able to suppress the growth of distant tumor. Our strategy pioneer a novel and simple strategy for the organic combination of bacteria and imaging-guided radiotherapy, and also pave the foundation for the combination with immunotherapy for better therapeutic effects.

Corrigendum: Biodegradable hollowed mesoporous SeO2 nanoplatform loaded with indocyanine green for simultaneous NIR II fluorescence imaging and synergistic breast carcinoma therapy.

[This corrects the article DOI: 10.3389/fbioe.2023.1151148.].

Research progress of the engagement of inorganic nanomaterials in cancer immunotherapy.

Cancer has attracted widespread attention from scientists for its high morbidity and mortality, posing great threats to people's health. Cancer immunotherapy with high specificity, low toxicity as well as triggering systemic anti-tumor response has gradually become common in clinical cancer treatment. However, due to the insufficient immunogenicity of tumor antigens peptides, weak ability to precisely target tumor sites, and the formation of tumor immunosuppressive microenvironment, the efficacy of immunotherapy is often limited. In recent years, the emergence of inorganic nanomaterials makes it possible for overcoming the limitations mentioned above. With self-adjuvant properties, high targeting ability, and good biocompatibility, the inorganic nanomaterials have been integrated with cancer immunotherapy and significantly improved the therapeutic effects.

New diagnostic and therapeutic strategies for myocardial infarction via nanomaterials.

Myocardial infarction is lethal to patients because of insufficient blood perfusion to vital organs. Several attempts have been made to improve its prognosis, among which nanomaterial research offers an opportunity to address this problem at the molecular level and has the potential to improve disease prevention, diagnosis, and treatment significantly. Up to now, nanomaterial-based technology has played a crucial role in broad novel diagnostic and therapeutic strategies for cardiac repair. This review summarizes various nanomaterial applications in myocardial infarction from multiple aspects, including high precision detection, pro-angiogenesis, regulating immune homeostasis, and miRNA and stem cell delivery vehicles. We also propose promising research hotspots that have not been reported much yet, such as conjugating pro-angiogenetic elements with nanoparticles to construct drug carriers, developing nanodrugs targeting other immune cells except for macrophages in the infarcted myocardium or the remote region. Though most of those strategies are preclinical and lack clinical trials, there is tremendous potential for their further applications in the future.

Glutathione-Sensitive Mesoporous Organosilica-Coated Gold Nanorods as Drug Delivery System for Photothermal Therapy-Enhanced Precise Chemotherapy.

The combination of photothermal therapy (PTT) and chemotherapy can remarkably improve the permeability of the cell membrane and reduce the concentration of chemotherapy agents that not only kill the tumor cells effectively but also have adverse effects on normal tissues. It is of great meaning to construct nanomaterials that could be simultaneously applied for tumor eradication with PTT and chemotherapy. In this work, we developed a novel gold nanorod coated with mesoporous organosilica nanoparticles (oMSN-GNR), which presented as an optimal photothermal contrast agent. Moreover, after doxorubicin loading (oMSN-GNR-DOX), the organosilica shell exhibited biodegradable properties under high glutathione in the tumor microenvironment, resulting in massively releasing doxorubicin to kill tumor cells. More importantly, the hyperthermia effect of GNR cores under near-infrared light provided promising opportunities for localized photothermal ablation in vivo. Therefore, the combination of precise chemotherapy and highly effective PTT successfully inhibited tumor growth in liver tumor-bearing mice. This versatile synergistic therapy with local heating and chemotherapeutics precise release opens up the potential clinical application of PTT and chemotherapy therapeutics for malignant tumor eradication.

miR-17-3p Contributes to Exercise-Induced Cardiac Growth and Protects against Myocardial Ischemia-Reperfusion Injury.

Limited microRNAs (miRNAs, miRs) have been reported to be necessary for exercise-induced cardiac growth and essential for protection against pathological cardiac remodeling. Here we determined members of the miR-17-92 cluster and their passenger miRNAs expressions in two distinct murine exercise models and found that miR-17-3p was increased in both. miR-17-3p promoted cardiomyocyte hypertrophy, proliferation, and survival. TIMP-3 was identified as a direct target gene of miR-17-3p whereas PTEN was indirectly inhibited by miR-17-3p. Inhibition of miR-17-3p in vivo attenuated exercise-induced cardiac growth including cardiomyocyte hypertrophy and expression of markers of myocyte proliferation. Importantly, mice injected with miR-17-3p agomir were protected from adverse remodeling after cardiac ischemia/reperfusion injury. Collectively, these data suggest that miR-17-3p contributes to exercise-induced cardiac growth and protects against adverse ventricular remodeling. miR-17-3p may represent a novel therapeutic target to promote functional recovery after cardiac ischemia/reperfusion.

Rapid detection of acute myocardial infarction-related miRNA based on a Capture-interCalation-electroCatalysis (3C) strategy.

Acute myocardial infarction (AMI) is one of the most urgent and serious diseases that may cause cardiac death in a few hours. Rapid diagnosis of AMI is the pre-requisite for timely interventions. Recently, several specific circulating miRNAs have been proven to have high correlation with AMI. To adopt miRNA as a biomarker may improve the diagnostic accuracy. However, it is a pity that the current available methods for the detection of miRNA usually require a few hours, which is too long for the diagnosis of AMI. In this paper, by adopting a capture DNA, an electrochemical active intercalator and an unimmobilized enzyme, we develop a Capture-interCalation-electroCatalysis (3C) strategy for the rapid detection of AMI-related miRNA. The whole detection process can be completed in 35 min, which is much shorter than most current methods and is acceptable for the diagnosis of AMI. This strategy also shows favorable sensitivity and selectivity, thus provides an alternative for the detection of miRNA. Most importantly, this effort may promote miRNA to work as an effective biomarker in the diagnosis of AMI.

Circulating miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in chronic heart failure patients.

Congestive heart failure (CHF) is a major cause of hospitalizations, morbidity, and mortality in Western societies. In addition to optimal medical and device therapy, exercise training is an important adjunct treatment option for CHF patients. MicroRNAs (miRNAs, miRs) participate in a variety of physiological and pathological processes. Dynamic regulation of circulating miRNAs during exercise in healthy persons and athletes has recently been documented, however, the response of circulating miRNAs to exercise in CHF patients is undetermined. Twenty-eight CHF patients underwent a symptom-limited incremental cardiopulmonary exercise test on a bicycle ergometer using a standardized exercise protocol of revised Ramp10 programs at Shanghai Tongji Hospital. Blood samples were collected before and immediately after an acute exercise session. RNA was extracted from the serum and selected miRNAs were determined using quantitative polymerase chain reactions. Moreover, inflammatory and muscle damage markers were determined by enzyme linked immunosorbent assays. We found that serum miR-21, miR-378 and miR-940 levels were significantly up-regulated immediately following an acute exercise while the rest were not changed. In addition, no robust correlation was identified between changes of these miRNAs and exercise capacity, muscle damage or inflammation. In conclusion, serum miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in CHF patients. Further studies are needed to clarify the potential use of circulating miRNAs as biomarkers of exercise adaptation in CHF patients, and if they have any use as prognostic markers of cardiovascular outcomes.

MicroRNA-221 is required for proliferation of mouse embryonic stem cells via P57 targeting.

Factors responsible for the rapid proliferative properties of embryonic stem (ES) cells are largely unknown. MicroRNA-221/222 (miR-221/222) regulate proliferation in many somatic cells, however, their roles in proliferation of ES cells are unclear. In this study, E14 mouse ES cells proliferation was determined by total cell counting, Cell Counting Kit (CCK-8), size of colonies and cell cycle analysis, while apoptosis and necrosis using Annexin V and propidium iodide staining. miR-221 inhibitor decreased proliferation of ES cells without inducing apoptosis and necrosis. miR-221 mimic, miR-222 mimic and miR-222 inhibitor did not affect ES cells proliferation. The expression level of miR-221 remained unchanged upon embryoid body (EB) formation. ES cells with miR-221 inhibition maintained an undifferentiated state, as indicated by unchanged alkaline phosphatase enzyme activity and Sox2, Nanong, and Oct4 expressions. P57 was post-transcriptionally regulated by miR-221 in ES cells. P57 knockdown completely abolished the inhibition effects of ES cells proliferation observed in miR-221 reduction, further indicating that miR-221 inhibition is likely to mediate its antiproliferative effects via P57 expression. To exclude that the function of miR-221 in ES cells is E14 specific, the effects of miR-221 mimic and inhibitor in size of colonies and cell cycle of R1 mouse ES cells were also determined and similar effects in inhibiting proliferation were achieved with miR-221 inhibition. Therefore, miR-221 is required for mouse ES cells proliferation via P57 targeting. This study indicates that miR-221 is among the regulators that control ES cells proliferation and might be used to influence the fate of ES cells.

Exercise-induced physiological hypertrophy initiates activation of cardiac progenitor cells.

OBJECTIVE: Physiological hypertrophy is featured by the hypertrophy of pre-existing cardiomyocytes and the formation of new cardiomyocytes. C-kit positive cardiac progenitor cells increased their numbers in exercise-induced physiological hypertrophy. However, the participation of Sca-1 positive cells in the physiological adaptation of the heart to exercise training is unclear. METHODS: Physiological hypertrophy was induced by swimming and the mRNA levels of GATA binding protein 4 (GATA4), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), endogenous hepatocyte growth factor (HGF), and insulin like growth factor-1 (IGF-1) from the whole heart were determined by real-time polymerase chain reactions (RT-PCRs) analysis. Immunofluorescent staining was used to compare the number of C-kit and Sca-1 positive cardiac progenitor cells. In addition, mRNA levels of C-kit and Sca-1 in left ventricle (LV), right ventricle (RV), and outflow tract (OFT) were determined in mice swimming for 7, 14, and 21 days by RT-PCRs. RESULTS: The ratio of heart weight (HW) to body weight and HW to tibia length and the mRNA level of GATA4 were increased while mRNA levels of ANP and BNP remained unchanged. C-kit and Sca-1 positive cardiac progenitor cells were activated by swimming training. An increased endogenous production of HGF and IGF was observed at least at the mRNA level. Swimming induced a significant up-regulation of C-kit in LV of mice swimming for 1, 2 and 3 weeks and in RV of mice swimming for 3 weeks. Sca-1 positive cardiac progenitor cells were increased in LV and OFT in mice swimming for 3 weeks. CONCLUSION: This study presents that swimming-induced physiological hypertrophy initiates activation of cardiac progenitor cells.