Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study.

To elucidate the mechanism and origins of chemo- and enantioselectivities of the reaction between aliphatic aldehydes and hydrazones catalyzed by triazolium-derived NHC, density functional theory computations have been performed. According to our calculated results, the whole catalytic cycle for the formation of dihydropyridazinones proceeds via the initial nucleophilic addition of NHC to an aliphatic aldehyde, followed by the concerted intramolecular proton transfer and C-Cl bond cleavage. Subsequent deprotonation generates an enolate intermediate. The enolate intermediate then undergoes 1,4-addition to hydrazone to construct a new carbon-carbon bond. The following ring-closure would lead to a six-membered ring intermediate, which, upon the release of NHC, affords the final product dihydropyridazinone. The computation results reveal that intramolecular proton transfer is significantly promoted by the Brønsted acid DIPEA·H+. The carbon-carbon bond formation step could determine not only the chemoselectivity but also the stereoselectivity and lead to the S-isomer product. It was found that the stereoselectivity arises from a combination of weak interactions, including C-H···O, C-H···N, C-H···π, and LP···π. NHC could enhance the nucleophilicity of the aliphatic aldehyde and facilitate further reaction with hydrazone. This work could be beneficial for the development of new catalytic strategies in the future.

Inhibition of Hmbox1 Promotes Cardiomyocyte Survival and Glucose Metabolism Through Gck Activation in Ischemia/Reperfusion Injury.

BACKGROUND: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored. METHODS: We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo. RESULTS: We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury. CONCLUSIONS: Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.

RNA-mediated epigenetic regulation in exercised heart: Mechanisms and opportunities for intervention.

Physical exercise has been widely acknowledged as a beneficial lifestyle alteration and a potent non-pharmacological treatment for heart disease. Extensive investigations have revealed the beneficial effects of exercise on the heart and the underlying mechanisms involved. Exercise is considered one of the key factors that can lead to epigenetic alterations. The increasing number of identified molecules in the exercised heart has led to many studies in recent years that have explored the cellular function of ncRNAs and RNA modifications in the heart. Investigating the regulatory role of RNA-mediated epigenetic regulation in exercised hearts will contribute to the development of therapeutic strategies for the management of heart diseases. This review aims to summarize the positive impact of exercise on cardiac health. We will first provide an overview of the mechanisms through which exercise offers protection to the heart. Subsequently, we will delve into the current understanding of ncRNAs, specifically miRNAs, lncRNAs, and circRNAs, as well as RNA modification, focusing on RNA m6A and RNA A-to-I editing, and how they contribute to exercise-induced benefits for the heart. Lastly, we will explore the emerging therapeutic strategies that utilize exercise-mediated RNA epigenetic regulation in the treatment of heart diseases, while also addressing the challenges faced in this field.

Intrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise.

Among its many cardiovascular benefits, exercise training improves heart function and protects the heart against age-related decline, pathological stress, and injury. Here, we focus on cardiac benefits with an emphasis on more recent updates to our understanding. While the cardiomyocyte continues to play a central role as both a target and effector of exercise's benefits, there is a growing recognition of the important roles of other, noncardiomyocyte lineages and pathways, including some that lie outside the heart itself. We review what is known about mediators of exercise's benefits-both those intrinsic to the heart (at the level of cardiomyocytes, fibroblasts, or vascular cells) and those that are systemic (including metabolism, inflammation, the microbiome, and aging)-highlighting what is known about the molecular mechanisms responsible.

Exercise training decreases lactylation and prevents myocardial ischemia-reperfusion injury by inhibiting YTHDF2.

Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.

Exercise-Induced miR-210 Promotes Cardiomyocyte Proliferation and Survival and Mediates Exercise-Induced Cardiac Protection against Ischemia/Reperfusion Injury.

Exercise can stimulate physiological cardiac growth and provide cardioprotection effect in ischemia/reperfusion (I/R) injury. MiR-210 is regulated in the adaptation process induced by exercise; however, its impact on exercise-induced physiological cardiac growth and its contribution to exercise-driven cardioprotection remain unclear. We investigated the role and mechanism of miR-210 in exercise-induced physiological cardiac growth and explored whether miR-210 contributes to exercise-induced protection in alleviating I/R injury. Here, we first observed that regular swimming exercise can markedly increase miR-210 levels in the heart and blood samples of rats and mice. Circulating miR-210 levels were also elevated after a programmed cardiac rehabilitation in patients that were diagnosed of coronary heart diseases. In 8-week swimming model in wild-type (WT) and miR-210 knockout (KO) rats, we demonstrated that miR-210 was not integral for exercise-induced cardiac hypertrophy but it did influence cardiomyocyte proliferative activity. In neonatal rat cardiomyocytes, miR-210 promoted cell proliferation and suppressed apoptosis while not altering cell size. Additionally, miR-210 promoted cardiomyocyte proliferation and survival in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and AC16 cell line, indicating its functional roles in human cardiomyocytes. We further identified miR-210 target genes, cyclin-dependent kinase 10 (CDK10) and ephrin-A3 (EFNA3), that regulate cardiomyocyte proliferation and apoptosis. Finally, miR-210 KO and WT rats were subjected to swimming exercise followed by I/R injury. We demonstrated that miR-210 crucially contributed to exercise-driven cardioprotection against I/R injury. In summary, this study elucidates the role of miR-210, an exercise-responsive miRNA, in promoting the proliferative activity of cardiomyocytes during physiological cardiac growth. Furthermore, miR-210 plays an essential role in mediating the protective effects of exercise against cardiac I/R injury. Our findings suggest exercise as a potent nonpharmaceutical intervention for inducing miR-210, which can alleviate I/R injury and promote cardioprotection.

Exercise Inhibits Doxorubicin-Induced Cardiotoxicity via Regulating B Cells.

BACKGROUND: Doxorubicin is an effective chemotherapeutic agent, but its use is limited by acute and chronic cardiotoxicity. Exercise training has been shown to protect against doxorubicin-induced cardiotoxicity, but the involvement of immune cells remains unclear. This study aimed to investigate the role of exercise-derived B cells in protecting against doxorubicin-induced cardiotoxicity and to further determine whether B cell activation and antibody secretion play a role in this protection. METHODS: Mice that were administered with doxorubicin (5 mg/kg per week, 20 mg/kg cumulative dose) received treadmill running exercise. The adoptive transfer of exercise-derived splenic B cells to µMT-/- (B cell-deficient) mice was performed to elucidate the mechanism of B cell regulation that mediated the effect of exercise. RESULTS: Doxorubicin-administered mice that had undergone exercise training showed improved cardiac function, and low levels of cardiac apoptosis, atrophy, and fibrosis, and had reduced cardiac antibody deposition and proinflammatory responses. Similarly, B cell pharmacological and genetic depletion alleviated doxorubicin-induced cardiotoxicity, which phenocopied the protection of exercise. In vitro performed coculture experiments confirmed that exercise-derived B cells reduced cardiomyocyte apoptosis and fibroblast activation compared with control B cells. Importantly, the protective effect of exercise on B cells was confirmed by the adoptive transfer of splenic B cells from exercised donor mice to µMT-/- recipient mice. However, blockage of Fc gamma receptor IIB function using B cell transplants from exercised Fc gamma receptor IIB-/- mice abolished the protection of exercise-derived B cells against doxorubicin-induced cardiotoxicity. Mechanistically, we found that Fc gamma receptor IIB, an important B cell inhibitory receptor, responded to exercise and increased B cell activation threshold, which participated in exercise-induced protection against doxorubicin-induced cardiotoxicity. CONCLUSIONS: Our results demonstrate that exercise training protects against doxorubicin-induced cardiotoxicity by upregulating Fc gamma receptor IIB expression in B cells, which plays an important anti-inflammatory role and participates in the protective effect of exercise against doxorubicin-induced cardiotoxicity.

The Complete Genomic Sequence of Microbial Transglutaminase Producer, Streptomyces mobaraensis DSM40587.

Actinomycetes are remarkable natural sources of active natural molecules and enzymes of considerable industrial value. Streptomyces mobaraensis is the first microorganism found to produce transglutaminase with broad industrial applications. Although transglutaminase in S. mobaraensis has been well studied over the past three decades, the genome of S. mobaraensis and its secondary metabolic potential were poorly reported. Here, we presented the complete genome of S. mobaraensis DSM40587 obtained from the German Collection of Microorganisms and Cell Cultures GmbH. It contains a linear chromosome of 7,633,041 bp and a circular plasmid of 23,857 bp. The chromosome with an average GC content of 73.49% was predicted to harbour 6683 protein-coding genes, seven rRNA and 69 tRNA genes. Comparative genomic analysis reveals its meaningful genomic characterisation. A comprehensive bioinformatics investigation identifies 35 putative BGCs (biosynthesis gene clusters) involved in synthesising various secondary metabolites. Of these, 13 clusters showed high similarity (> 55%) to known BGCs coding for polyketides, nonribosomal peptides, hopene, RiPP (Ribosomally synthesized and post-translationally modified peptides), and others. Furthermore, these BGCs with over 65% similarity to the known BGCs were analysed in detail. The complete genome of S. mobaraensis DSM40587 reveals its capacity to yield diverse bioactive natural products and provides additional insights into discovering novel secondary metabolites.

Closer to The Heart: Harnessing the Power of Targeted Extracellular Vesicle Therapies.

Extracellular vesicles (EVs) have emerged as novel diagnostic and therapeutic approaches for cardiovascular diseases. EVs derived from various origins exhibit distinct effects on the cardiovascular system. However, the application of native EVs is constrained due to their poor stabilities and limited targeting capabilities. Currently, targeted modification of EVs primarily involves genetic engineering, chemical modification (covalent, non-covalent), cell membrane modification, and biomaterial encapsulation. These techniques enhance the stability, biological activity, target-binding capacity, and controlled release of EVs at specific cells and tissues. The diverse origins of cardioprotective EVs are covered, and the applications of cardiac-targeting EV delivery systems in protecting against cardiovascular diseases are discussed. This review summarizes the current stage of research on the potential of EV-based targeted therapies for addressing cardiovascular disorders.

Circular RNA Translation in Cardiovascular Diseases.

Circular RNAs (circRNAs) are a class of endogenous functional RNA generated by back-splicing. Recently, circRNAs have been found to have certain coding potential. Proteins/peptides translated from circRNAs play essential roles in various diseases. Here, we briefly summarize the basic knowledge and technologies that are usually applied to study circRNA translation. Then, we focus on the research progress of circRNA translation in cardiovascular diseases and discuss the perspective and future direction of translatable circRNA study in cardiovascular diseases.

Differential expression of miR-140-3p and its potential role during the development of the acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) is a category of cardiovascular disease with a high fatality rate. AIMS: We searched the differential expressed miRNAs (DEmiRNAs) in ACS based on bioinformatic analysis and investigated the diagnostic value of plasma miR-140-3p in patients with ACS and its potential functional role in ACS. METHODS: The miRNAs (GSE94605, GSE49823, and GSE185729) microarray datasets of ACS were downloaded from the GEO datasets. After integrating the miRNA and mRNA interaction, a protein-protein interaction (PPI) network was constructed with 36 overlapped target mRNAs using STRING database. The plasma levels of miR-140-3p were detected by RT-qPCR, and its clinical diagnostic value was evaluated using the ROC curve. The potential effects of the miR-140-3p/RHOA axis in ACS were explored using human coronary endothelial cells (HCAECs). RESULTS: After overlapping the GEO datasets, miR-140-3p was identified in the microarray datasets of ACS. The plasma miR-140-3p expression levels were highly expressed in ACS patients than in healthy control and had diagnostic significance. The target mRNAs of miR-140-3p were predicted using TargetScan, miRWalk, TarBase, and miRDB databases. The PPI network identified ten hub genes. miR-140-3p could decrease the HCAECs' cell viability, while RHOA reversed the inhibition effect of miR-140-3p. CONCLUSIONS: The plasma expression of miR-140-3p was upregulated in ACS patients. miR-140-3p could decrease the HCAECs' cell viability, while RHOA reversed the inhibition effect of miR-140-3p. The miR-140-3p may be a potential diagnostic biomarker for the early detection of ACS.

Exercise and microbiome: From big data to therapy.

Exercise is a vital component in maintaining optimal health and serves as a prospective therapeutic intervention for various diseases. The human microbiome, comprised of trillions of microorganisms, plays a crucial role in overall health. Given the advancements in microbiome research, substantial databases have been created to decipher the functionality and mechanisms of the microbiome in health and disease contexts. This review presents an initial overview of microbiomics development and related databases, followed by an in-depth description of the multi-omics technologies for microbiome. It subsequently synthesizes the research pertaining to exercise-induced modifications of the microbiome and diseases that impact the microbiome. Finally, it highlights the potential therapeutic implications of an exercise-modulated microbiome in intestinal disease, obesity and diabetes, cardiovascular disease, and immune/inflammation-related diseases.

Exercise-induced circular RNA circUtrn is required for cardiac physiological hypertrophy and prevents myocardial ischaemia-reperfusion injury.

AIMS: Regular exercise training benefits cardiovascular health and effectively reduces the risk for cardiovascular disease. Circular RNAs (circRNAs) play important roles in cardiac pathophysiology. However, the role of circRNAs in response to exercise training and biological mechanisms responsible for exercise-induced cardiac protection remain largely unknown. METHODS AND RESULTS: RNA sequencing was used to profile circRNA expression in adult mouse cardiomyocytes that were isolated from mice with or without exercise training. Exercise-induced circRNA circUtrn was significantly increased in swimming-trained adult mouse cardiomyocytes. In vivo, circUtrn was found to be required for exercise-induced physiological cardiac hypertrophy. circUtrn inhibition abolished the protective effects of exercise on myocardial ischaemia-reperfusion remodelling. circUtrn overexpression prevented myocardial ischaemia-reperfusion-induced acute injury and pathological cardiac remodelling. In vitro, overexpression of circUtrn promoted H9 human embryonic stem cell-induced cardiomyocyte growth and survival via protein phosphatase 5 (PP5). Mechanistically, circUtrn directly bound to PP5 and regulated the stability of PP5 in a ubiquitin-proteasome-dependent manner. Hypoxia-inducible factor 1α-dependent splicing factor SF3B1 acted as an upstream regulator of circUtrn in cardiomyocytes. CONCLUSION: The circRNA circUtrn is upregulated upon exercise training in the heart. Overexpression of circUtrn can prevent myocardial I/R-induced injury and pathological cardiac remodelling.

Graph Sampling-Based Multi-Stream Enhancement Network for Visible-Infrared Person Re-Identification.

With the increasing demand for person re-identification (Re-ID) tasks, the need for all-day retrieval has become an inevitable trend. Nevertheless, single-modal Re-ID is no longer sufficient to meet this requirement, making Multi-Modal Data crucial in Re-ID. Consequently, a Visible-Infrared Person Re-Identification (VI Re-ID) task is proposed, which aims to match pairs of person images from the visible and infrared modalities. The significant modality discrepancy between the modalities poses a major challenge. Existing VI Re-ID methods focus on cross-modal feature learning and modal transformation to alleviate the discrepancy but overlook the impact of person contour information. Contours exhibit modality invariance, which is vital for learning effective identity representations and cross-modal matching. In addition, due to the low intra-modal diversity in the visible modality, it is difficult to distinguish the boundaries between some hard samples. To address these issues, we propose the Graph Sampling-based Multi-stream Enhancement Network (GSMEN). Firstly, the Contour Expansion Module (CEM) incorporates the contour information of a person into the original samples, further reducing the modality discrepancy and leading to improved matching stability between image pairs of different modalities. Additionally, to better distinguish cross-modal hard sample pairs during the training process, an innovative Cross-modality Graph Sampler (CGS) is designed for sample selection before training. The CGS calculates the feature distance between samples from different modalities and groups similar samples into the same batch during the training process, effectively exploring the boundary relationships between hard classes in the cross-modal setting. Some experiments conducted on the SYSU-MM01 and RegDB datasets demonstrate the superiority of our proposed method. Specifically, in the VIS→IR task, the experimental results on the RegDB dataset achieve 93.69% for Rank-1 and 92.56% for mAP.