Cardiac Homing Peptide-Functionalized Polymeric Nanoparticles Suppressing SHP1 Alleviate Acute Myocardial Infarction Injury by Promoting Efferocytosis and Inhibiting Inflammation.

Purpose: Acute myocardial infarction (AMI) is a major global health concern worldwide. The upregulation of the CD47 on apoptotic cardiomyocytes acts as a "don't-eat-me" signal, inhibiting the clearance of apoptotic cells by macrophages (a process known as efferocytosis) via the Signal Regulatory Protein α (SIRPα)/ SH2 Domain-Containing Phosphatase 1 (SHP1) axis, leading to secondary inflammatory activation. Additionally, impairment of this process can result in insufficient macrophage polarization towards the reparative M2 phenotype.

Engineering Strategies of Plant-Derived Exosome-Like Nanovesicles: Current Knowledge and Future Perspectives.

Plant-derived exosome-like nanovesicles (PELNs) from edible plants, isolated by ultracentrifugation, size exclusion chromatography or other methods, were proved to contain a variety of biologically active and therapeutically specific components. Recently, investigations in the field of PELN-based biomedicine have been conducted, which positioned those nanovesicles as promising tools for prevention and treatment of several diseases, with their natural origin potentially offering superior biocompatibility and bioavailability. However, the inadequate targeting and limited therapeutic effects constrain the utility and clinical translation of PELNs.

Triple Hybrid Cellular Nanovesicles Promote Cardiac Repair after Ischemic Reperfusion.

The management of myocardial ischemia/reperfusion (I/R) damage in the context of reperfusion treatment remains a significant hurdle in the field of cardiovascular disorders. The injured lesions exhibit distinctive features, including abnormal accumulation of necrotic cells and subsequent inflammatory response, which further exacerbates the impairment of cardiac function. Here, we report genetically engineered hybrid nanovesicles (hNVs), which contain cell-derived nanovesicles overexpressing high-affinity SIRPα variants (SαV-NVs), exosomes (EXOs) derived from human mesenchymal stem cells (MSCs), and platelet-derived nanovesicles (PLT-NVs), to facilitate the necrotic cell clearance and inhibit the inflammatory responses.

Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial.

Importance: Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials.

Objective: To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design, Setting, And Participants: Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China.

Development of heart failure with preserved ejection fraction is independent of eosinophils in a preclinical model.

The increasing burden of heart failure with preserved ejection fraction (HFpEF) has become a global health problem. HFpEF is characterized by systematic inflammation, cardiac metabolic remodeling, and fibrosis. Eosinophils act as an essential but generally overlooked subgroup of white blood cells, which participate in cardiac fibrosis, as reported in several recent studies.

Management of the Uncinate Process in No-Touch Laparoscopic Pancreaticoduodenectomy.

Laparoscopic pancreatoduodenectomy (LPD) is a demanding abdominal operation that necessitates meticulous surgical skills and teamwork. The management of the pancreatic uncinate process is one of the most important and difficult processes in LPD because of its deep anatomical location and difficult exposure. Complete resection of the uncinate process and mesopancreas has become the cornerstone of LPD.

Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway.

Background: Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSC-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSC-EV.

Levosimendan Reverses Cardiac Malfunction and Cardiomyocyte Ferroptosis During Heart Failure with Preserved Ejection Fraction via Connexin 43 Signaling Activation.

Purpose: In recent decades, the occurrence of heart failure with preserved ejection fraction (HFpEF) has outweighed that of heart failure with reduced ejection fraction by degrees, but few drugs have been demonstrated to improve long-term clinical outcomes in patients with HFpEF. Levosimendan, a calcium-sensitizing cardiotonic agent, improves decompensated heart failure clinically. However, the anti-HFpEF activities of levosimendan and underlying molecular mechanisms are unclear.

Laparoscopic Radical Antegrade Modular Pancreatosplenectomy via Dorsal-Caudal Artery Approach for Pancreatic Neck-Body Cancer.

Laparoscopic radical resection of the pancreatic neck is one of the most complicated radical operations for pancreatic cancer, especially for patients who have had neoadjuvant chemotherapy. Here, we present a technique to perform laparoscopic radical antegrade modular pancreatosplenectomy (L-RAMPS) using the dorsal-caudal artery approach by making full use of the high-definition vision and operation modes of the laparoscope. The innovation and optimization of this operation are provided in the protocol.

Tongxinluo-pretreated mesenchymal stem cells facilitate cardiac repair via exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway.

Background: Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCs) in enhancing cardiac repair and further investigated the underlying mechanism.

Laparoscopic Pancreatoduodenectomy for Pancreatic Cancer using In-Situ No-Touch Isolation Technique.

Laparoscopic pancreatoduodenectomy (LPD) is a standard radical operation for pancreatic head malignant tumors by now. Due to the complex laparoscopic resection and reconstruction techniques, it is difficult to perform LPD for patients with locally advanced pancreatic head cancer after neoadjuvant therapy. Our team initiates LPD using the in-situ No-Touch isolation technique.

Sequential transplantation of exosomes and mesenchymal stem cells pretreated with a combination of hypoxia and Tongxinluo efficiently facilitates cardiac repair.

Background: Bone marrow-derived mesenchymal stem cells (MSCs), which possess immunomodulatory characteristic, are promising candidates for the treatment of acute myocardial infarction (AMI). However, the low retention and survival rate of MSCs in the ischemic heart limit their therapeutic efficacy. Strategies either modifying MSCs or alleviating the inflammatory environment, which facilitates the recruitment and survival of the engrafted MSCs, may solve the problem.

Isoform-Selective HDAC Inhibitor Mocetinostat (MGCD0103) Alleviates Myocardial Ischemia/Reperfusion Injury Via Mitochondrial Protection Through the HDACs/CREB/PGC-1α Signaling Pathway.

Over the past decade, histone deacetylases (HDACs) has been proven to manipulate development and exacerbation of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiac hypertrophy, ventricular remodeling, and myocardial fibrosis. Inhibition of HDACs, especially class-I HDACs, is potent to the protection of ischemic myocardium after ischemia/reperfusion (I/R). Herein, we examine whether mocetinostat (MGCD0103, MOCE), a class-I selective HDAC inhibitor in phase-II clinical trial, shows cardioprotection under I/R in vivo and in vitro, if so, reveal its potential pharmacological mechanism to provide an experimental and theoretical basis for mocetinostat usage in a clinical setting.

The mechanistic target of rapamycin complex 1 critically regulates the function of mononuclear phagocytes and promotes cardiac remodeling in acute ischemia.

Monocytes and macrophages are cellular forces that drive and resolve inflammation triggered by acute myocardial ischemia. One of the most important but least understood regulatory mechanisms is how these cells sense cues from the micro-milieu and integrate environmental signals with their response that eventually determines the outcome of myocardial repair. In the current study, we investigated if the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) plays this role.

PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart.

Background: Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated.

Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy.

Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK (mitogen-activated protein kinase)/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. How these pathways interact remains unclear and few direct targets responsible for the prohypertrophic role of NFAT have been described.

Cardiomyocyte-derived small extracellular vesicles can signal eNOS activation in cardiac microvascular endothelial cells to protect against Ischemia/Reperfusion injury.

The crosstalk between cardiac microvascular endothelial cells (CMECs) and cardiomyocytes (CMs) has emerged as a key component in the development of, and protection against, cardiac diseases. For example, activation of endothelial nitric oxide synthase (eNOS) in CMECs, by therapeutic strategies such as ischemic preconditioning, plays a critical role in the protection against myocardial ischemia/reperfusion (I/R) injury. However, much less is known about the signals produced by CMs that are able to regulate CMEC biology.

Tongxinluo attenuates oxygen-glucose-serum deprivation/restoration-induced endothelial barrier breakdown via peroxisome proliferator activated receptor-α/angiopoietin-like 4 pathway in high glucose-incubated human cardiac microvascular endothelial cells.

Background: Traditional Chinese medicine Tongxinluo (TXL) has been widely used to treat coronary artery disease in China, since it could reduce myocardial infarct size and ischemia/reperfusion injury in both non-diabetic and diabetic conditions. It has been shown that TXL could regulate peroxisome proliferator activated receptor-α (PPAR-α), a positive modulator of angiopoietin-like 4 (Angptl4), in diabetic rats. Endothelial junction substructure components, such as VE-cadherin, are involved in the protection of reperfusion injury.

China Tongxinluo Study for myocardial protection in patients with Acute Myocardial Infarction (CTS-AMI): Rationale and design of a randomized, double-blind, placebo-controlled, multicenter clinical trial.

Acute ST-segment elevation myocardial infarction (STEMI) remains a serious life-threatening event. Despite coronary revascularization, patients might still suffer from poor outcomes caused by myocardial no-reflow and ischemic/reperfusion injury. Tongxinluo (TXL), a traditional Chinese medicine, has been preliminarily demonstrated to reduce myocardial no-reflow and ischemic/reperfusion injury.

Laparoscopic Anatomical Segment VII Resection for Hepatocellular Carcinoma Using the Glissonian Approach with Indocyanine Green Dye Fluorescence.

Background: Many studies confirm that anatomical resection was associated with favorable oncologic outcomes for patients with HCC who had preserved as much of the remnant liver tissue as possible. In recent years, laparoscopic liver resection has been widely extended from minor resection to complex hepatectomy, However, surgery on tumors located in the posterosuperior segment remains a demanding procedure regardless of the extent of resection. Laparoscopic anatomical segment VII resection has one of the highest difficulty scores based on the tumor location due to poor accessibility, hard to exposure, and difficulty in obtaining sufficient surgical margins.

Transplantation efficacy of autologous bone marrow mesenchymal stem cells combined with atorvastatin for acute myocardial infarction (TEAM-AMI): rationale and design of a randomized, double-blind, placebo-controlled, multi-center, Phase II TEAM-AMI trial.

To determine the efficacy and safety of intracoronary infusion of autologous bone marrow mesenchymal stem cells (MSC) in combination with intensive atorvastatin (ATV) treatment for patients with anterior ST-segment elevation myocardial infarction-elevation myocardial infarction. The trial enrolls a total of 100 patients with anterior ST-elevation myocardial infarction. The subjects are randomly assigned (1:1:1:1) to receive routine ATV (20 mg/d) with placebo or MSCs and intensive ATV (80 mg/d) with placebo or MSCs.

Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance.

Background: Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs.

Combined therapy with atorvastatin and atorvastatin-pretreated mesenchymal stem cells enhances cardiac performance after acute myocardial infarction by activating SDF-1/CXCR4 axis.

The SDF-1/CXCR4 signaling plays a critical role in the trafficking of mesenchymal stem cells (MSCs) to the sites of tissue damage. Our recent study demonstrated that atorvastatin (ATV) treatment improved the survival of MSCs, and ATV pretreated MSCs (MSCs) exhibited enhanced engraftment to injured myocardium. In this study, we investigated whether combined treatment with ATV and MSCs enhances cardiac repair and regeneration by activating SDF-1/CXCR4 signaling in a rat model of acute myocardial infarction.

Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19.

Aims: Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms.