FPR1: A critical gatekeeper of the heart and brain.

G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.

Isopropyl 3-(3,4-dihydroxyphenyl) 2-hydroxypropanoate protects septic myocardial injury via regulating GAS6/Axl-AMPK signaling pathway.

In a previous study, we used metabolomic techniques to identify a new metabolite of Danshen Dripping Pills called isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP), which has potential as a drug candidate for cardiovascular diseases. This study aimed to explore the protective effects of IDHP against septic myocardial injury, as well as its molecular mechanism. Wild type or GAS6 knockout mice injured by cecal ligation and puncture (CLP) were used to observe the effect of IDHP. Here, we found that a specific concentration of IDHP (60 mg/kg) significantly increased the survival rate of septic mice to about 75 % at 72 h post CLP, and showed improvements in sepsis score, blood biochemistry parameters, cardiac function, and myocardial tissue damage. Furthermore, IDHP inhibited myocardial oxidative stress, inflammatory response, apoptosis, and mitochondrial dysfunction. Molecularly, we discovered that IDHP treatment reversed the CLP-induced downregulation of GAS6, Axl, and p-AMPK/AMPK expression. In addition, GAS6 knockout reversed the positive effect of IDHP in septic mice, indicated by more severe myocardial tissue damage, oxidative stress, inflammatory response, and mitochondrial dysfunction. GAS6 knockout also resulted in decreased levels of GAS6, Axl, and p-AMPK/AMPK. Taken together, our study provides evidence that IDHP has significant cardioprotective effects against sepsis by regulating the GAS6/Axl-AMPK signaling pathway. This finding has important therapeutic potential for treating sepsis.

Exploring the role of ITGB6: fibrosis, cancer, and other diseases.

Integrin ß6 (ITGB6), a member of the integrin family of proteins, is only present in epithelial tissues and frequently associates with integrin subunit αv to form transmembrane heterodimers named integrin αvß6. Importantly, ITGB6 determines αvß6 expression and availability. In addition to being engaged in organ fibrosis, ITGB6 is also directly linked to the emergence of cancer, periodontitis, and several potential genetic diseases. Therefore, it is of great significance to study the molecular-biological mechanism of ITGB6, which could provide novel insights for future clinical diagnosis and therapy. This review introduces the structure, distribution, and biological function of ITGB6. This review also expounds on ITGB6-related diseases, detailing the known biological effects of ITGB6.

Application of three-dimensional transesophageal echocardiography in preoperative evaluation of transcatheter aortic valve replacement.

BACKGROUND: Our goal was to determine the accuracy of 3-dimensional transesophageal echocardiography (3D-TEE) compared with that of computed tomography (CT) in the preoperative evaluation for transcatheter aortic valve replacement (TAVR) when the errors caused by inconsistent software and method have been eliminated and the representativeness of the sample has been improved. We also investigated the influence of aortic root calcification on the accuracy of 3D-TEE in aortic annulus evaluations. METHODS: Part I: 45 of 233 patients who underwent TAVR in the department of cardiovascular surgery at the Xijing hospital from January 2016 to August 2019 were studied retrospectively. Materialise Mimics software and the multiplanar reconstruction method were used for evaluation, based on 3D-TEE and CT. The annulus area-derived diameter, the annulus perimeter-derived diameter (Dp), the annulus mean diameter, the left ventricular outflow tract Dp diameter, the sinotubular junction (STJ) diameter-Dp, and the aortic sinus diameter were compared and analyzed. Part II: 31 of 233 patients whose 3D-TEE and CT data were well preserved and in the required format were included. HU450 and HU850 were used as indicators to measure the severity of calcification. The Spearman rank correlation and Linear regression were used to analyze the correlation between aortic root calcification and the accuracy of 3D-TEE in aortic annulus measurement. RESULTS: The measurement results based on 3D-TEE were significantly lower than those obtained using CT (P < 0.05), except for the STJ diameter-Dp in diastole (P = 0.11). The correlation coefficient of the two groups was 0.699-0.954 (P < 0.01), which also indicated a significant correlation between the two groups. A Bland-Altman plot showed that the ordinate values were mostly within the 95% consistency limit; the consistency of the two groups was good. By establishing the linear regression equation, the two groups can be inferred from each other. The Spearman rank correlation analysis and the Linear regression analysis showed that the influence of aortic calcification on the accuracy of the 3D-TEE annulus evaluation was limited. CONCLUSIONS: Although an evaluation based on 3D-TEE underestimated the results, we can deduce CT results from 3D-TEE because the two methods exhibit considerable correlation and consistency. TRIAL REGISTRATION: Name: Surgery and Transcatheter Intervention for Structural Heart Diseases. Number: NCT02917980. URL: https://clinicaltrials.gov/ct2/results?term=NCT02917980 .

Transcatheter Closure of Mitral Paravalvular Leak via Multiple Approaches.

OBJECTIVES: The purpose of this study was to review the experiences with transcatheter closure of mitral PVL after surgical valve replacement. BACKGROUND: Transcatheter closure of paravalvular leak (PVL) is an intricate alternative to surgical closure. But it represents one of the most intricate procedures in the field of structural heart interventions, especially for patients with mitral PVL. METHODS: From January 2015 through January 2019, 35 patients with mitral PVL after valve replacement underwent transcatheter closure. We reviewed the catheter techniques, perioperative characteristics, and prognosis. The median follow-up was 26 (3-48) months. RESULTS: Acute procedural success was achieved in 33/35 (94.3%) patients. Twenty-five patients had single mitral prosthetic valve replacements; 10 had combined aortic and mitral prosthetic valve replacements previously; 28 had mechanical valves; and 7 had bioprosthetic valves. All percutaneous procedures were performed with local anesthesia except for seven transapical cases with general anesthesia. Multiple approaches were used: transfemoral, transapical, and transseptal via an arteriovenous loop. Multiple devices were deployed. There were no hospital deaths. The procedural time was 67-300 (124 ± 62) minutes. Fluoroscopic time was 17-50 (23.6 ± 12.1) minutes. The hospital stay was 5-17 (8.3 ± 3.2) days. Complications included recurrent hemolysis, residual regurgitation, acute renal insufficiency, and anemia. Twenty-seven (77.1%) patients improved by ≥1 New York Heart Association functional class at the 1-year follow-up. CONCLUSIONS: Transcatheter mitral PVL closure requires complex catheter techniques. However, this minimally invasive treatment could provide reliable outcomes and shorter hospital stays in selected patients. This trial is registered with NCT02917980.

Transcatheter mitral valve implantation using a novel system: preclinical results.

BACKGROUND: This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system (Mi-thos valve) composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis. METHODS: The valve was implanted in 26 sheep using a transapical approach for short- and long-term evaluation. The technical feasibility, safety, durability, and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography, multisliced computed tomography, histological analysis, and electron microscopy. RESULTS: The success rate of valve implantation was 100%, and the immediate survival rate after surgery was 84%. Five animals died within 90 min after the development of the prosthetic valve due to an acute left ventricular outflow tract obstruction (n = 2) and sudden intraoperative ventricular fibrillation (n = 3). Twelve animals died within 1 month due to acute left heart dysfunction. Mild (n = 5) and moderate (n = 2) paravalvular leakage occurred in seven animals, and two moderate PVL animals died of chronic heart failure within three months. Multimodality imaging studies of the remaining seven animals showed excellent function and alignment of the valves, with no coronary artery obstruction, no left ventricular outflow tract obstruction, no severe transvalvular gradients and no paravalvular leakage. Macroscopic evaluation demonstrated stable, secure positioning of the valve, with full endothelialization of the valve leaflets without injury to the ventricular or atrial walls. Histological and electron microscopic examinations at six months showed no obvious macro- or microcalcification in the leaflets. CONCLUSIONS: Preclinical studies indicate that transcatheter implantation of the Mi-thos valve is technically safe and feasible. The durability, functionality, and lack of leaflet calcification were all verified in animal experiments. The information from these preclinical studies will be applied to patient selection criteria and the first-in-human studies.

Exosomes Derived from Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Inhibiting Pyroptosis.

OBJECTIVE: Mesenchymal stem cells (MSCs) show unique advantages in cardiomyocyte repairment. Exosomes derived from MSCs can enhance the viability of myocardial cells after ischemia/reperfusion (I/R) injury and regulate inflammation response. The study was designed to ascertain whether MSCs-exo protect the myocardium against I/R injury through inhibiting pyroptosis, and the underlying mechanisms. METHODS AND RESULTS: Experiments were carried out in H/R and I/R model. Cell viability was inhibited and NLRP3 and caspase1 protein levels were upregulated in H/R model. However, MSCs could inhibit cell apoptosis and pyroptosis in H/R model. Moreover, we used MSCs-exo to treated H/R model, and flow cytometric analysis results showed the inhibition function of MSCs-exo on cell apoptosis, and Western blot data suggested that NLRP3 and Caspase-1 expressions were downregulated in H/R model. Furthermore, exosomal miR-320b targeted NLRP3 protein, and MSCs-exo OE could inhibit NLRP3 expression and pyroptosis in H/R. In addition, the inhibition function of MSCs-exo on pyroptosis also was found in I/R model, and HE and Tunel staining also got similar results. CONCLUSION: Exosomes derived from mesenchymal stem cells could protect the myocardium against ischemia/reperfusion injury through inhibiting pyroptosis.

Irisin attenuates myocardial ischemia/reperfusion-induced cardiac dysfunction by regulating ER-mitochondria interaction through a mitochondrial ubiquitin ligase-dependent mechanism.

BACKGROUND: Myocardial ischemia/reperfusion (MI/R) injury imposes devastating cardiovascular sequelae in particular cardiac dysfunction as a result of restored blood flow. However, the mechanism behind MI/R injury remains elusive. Mitochondrial ubiquitin ligase (MITOL/MARCH5) is localized at the mitochondria-ER contact site and may be activated in response to a variety of pathophysiological processes, such as apoptosis, mitochondrial injury, ER stress, hypoxia, and reactive oxygen species (ROS) generation. Irisin as a cleaved product of fibronectin type III domain-containing protein 5 (FNDC5) displays cardioprotection in diverse cardiac diseases. METHODS: This study was designed to examine the role of irisin and MITOL in MI/R injury. Male C57BL/6J mice (8-10-week-old) were administered adenovirus MITOL shRNA through intracardiac injection followed by MI/R surgery through ligation and release the slipknot of cardiac left anterior descending coronary artery. RESULTS: Our results showed that irisin improved myocardial function in the face of MI/R injury as evidenced by reduced myocardial infarct size, apoptotic rate, serum lactate dehydrogenase (LDH), ROS generation, and malondialdehyde (MDA) levels as well as lessened ER stress injury. Moreover, our results indicated that protective role of irisin was mediated by upregulation of MITOL. Irisin also protected H9c2 cells against simulated I/R through negating ER stress, apoptosis, ROS and MDA levels, as well as facilitating superoxide dismutase (SOD) by way of elevated MITOL expression. CONCLUSIONS: To this end, our data favored that irisin pretreatment protects against MI/R injury, ER stress, ROS production, and mitochondrial homeostasis through upregulation of MITOL. These findings depicted the therapeutic potential of irisin and MITOL in the management of MI/R injury in patients with ST-segment elevation.

Prognosis of Transcatheter Closure Compared with Surgical Repair of Paravalvular Leak after Prosthetic Valve Replacement: A Retrospective Comparison.

OBJECTIVE: Paravalvular leak (PVL) after valve replacement remains clinically challenging. Percutaneous closure is an effective therapy for patients with PVLs because reoperation is associated with high rates of morbidity and mortality. The purpose of this study was to retrospectively compare the clinical outcome of transcatheter closure and surgical repair in patients with a PVL. METHODS: From January 2000 to May 2016, 131 patients with PVL were treated at three major medical centers in China. Perioperative characteristics and outcomes of the procedure were reviewed. RESULTS: Sixty-eight (51.9%) patients with PVLs were treated with percutaneous transcatheter closure (group I). The procedure was successful in 67 (98%) with no hospital deaths. Sixty-three (48.1%) patients with PVLs had a reoperation (group II). Five of the surgical patients had a third open-heart operation for residual regurgitation, and one underwent successful percutaneous closure. Six patients died in the hospital postoperatively. All patients in group II but only 11 in group I needed perioperative blood transfusions. The procedural time and hospital stay after the procedure were significantly shorter in group I than in group II. At the 1-year follow-up, cardiac function improved by ≥ 1 New York Heart Association functional class in 55 (82%) patients in group I and in 39 (68%) patients in group II. CONCLUSIONS: Transcatheter closure was shown to be a safe, effective therapeutic option in patients with PVL. It was associated with a lower hospital mortality rate, shorter procedural time, and fewer blood transfusions than surgical treatment in selected patients.

Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1.

Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases.

Tissue resident regulatory T cells: novel therapeutic targets for human disease.

Over the past decade, the ability of regulatory T cells (Tregs) to suppress multiple types of immune cells has received tremendous attention. Mounting evidence has revealed that tissue resident Tregs control non-immunological processes of their target tissues and contribute to a plethora of human diseases. The identification of novel tissue-specific Tregs has highlighted their heterogeneity and complexity. This review summarizes the recent findings for visceral adipose tissue CD4+Foxp3+ regulatory T cells (VAT Tregs), muscle Tregs, bone Tregs and skin memory Tregs, with a focus on their unique functions in local tissues. This interpretation of the roles of tissue-specific Tregs and of their involvement in disease progression provides new insight into the discovery of potential therapeutic targets of human diseases.

IL-25 regulates the polarization of macrophages and attenuates obliterative bronchiolitis in murine trachea transplantation models.

Obliterative bronchiolitis (OB) remains the major limitations for the long-term survival of allografts after lung transplantation. Th17 cells and IL-17 have been recognized as mediators of the development of OB in both animal models and human beings. IL-25, also called IL-17E, is the only anti-inflammatory cytokine of the IL-17 family, capable of regulating Th17 cells function in autoimmune inflammations. Whether IL-25 affects Th17 cells responses and the development of OB remains poorly understood. Acute rejection (AR) of the lung allograft has been regarded as the main problem for the development of OB, in which infiltrations of monocytes/macrophages play important roles. This study explored the potential role of IL-25 in regulation of macrophages polarization and inhibition of IL-17 production in the progression of OB. Here, we showed that IL-25 directly suppressed the expression of inflammatory cytokines, such as IL-6, IL-23, TNF-α, and IL-1ß in LPS-induced pro-inflammatory M1 macrophages in vitro. In vivo data demonstrated that IL-25 deficiency promoted the polarization and function of M1 macrophages and aggravated the progression of OB in murine models of both orthotopic and heterotopic trachea transplantation. In conclusion, these data indicated that IL-25 attenuated OB by suppressing the function of M1 macrophages and IL-17 expression, providing an alternative strategy to intervene the development of OB.

USP22 is a positive regulator of NFATc2 on promoting IL2 expression.

Nuclear factor of activated T cells (NFAT) is an important regulator of T cell activation. However, the molecular mechanism whereby NFATc2 regulates IL2 transcription is not fully understood. In this study, we showed that ubiquitin-specific protease 22 (USP22), known as a cancer stem cell marker, specifically interacted with and deubiquitinated NFATc2. USP22 stabilized NFATc2 protein levels, which required its deubiquitinase activity. Consistent with these observations, depletion of USP22 in T cells reduced the expression of IL2, which is a cytokine that signifies T effector cell activation. Our findings thus unveil a previously uncharacterized positive regulator of NFATc2, suggesting that targeting the deubiquitinase activity of USP22 could have therapeutic benefit to control IL2 expression and T cell function.