Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis.

Myocardial infarction (MI) is defined as sudden ischemic death of myocardial tissue. Amphiregulin (Areg) regulates cell survival and is crucial for the healing of tissues after damage. However, the functions and mechanisms of Areg after MI remain unclear. Here, we aimed to investigate Areg's impact on myocardial remodeling. Mice model of MI was constructed and Areg-/- mice were used. Expression of Areg was analyzed using western blotting, RT-qPCR, flow cytometry, and immunofluorescence staining. Echocardiographic analysis, Masson's trichrome, and triphenyltetrazolium chloride staining were used to assess cardiac function and structure. RNA sequencing was used for unbiased analysis. Apoptosis and autophagy were determined by western blotting, TUNEL staining, electron microscopy, and mRFP-GFP-LC3 lentivirus. Lysosomal acidity was determined by Lysotracker staining. Areg was elevated in the infarct border zone after MI. It was mostly secreted by macrophages. Areg deficiency aggravated adverse ventricular remodeling, as reflected by worsening cardiac function, a lower survival rate, increased scar size, and interstitial fibrosis. RNA sequencing analyses showed that Areg related to the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR) signaling pathways, V-ATPase and lysosome pathways. Mechanistically, Areg exerts beneficial effects via increasing lysosomal acidity to promote autophagosome clearance, and activating the EGFR/PI3K/Akt/mTOR signaling pathway, subsequently inhibiting excessive autophagosome formation and apoptosis in cardiomyocytes. This study provides a novel evidence for the role of Areg in inhibiting ventricular remodeling after MI by regulating autophagy and apoptosis and identifies Areg as a potential therapeutic target in ventricular remodeling after MI.

Unravelling CD4+ T cell diversity and tissue adaptation of Tregs in abdominal aortic aneurysms through single-cell sequencing.

Immune cell infiltration is a significant pathological process in abdominal aortic aneurysms (AAA). T cells, particularly CD4+ T cells, are essential immune cells responsible for substantial infiltration of the aorta. Regulatory T cells (Tregs) in AAA have been identified as tissue-specific; however, the time, location, and mechanism of acquiring the tissue-specific phenotype are still unknown. Using single-cell RNA sequencing (scRNA-seq) on CD4+ T cells from the AAA aorta and spleen, we discovered heterogeneity among CD4+ T cells and identified activated, proliferating and developed aorta Tregs. These Tregs originate in the peripheral tissues and acquire the tissue-specific phenotype in the aorta. The identification of precursors for Tregs in AAA provides new insight into the pathogenesis of AAA.

Research Progress on Flavonoids in Traditional Chinese Medicine to Counteract Cardiotoxicity Associated with Anti-Tumor Drugs.

The development of anti-tumor drugs has notably enhanced the survival rates and quality of life for patients with malignant tumors. However, the side effects of these drugs, especially cardiotoxicity, significantly limit their clinical application. The cardiotoxicity associated with anti-tumor drugs has been a subject of extensive attention and research. Traditional to mitigate these side effects have included reducing drug dosages, shortening treatment duration, modifying administration methods, and opting for drugs with lower toxicity. However, either approach may potentially compromise the anti-tumor efficacy of the medications. Therefore, exploring other effective methods for anti-cardiotoxicity will be the focus of future research. The potential of traditional Chinese medicine (TCM) in managing cardiovascular diseases and cancer treatment has gained widespread recognition. TCM is valued for its minimal side effects, affordability, and accessibility, offering promising avenues in the prevention and treatment of cardiotoxicity caused by anti-tumor drugs. Among its constituents, flavonoids, which are present in many TCMs, are particularly notable. These monomeric compounds with distinct structural components have been shown to possess both cardiovascular protective properties and anti-tumor capabilities. In this discussion, we will delve into the classification of anti-tumor drugs and explore the underlying mechanisms of their associated cardiotoxicity. Additionally, we will examine flavonoids found in TCM and investigate their mechanisms of cardiovascular protection. This will include an analysis of how these natural compounds can mitigate the cardiac side effects of anti-tumor therapies while potentially enhancing overall patient health and treatment outcomes.

Evaluation of Radiotherapy Efficacy and Prognostic Analysis for Solid and Cystic Brain Metastases.

OBJECTIVES: Brain metastases (BMs) are commonly categorized into cystic and solid. However, the difference in the prognosis of patients with either cystic or solid BMs following radiotherapy remains poorly understood. We used a retrospective design to elucidate the disparities in survival between these two patient groups undergoing radiotherapy and to identify factors influencing the overall survival (OS) of patients with BMs. METHODS: This retrospective study encompasses 212 patients diagnosed with BMs. We meticulously analyzed the clinical characteristics, radiation therapy modalities, and risk factors influencing the OS among these patients, categorized by BMs type, post-brain radiation therapy. RESULTS: A statistically significant difference in mOS was observed between the two cohorts (Solid vs Cystic: 23.1 vs 14.6 months). Subgroup analysis unveiled distinctions in mOS, particularly in patients with EGFR-mutant lung adenocarcinoma (Solid vs Cystic: 23.1 vs 6.43 months). The volume of BMs and the biological effective dose (BED) emerged as significantly prognostic factors for patients with cystic BMs. For patients with solid BMs, fraction dose, BED, and the number of BMs were identified as independent prognostic factors for survival. CONCLUSION: Brain radiotherapy shows superior survival benefits for lung cancer patients with solid BMs compared to those with cystic BMs, particularly in EGFR-mutant lung cancer. In particular, patients receiving BED ≥60 Gy have a more favorable prognosis than those receiving BED <60 Gy, regardless of the type of BM (solid or cystic) in lung cancer.

Fulvic acid alleviates the stress of low nitrogen on maize by promoting root development and nitrogen metabolism.

The potential of fulvic acid (FA) to improve plant growth has been acknowledged, but its effect on plant growth and nutrient uptake under nutrient stress remains unclear. This study investigated the effects of different FA application rates on maize growth and nitrogen utilization under low nitrogen stress. The results showed that under low nitrogen stress, FA significantly stimulated maize growth, particularly root development, biomass, and nitrogen content. The enhanced activity levels of key enzymes in nitrogen metabolism were observed, along with differential gene expression in maize, which enriched nitrogen metabolism, amino acid metabolism and plant hormone metabolism. The application of FA regulated the hormones' level, reduced abscisic acid content in leaves and Me-JA content in roots, and increased auxin and zeatin ribose content in leaves. This study concludes that, by promoting root development, nitrogen metabolism, and hormone metabolism, an appropriate concentration of FA can enhance plant tolerance to low nitrogen conditions and improve nitrogen use efficiency.

Recent advances in potential targets for myocardial ischemia reperfusion injury: Role of macrophages.

Myocardial ischemia-reperfusion injury (MIRI) is a complex process that occurs when blood flow is restored after myocardium infarction (MI) with exacerbated tissue damage. Macrophages, essential cell type of the immune response, play an important role in MIRI. Macrophage subpopulations, namely M1 and M2, are distinguished by distinct phenotypes and functions. In MIRI, macrophages infiltrate in infarcted area, shaping the inflammatory response and influencing tissue healing. Resident cardiac macrophages interact with monocyte-derived macrophages in MIRI, and influence injury progression. Key factors including chemokines, cytokines, and toll-like receptors modulate macrophage behavior in MIRI. This review aims to address recent findings on the classification and the roles of macrophages in the myocardium, spanning from MI to subsequent MIRI, and highlights various signaling pathways implicated in macrophage polarization underlining the complexity of MIRI. This article will shed light on developing advanced therapeutic strategies for MIRI management.

The Role of Short-Chain Fatty Acids in Myocardial Ischemia-Reperfusion Injury.

PURPOSE OF REVIEW: This study aims to review the effects of short-chain fatty acids (SCFAs) in regulating the myocardial ischemia-reperfusion injury (MIRI). RECENT FINDINGS: Coronary heart disease (CHD) is a well-known leading cause of death and disability worldwide. Cardiac substrate metabolism plays the determinant role in assessing the severity of heart injury due to the abruptly shifted energy production during the MIRI. Fatty acids are the main energy fuels for the heart, which are classified into long-, medium- and short chain fatty acids by the length of carbon chain. SCFAs are the main metabolites derived from the anaerobic bacterial fermentation of fiber-rich diets, which are shown to play a protective role in cerebrovascular disease previously. Meanwhile, accumulating evidences suggest that SCFAs can also play a crucial role in cardiac energy metabolism. Results of various studies revealed the cardioprotective effects of SCFAs by displaying anti-inflammatory and anti-ferroptotic function, connecting gut-brain neural circuit and regulating the intestinal flora.

The combination of Tanshinone IIA and Astragaloside IV attenuates myocardial ischemia-reperfusion injury by inhibiting the STING pathway.

BACKGROUND: Astragaloside IV (As-IV) and Tanshinone IIA (Ta-IIA) are the main ingredients of traditional Chinese medicinal Astragalus membranaceus (Fisch.) Bunge and Salvia miltiorrhiza Bunge, respectively, both of which have been employed in the treatment of cardiovascular diseases. Nevertheless, the efficacy of the combination (Co) of Ta-IIA and As-IV for cardiovascular diseases remain unclear and warrant further investigation. This study aimed to investigate the efficacy and the underlying molecular mechanism of Co in treating myocardial ischemia-reperfusion injury (MIRI). METHODS: In order to assess the efficacy of Co, an in vivo MIRI mouse model was created by temporarily blocking the coronary arteries for 30 min and then releasing the blockage. Parameters such as blood myocardial enzymes, infarct size, and ventricular function were measured. Additionally, in vitro experiments were conducted using HL1 cells in both hypoxia-reoxygenation model and oxidative stress models. The apoptosis rate, expression levels of apoptosis-related proteins, oxidative stress indexes, and release of inflammatory factors were detected. Furthermore, molecular docking was applied to examine the binding properties of Ta-IIA and As-IV to STING, and western blotting was performed to analyze protein expression of the STING pathway. Additionally, the protective effect of Ta-IIA, As-IV and Co via inhibiting STING was further confirmed in models of knockdown STING by siRNA and adding STING agonist. RESULTS: Both in vitro and in vivo data demonstrated that, compared to Ta-IIA or As-IV alone, the Co exhibited superior efficacy in reducing the area of myocardial infarction, lowering myocardial enzyme levels, and promoting the recovery of myocardial contractility. Furthermore, the Co showed more potent anti-apoptosis, antioxidant, and anti-inflammation effects. Additionally, the Co enhanced the inhibitory effects of Ta-IIA and As-IV on STING phosphorylation and the activation of STING signaling pathway. However, the administration of a STING agonist attenuated the protective effects of the Co, Ta-IIA, and As-IV by compromising their anti-apoptotic, antioxidant, and anti-inflammatory effects in MIRI. CONCLUSION: Compared to the individual administration of Ta-IIA or As-IV, the combined treatment demonstrated more potent ability in inhibiting apoptosis, oxidative stress, inflammation, and the STING signaling pathway in the context of MIRI, indicating a more powerful protective effect against MIRI.

Single-cell profile reveals the landscape of cardiac immunity and identifies a cardio-protective Ym-1hi neutrophil in myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a major hindrance to the success of cardiac reperfusion therapy. Although increased neutrophil infiltration is a hallmark of MIRI, the subtypes and alterations of neutrophils in this process remain unclear. Here, we performed single-cell sequencing of cardiac CD45+ cells isolated from the murine myocardium subjected to MIRI at six-time points. We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI. Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations, including Ccl3hi Neu and Ym-1hi Neu, which were increased at 6 h and 1 d after reperfusion, respectively. Ym-1hi Neu selectively expressed genes with protective effects and was, therefore, identified as a novel specific type of cardiac cell in the injured heart. Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues, especially instructing the response of macrophages. The abundance of Ym-1hi Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D (Ly6G) or anti-Intercellular cell adhesion molecule-1 (ICAM-1) neutralizing antibodies. In addition, a neutrophil subtype with the same phenotype as Ym-1hi Neu was detected in clinical samples and correlated with prognosis. Ym-1 inhibition exacerbated myocardial injury, whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice, which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue. Overall, our findings reveal the anti-inflammatory phenotype of Ym-1hi Neu and highlight its critical role in myocardial protection during the early stages of MIRI.

Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC.

Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non-small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome-1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO-induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti-PD-L1/TGF-ß bispecific antibody in inhibiting LLC-derived subcutaneous tumor models. Thus, ALO is first identified as a novel late-stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.