Search

Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of aryl

An efficient, transition-metal-free, photocatalytic three-component intermolecular trifluoromethylation-gem-difluoroallylation of unactivated alkenes has been achieved.

Aging-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are gradually becoming the primary burden of society and cause significant health-care concerns. Aging is a critical independent risk factor for neurodegenerative diseases. The pathological alterations of neurodegenerative diseases are tightly associated with mitochondrial dysfunction, inflammation, and oxidative stress, which in turn stimulates the further progression of neurodegenerative diseases. Given the potential research value, lncRNAs have attracted considerable attention. LncRNAs play complex and dynamic roles in multiple signal transduction axis of neurodegeneration. Emerging evidence indicates that lncRNAs exert crucial regulatory effects in the initiation and development of aging-related neurodegenerative diseases. This review compiles the underlying pathological mechanisms of aging and related neurodegenerative diseases. Besides, we discuss the roles of lncRNAs in aging. In addition, the crosstalk and network of lncRNAs in neurodegenerative diseases are also explored.

Exosomes play a role as mediators of cell-to-cell communication, thus exhibiting pleiotropic activities to homeostasis regulation. Exosomal non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are closely related to a variety of biological and functional aspects of human health. When the exosomal ncRNAs undergo tissue-specific changes due to diverse internal or external disorders, they can cause tissue dysfunction, aging, and diseases. In this review, we comprehensively discuss the underlying regulatory mechanisms of exosomes in human diseases. In addition, we explore the current knowledge on the roles of exosomal miRNAs, lncRNAs, and circRNAs in human health and diseases, including cancers, metabolic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and infectious diseases, to determine their potential implication in biomarker identification and therapeutic exploration.

Long noncoding RNAs (lncRNAs) have been investigated as novel regulatory molecules involved in diverse biological processes. Our previous study demonstrated that lncRNA-ES3 is associated with the high glucose-induced calcification/senescence of human aortic vascular smooth muscle cells (HA-VSMCs). However, the mechanism of lncRNA-ES3 in vascular calcification/aging remained largely unknown. Here, we report that the expression of basic helix-loop-helix family member e40 (Bhlhe40) was decreased significantly in HA-VSMCs treated with high glucose, whereas the expression of basic leucine zipper transcription factor (BATF) was increased. Overexpression of Bhlhe40 and inhibition of BATF alleviated calcification/senescence of HA-VSMCs, as confirmed by Alizarin Red S staining and the presence of senescence-associated β-galactosidase-positive cells. Moreover, we identified that Bhlhe40 regulates lncRNA-ES3 in HA-VSMCs by binding to the promoter region of the lncRNA-ES3 gene (LINC00458). Upregulation or inhibition of lncRNA-ES3 expression significantly promoted or reduced calcification/senescence of HA-VSMCs, respectively. Additionally, we identified that lncRNA-ES3 functions in this process by suppressing the expression of miR-95-5p, miR-6776-5p, miR-3620-5p, and miR-4747-5p. The results demonstrate that lncRNA-ES3 triggers gene silencing of multiple miRNAs by binding to Bhlhe40, leading to calcification/senescence of VSMCs. Our findings suggest that pharmacological interventions targeting lncRNA-ES3 may be therapeutically beneficial in ameliorating vascular calcification/aging.

Objective Cardiovascular diseases and vascular aging are common in patients with diabetes. High glucose is a major cause of vascular aging and cardiovascular diseases. Premature senescence of vascular smooth muscle cells (VSMCs) is one of the main contributors to vascular aging. Adiponectin has been demonstrated to have an anti‐aging effect. The present study explored the mechanisms by which adiponectin protects VSMCs against high‐glucose‐induced senescence. Methods Senescence‐associated β‐galactosidase (SA‐β‐gal) staining was used to detect senescence cells. Western blot was used for measuring protein levels. Flow cytometry was carried out to detect the cell cycle and telomeric repeat amplification protocol (TRAP)–polymerase chain reaction (PCR) silver staining was selected to measure the telomerase activity. Results Premature senescence of VSMCs was induced by high glucose (30 mM) in a time‐dependent manner, which was verified by an increased number of senescence cells, p21 and p53 expression, as well as the decreased proliferation index. High glucose reduced telomerase activity of VSMCs via inhibition of the AMPK/TSC2/mTOR/S6K1 pathway and activation of the PI3K/Akt/mTOR/S6K1 pathway, while adiponectin treatment significantly increased telomerase activity of VSMCs through activation of AMPK/TSC2/mTOR/S6K1 signaling and inhibition of PI3K/Akt/mTOR/S6K1 signaling. Conclusion Adiponectin attenuated the high‐glucose‐induced premature senescence of VSMCs via increasing telomerase activity of VSMCs, which was achieved by activation of AMPK/TSC2/mTOR/S6K1 signaling and inhibition of PI3K/Akt/mTOR/S6K1 signaling.

Vascular calcification/aging is a crucial feature of diabetic macro vasculopathy, resulting in serious cardiovascular diseases. The calcification/senescence of vascular smooth muscle cells (VSMCs) induced by hyperglycemia can cause diabetic vascular calcification/aging. However, the mechanism of VSMCs calcification/senescence involved in diabetic vascular calcification/aging remains unknown. The purpose of this study was to determine how the high glucose (HG) information in circulating blood is transmitted from vascular endothelial cells (ECs) to VSMCs, which are not contacted with blood directly. Exosomes have attracted much attention for their vital roles in regulating cell-to-cell communication. In this study, we found that milk fat globule epidermal growth factor 8 (MFGE8) was enriched in high glucose induced human umbilical vein endothelial cell exosomes (HG-HUVEC-Exo) and regulate VSMCs calcification/senescence, characterized by up-regulated expressions of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as the increased mineralized nodules and senescence-associated β-galactosidase (SA-β-gal) positive cells. Upstream mechanism studies showed that sirtuin1 (SIRT1) was involved in VSMCs calcification/senescence by affecting the expression of MFGE8. We also found that inflammatory response mediated by IL-1β, IL-6, and IL-8 was closely associated with MFGE8 and played a key role in regulating HG-HUVEC-Exo-induced VSMCs calcification/senescence. These findings provide a new insight into the mechanism of exosomal MFGE8 as a potential preventive and therapeutic target for the intervention of diabetic vascular calcification/aging.

Vascular aging is defined as organic and functional changes in blood vessels, in which decline in autophagy levels, DNA damage, MicroRNA (miRNA), oxidative stress, sirtuin, and apoptosis signal-regulated kinase 1 (ASK1) are integral thereto. With regard to vascular morphology, the increase in arterial stiffness, atherosclerosis, vascular calcification and high amyloid beta levels are closely related to vascular aging. Further closely related thereto, at the cellular level, is the aging of vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Vascular aging seriously affects the health, economy and life of patients, but can be delayed by SGLT2 inhibitors through the improvement of vascular function. In the present article, a review is conducted of recent domestic and international progress in research on SGLT2 inhibitors,vascular aging and diseases related thereto, thereby providing theoretical support and guidance for further revealing the relationship between SGLT2 inhibitors and diseases related to vascular aging.

Background: Postinfarction ventricular septal rupture (PI-VSR) is a rare but devastating complication of acute myocardial infarction (AMI). Risk stratification in the acute phase is crucial for decision-making, and this study analyzed the risk factors for early mortality and the effects of various management options on the outcome of PI-VSR patients in the era of percutaneous intervention. Methods: A total of 96 patients with PI-VSR were identified and divided into an acute-phase survivor group (n = 46, survived ≥2 weeks after admission) and a nonsurvivor group (n = 50, died within 2 weeks after admission). Percutaneous closure was considered in acute-phase survivors. Patients were followed up for a mean 47 (quartiles 15–71) months by clinical visit or telephone interview. Results: The overall acute-phase (i.e., < 2 weeks after the diagnosis of PI-VSR) mortality rate was 52%. Female sex and Killip Class III–IV at admission were associated with an increased risk of acute-phase death. Of the 46 patients who survived ≥2 weeks, 20 underwent interventional occlusion and the procedure was successful in 19. Percutaneous closure in the acute-phase survivor group improved the immediate (21% in-hospital mortality rate) and long-term (53% mortality) outcomes. Conclusions: Patients with PI-VSR are at a high risk of acute-phase mortality. Female sex and severe cardiac dysfunction at admission are linked with a high rate of acute-phase deaths. Percutaneous closure in acute-phase survivors results in favorable short- and long-term benefits for PI-VSR patients.

The aging of the vasculature plays a crucial role in the pathological progression of various vascular aging-related diseases. As endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are essential parts in the inner and medial layers of vessel wall, respectively, the structural and functional alterations of ECs and VSMCs are the major causes of vascular aging. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a multifunctional glycoprotein which exerts a regulatory role in the intercellular interactions involved in a variety of biological and pathological processes. Emerging evidence suggests that MFG-E8 is a novel and outstanding modulator for vascular aging via targeting at ECs and VSMCs. In this review, we will summarise the cumulative roles and mechanisms of MFG-E8 in vascular aging and vascular aging-related diseases with special emphasis on the functions of ECs and VSMCs. In addition, we also aim to focus on the promising diagnostic function as a biomarker and the potential therapeutic application of MFG-E8 in vascular aging and the clinical evaluation of vascular aging-related diseases.

Aging is a progressive loss of physiological integrity and functionality process which increases susceptibility and mortality to diseases. Vascular aging is a specific type of organic aging. The structure and function changes of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are the main cause of vascular aging, which could influence the threshold, process, and severity of vascular related diseases. Accumulating evidences demonstrate that exosomes serve as novel intercellular information communicator between cell to cell by delivering variety biologically active cargos, especially exosomal non-coding RNAs (ncRNAs), which are associated with most of aging-related biological and functional disorders. In this review, we will summerize the emerging roles and mechanisms of exosomal ncRNAs in vascular aging and vascular aging related diseases, focusing on the role of exosomal miRNAs and lncRNAs in regulating the functions of ECs and VSMCs. Moreover, the relationship between the ECs and VSMCs linked by exosomes, the potential diagnostic and therapeutic application of exosomes in vascular aging and the clinical evaluation and treatment of vascular aging and vascular aging related diseases will also be discussed.