Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure.

[Figure: see text].

Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.

Diabetic cardiomyopathy (DCM), an important complication of diabetes mellitus (DM), is one of the most serious chronic heart diseases and has become a major cause of heart failure worldwide. At present, the pathogenesis of DCM is unclear, and there is still a lack of effective therapeutics. Previous studies have shown that the homeostasis of mitochondria and the endoplasmic reticulum (ER) play a core role in maintaining cardiovascular function, and structural and functional abnormalities in these organelles seriously impact the occurrence and development of various cardiovascular diseases, including DCM. The interplay between mitochondria and the ER is mediated by the mitochondria-associated ER membrane (MAM), which participates in regulating energy metabolism, calcium homeostasis, mitochondrial dynamics, autophagy, ER stress, inflammation, and other cellular processes. Recent studies have proven that MAM is closely related to the initiation and progression of DCM. In this study, we aim to summarize the recent research progress on MAM, elaborate on the key role of MAM in DCM, and discuss the potential of MAM as an important therapeutic target for DCM, thereby providing a theoretical reference for basic and clinical studies of DCM treatment.

Emerging role of antidiabetic drugs in cardiorenal protection.

The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.

Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions.

Diabetic cardiomyopathy (DCM) mainly refers to myocardial metabolic dysfunction caused by high glucose, and hyperglycemia is an independent risk factor for cardiac function in the absence of coronary atherosclerosis and hypertension. DCM, which is a severe complication of diabetes, has become the leading cause of heart failure in diabetic patients. The initial symptoms are inconspicuous, and patients gradually exhibit left ventricular dysfunction and eventually develop total heart failure, which brings a great challenge to the early diagnosis of DCM. To date, the underlying pathological mechanisms of DCM are complicated and have not been fully elucidated. Although there are therapeutic strategies available for DCM, the treatment is mainly focused on controlling blood glucose and blood lipids, and there is a lack of effective drugs targeting myocardial injury. Thus, a large percentage of patients with DCM inevitably develop heart failure. Given the neglected initial symptoms, the intricate cellular and molecular mechanisms, and the lack of available drugs, it is necessary to explore early diagnostic biomarkers, further understand the signaling pathways involved in the pathogenesis of DCM, summarize the current therapeutic strategies, and develop new targeted interventions.

The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application.

LAG-3, a type of immune checkpoint receptor protein belonging to the immunoglobulin superfamily, is confirmed to be expressed on activated immune cells, mainly including activated T cells. LAG-3 can negatively regulate the function of T cells, exerting important effects on maintaining the homeostasis of the immune system under normal physiological conditions and promoting tumor cells immune escape in the tumor microenvironment. Given its important biological roles, LAG-3 has been regarded as a promising target for cancer immunotherapy. To date, many LAG-3 inhibitors have been reported, which can be divided into monoclonal antibody, double antibody, and small molecule drug, some of which have entered the clinical research stage. LAG-3 inhibitors can negatively regulate and suppress T cell proliferation and activation through combination with MHC II ligand. Besides, LAG-3 inhibitors can also affect T cell function via binding to Galectin-3 and LSECtin. In addition, LAG-3 inhibitors can prevent the FGL1-LAG-3 interaction, thereby enhancing the human body's antitumor immune effect. In this review, we will describe the function of LAG-3 and summarize the latest LAG-3 inhibitors in the clinic for cancer therapy.

Research advance of natural products in tumor immunotherapy.

Cancer immunotherapy has emerged as a novel anti-tumor treatment. Despite significant breakthroughs, cancer immunotherapy remains focused on several types of tumors that are sensitive to the immune system. Therefore, effective strategies to expand its indications and improve its efficacy become key factors for the further development of cancer immunotherapy. In recent decades, the anticancer activities of natural products are reported to have this effect on cancer immunotherapy. And the mechanism is largely attributed to the remodeling of the tumor immunosuppressive microenvironment. The compelling data highlight that natural products offer an alternative method option to improve immune function in the tumor microenvironment (TME). Currently, more attention is being paid to the discovery of new potential modulators of tumor immunotherapy from natural products. In this review, we describe current advances in employing natural products and natural small-molecule drugs targeting immune cells to avoid tumor immune escape, which may bring some insight for guiding tumor treatment.

Discovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects.

DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin-RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular and cellular levels as shown by molecular modeling studies, HTRF, cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast activation, which was associated with the inhibition of cullin 3 neddylation. Our findings indicate a potentially unrecognized role of DCN1 inhibition for anticardiac fibrotic effects. DN-2 may be used as a lead compound for further development.

Discovery of [1,2,4]triazolo[1,5-a]pyrimidines derivatives as potential anticancer agents.

In this work, we reported the discovery of compound 6i with potent antiproliferative activity against MGC-803. Among these compounds, the most potent compound 6i could effectively inhibit MGC-803 (IC50 = 0.96 µM), being around 38-fold selectivity over GES-1. Further underlying mechanism studies indicated that 6i inhibited the colony formation, migration of MGC-803, and exerted anti-proliferative effect by inducing G0/G1 phase arrest in MGC-803 cells. Cell apoptosis was induced by 6i through activating mitochondria-mediated intrinsic pathway and the death receptor-mediated extrinsic pathway. 6i induced cell apoptosis by elevating the level of ROS. Also, 6i up-regulated pro-apoptotic Bax and p53 level, while down-regulating anti-apoptotic Bcl-2 protein expression. Furthermore, acute toxicity experiment indicated 6i exhibited good safety in vivo. Therefore, 6i may be a template for future development of [1,2,4]triazolo [1,5-a]pyrimidine-based anti-cancer agents.

Design, synthesis and biological evaluation of novel thiosemicarbazone-indole derivatives targeting prostate cancer cells.

To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 µM, compared with normal WPMY-1 cells with the IC50 value of 19.470 µM. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.

Drug repurposing: Discovery of troxipide analogs as potent antitumor agents.

Drug repurposing plays a vital role in the discovery of undescribed bioactivities in clinical drugs. Based on drug repurposing strategy, we for the first time reported a novel series of troxipide analogs and then evaluated their antiproliferative activity against MCF-7, PC3, MGC-803, and PC9 cancer cell lines and WPMY-1, most of which showed obvious selectivity toward PC-3 over the other three cancer cell lines and WPMY-1. Compound 5q, especially, could effectively inhibit PC3 with an IC50 value of 0.91 µM, which exhibited around 53-fold selectivity toward WPMY-1. Data indicated that 5q effectively inhibited the colony formation, suppressed the cell migration, and induced G1/S phase arrest in PC3 cells. Also, compound 5q induced cell apoptosis by activating the two apoptotic signaling pathways in PC3 cells: death receptor-mediated extrinsic pathway and mitochondria-mediated intrinsic pathway. Compound 5q up-regulated the expression of both pro-apoptotic Bax and P53, while down-regulated anti-apoptotic Bcl-2 expression. Besides, compound 5q significantly increased the expression of cleaved caspase 3/9 and cleaved PARP. Therefore, the successful discovery of compound 5q may further validate the feasibility of this theory, which will encourage researchers to reveal undescribed bioactivities in traditional drugs.