SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling.

Background: SGLT2 inhibitors, a T2DM medication to lower blood glucose, markedly improve cardiovascular outcomes but the underlying mechanism(s) are not fully understood. SGLT2i's produce a unique metabolic pattern by lowering blood glucose without increasing insulin while increasing ketone body and glucagon levels and reducing body weight. We tested if glucagon signaling contributes to SGLT2i induced improvement in CV function.

RIP3 regulates doxorubicin-induced intestinal mucositis via FUT2-mediated α-1,2-fucosylation.

Objective: Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms.

Activation of GPR81 by lactate drives tumour-induced cachexia.

Cachexia affects 50-80% of patients with cancer and accounts for 20% of cancer-related death, but the underlying mechanism driving cachexia remains elusive. Here we show that circulating lactate levels positively correlate with the degree of body weight loss in male and female patients suffering from cancer cachexia, as well as in clinically relevant mouse models. Lactate infusion per se is sufficient to trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner.

Intestinal SURF4 is essential for apolipoprotein transport and lipoprotein secretion.

Objective: Lipoprotein assembly and secretion in the small intestine are critical for dietary fat absorption. Surfeit locus protein 4 (SURF4) serves as a cargo receptor, facilitating the cellular transport of multiple proteins and mediating hepatic lipid secretion in vivo. However, its involvement in intestinal lipid secretion is not fully understood.

E3 ligase MG53 suppresses tumor growth by degrading cyclin D1.

Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival.

Blocking IL-6 signaling improves glucose tolerance via SLC39A5-mediated suppression of glucagon secretion.

Background And Aims: Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood.

Single-cell analysis reveals an Angpt4-initiated EPDC-EC-CM cellular coordination cascade during heart regeneration.

Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process.

Targeting ANGPTL3 by GalNAc-conjugated siRNA lowers blood lipids with long-lasting and potent efficacy in mice and monkeys.

Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipoproteins by inhibiting both lipoprotein and endothelial lipases. It has been intensively investigated as a drug target for the treatment of dyslipidemia. In the present study, a modified small interfering RNA (siRNA) conjugated with GalNAc was characterized by and studies for its effect on silencing, the reduction of plasma triglycerides (TGs), and cholesterol levels in disease models.

Blocking MG53 Phosphorylation Protects Diabetic Heart From Ischemic Injury.

Background: As an integral component of cell membrane repair machinery, MG53 (mitsugumin 53) is important for cardioprotection induced by ischemia preconditioning and postconditioning. However, it also impairs insulin signaling via its E3 ligase activity-mediated ubiquitination-dependent degradation of IR (insulin receptor) and IRS1 (insulin receptor substrate 1) and its myokine function-induced allosteric blockage of IR. Here, we sought to develop MG53 into a cardioprotection therapy by separating its detrimental metabolic effects from beneficial actions.

Dusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction.

Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction.

Cryo-EM structure of human MG53 homodimer.

MG53 is a tripartite motif (TRIM) family E3 ligase and plays important biological functions. Here we present the cryo-EM structure of human MG53, showing that MG53 is a homodimer consisting of a 'body' and two 'wings'. Intermolecular interactions are mainly distributed in the 'body' which is relatively stable, while two 'wings' are more dynamic.

Vitamin B and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation.

Background & Aims: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B (B) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH.

Methods: We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates.

Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth.

Background: Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac I/R injury. CaMKII (Ca/calmodulin-dependent kinase II) plays a pivotal role in the pathogenesis of severe heart conditions, including I/R injury.

Targeting CaMKII-δ9 Ameliorates Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Inflammation.

Background: CaMKII (Ca/calmodulin-dependent kinase II) plays a central role in cardiac ischemia/reperfusion (I/R) injury-an important therapeutic target for ischemic heart disease. In the heart, CaMKII-δ is the predominant isoform and further alternatively spliced into 11 variants. In humans, CaMKII-δ9 and CaMKII-δ3, the major cardiac splice variants, inversely regulate cardiomyocyte viability with the former pro-death and the latter pro-survival.

MG53 E3 Ligase-Dead Mutant Protects Diabetic Hearts From Acute Ischemic/Reperfusion Injury and Ameliorates Diet-Induced Cardiometabolic Damage.

Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading causes of death, highlighting a major unmet medical need. Over the past decade, mitsugumin 53 (MG53), also called TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity, which mediates metabolic disorders. Here, we show that an E3 ligase-dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic adverse effects.

Protocol for cell preparation and gene delivery in HEK293T and C2C12 cells.

Exogenous overexpression of target genes in both general and specific cell types is important for mechanistic studies of gene function. Here, we provide a step-by-step protocol for cell culture, plasmid transfection in HEK293T, and adenoviral infection in C2C12 cells for gene overexpression using as an example. This protocol enables sufficient and efficient gene expression for the downstream functional analysis.

Evaluation of AMPK activity in mice by measuring activator-induced glucose uptake.

The AMP-activated protein kinase (AMPK) is a principal nutrient sensor and a master regulator of cellular energy homeostasis. Once activated, AMPK induces glucose uptake, which leads to a transient decrease in blood glucose level and can be used as an indicator of AMPK activity. Here, we present a protocol accessing AMPK activity in mice by measuring glucose uptake induced by AMPK activators, MK8722 and A769662.

Functional and Adaptive Significance of Promoter Mutations That Affect Divergent Myocardial Expressions of TRIM72 in Primates.

Cis-regulatory elements play important roles in tissue-specific gene expression and in the evolution of various phenotypes, and mutations in promoters and enhancers may be responsible for adaptations of species to environments. TRIM72 is a highly conserved protein that is involved in energy metabolism. Its expression in the heart varies considerably in primates, with high levels of expression in Old World monkeys and near absence in hominids.

Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53.

As a master regulator of metabolism, AMP-activated protein kinase (AMPK) is activated upon energy and glucose shortage but suppressed upon overnutrition. Exaggerated negative regulation of AMPK signaling by nutrient overload plays a crucial role in metabolic diseases. However, the mechanism underlying the negative regulation is poorly understood.

Heterodimerization With 5-HTR Is Indispensable for βAR-Mediated Cardioprotection.

Rationale: The β-adrenoceptor (β-AR), a prototypical GPCR (G protein-coupled receptor), couples to both G and G proteins. Stimulation of the β-AR is beneficial to humans and animals with heart failure presumably because it activates the downstream G-PI3K-Akt cell survival pathway. Cardiac β-AR signaling can be regulated by crosstalk or heterodimerization with other GPCRs, but the physiological and pathophysiological significance of this type of regulation has not been sufficiently demonstrated.

Cardiac Ischemic Preconditioning Promotes MG53 Secretion Through HO-Activated Protein Kinase C-δ Signaling.

Background: Ischemic heart disease is the leading cause of morbidity and mortality worldwide. Ischemic preconditioning (IPC) is the most powerful intrinsic protection against cardiac ischemia/reperfusion injury. Previous studies have shown that a multifunctional TRIM family protein, MG53 (mitsugumin 53; also called TRIM72), not only plays an essential role in IPC-mediated cardioprotection against ischemia/reperfusion injury but also ameliorates mechanical damage.

Renal Dysfunction and In-Hospital Outcomes in Patients With Acute Ischemic Stroke After Intravenous Thrombolytic Therapy.

Background The impact of estimated glomerular filtration rate (eGFR) on clinical short-term outcomes after stroke thrombolysis with tissue plasminogen activator remains controversial. Methods and Results We analyzed 18 320 ischemic stroke patients who received intravenous tissue plasminogen activator at participating hospitals in the Chinese Stroke Center Alliance between June 2015 and November 2017. Multivariate logistic regression models were used to evaluate associations between eGFR (<45, 45-59, 60-89, and ≥90 mL/min per 1.

CaMKII-δ9 promotes cardiomyopathy through disrupting UBE2T-dependent DNA repair.

Ca/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its δ isoform is predominant in the heart. Excessive CaMKII activation plays a pivotal role in the pathogenesis of severe heart conditions, including myocardial infarction, cardiomyopathy and heart failure. However, the identity of CaMKII splice variants and the mechanism(s) underlying CaMKII-mediated cardiac pathology remain elusive.