• adropin
• apoptosis
• cardiovascular
• inflammation
• polycystic ovarian syndrome
• tirzepatide

• Animals
• Female
• Polycystic Ovary Syndrome/metabolism
• Polycystic Ovary Syndrome/drug therapy
• Proto-Oncogene Proteins c-akt/metabolism
• Rats
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Glycogen Synthase Kinase 3 beta/metabolism
• NF-kappa B/metabolism
• Signal Transduction/drug effects
• Disease Models, Animal
• Rats, Wistar
• Endoplasmic Reticulum Stress/drug effects
• Peptides/pharmacology
• Myocardium/metabolism
• Tirzepatide
• Blood Proteins

• Biological sciences
• Endocrinology
• Health sciences
• Natural sciences
• Physiology

• K01 DK105109 NIDDK NIH HHS
• P30 CA016058 NCI NIH HHS
• R01 HL138738 NHLBI NIH HHS
• T32 HL134616 NHLBI NIH HHS

• Male
• Humans
• Female
• Fluorodeoxyglucose F18
• Metabolic Syndrome/epidemiology
• Insulin Resistance
• Heart/diagnostic imaging
• Atherosclerosis
• Positron-Emission Tomography
• Radiopharmaceuticals

• Severo Ochoa Center of Excellence
• Spanish Ministry of Science and Innovation
• European Commission
• CNIC

• caveolin 3
• diabetes mellitus
• protein processing, posttranslational
• reperfusion injury

• Mice
• Animals
• Prediabetic State
• Caveolin 3/genetics
• Caveolin 3/metabolism
• Insulin Resistance
• Adiponectin/metabolism
• Adiponectin/pharmacology
• Chlorides/metabolism
• Chlorides/pharmacology
• Myocardial Reperfusion Injury/metabolism
• Myocytes, Cardiac/metabolism
• Heart Failure/etiology
• Heart Failure/metabolism

• R01 HL096686 NHLBI NIH HHS
• R01 HL158612 NHLBI NIH HHS
• R56 HL123404 NHLBI NIH HHS
• R01 HL157495 NHLBI NIH HHS
• R01 HL123404 NHLBI NIH HHS

Sporothrix schenckii modulates the expression of its cell wall proteins (CWPs) in response to reactive oxygen species (ROS) generated by the phagocytic cells of the human host, which allows it to evade and escape the immune system. In this study, we performed a comparative proteomic analysis of the CW of S. schenckii after exposure and nonexposure to H₂O₂. Several CWPs involved in CW remodeling and fungal pathogenesis that modulated their expression in response to this oxidizing agent were identified, as were a number of antioxidant enzymes and atypical CWPs, called moonlighting proteins, such as the Hsp70-5, lipase 1 (Lip1), enolase (Eno), and pyruvate kinase (Pk). Moreover, RT-qPCR assays demonstrated that the transcription of genes HSP70-5, LIP1, ENO, and PK is regulated in response to the oxidant. The results indicated that S. schenckii differentially expressed CWPs to confer protection against ROS upon this fungus. Furthermore, among these proteins, antioxidant enzymes and interestingly, moonlighting-like CWPs play a role in protecting the fungus from oxidative stress (OS), allowing it to infect human host cells.

• Body fat mass
• Garcinia
• insulin resistance
• metabolic syndrome
• obesity

Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations, including insulin resistance, visceral fat accumulation, and dyslipidemias, which increase the risk for developing cardiovascular disease. Metabolic syndrome is associated with augmented sympathetic tone, which could account for the etiology of pre-diabetic cardiomyopathy. This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustained β-adrenergic response in pre-diabetes, focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy. The research reviewed indicates that both protein kinase A and Ca²⁺/calmodulin-dependent protein kinase II play important roles in functional responses mediated by β₁-adrenoceptors; therefore, alterations in the expression or function of these kinases can be deleterious. This review also outlines recent information on the role of protein kinase A and Ca²⁺/calmodulin-dependent protein kinase II in abnormal Ca²⁺ handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.

• Ca²⁺/calmodulin-dependent protein kinase II
• Protein kinase A
• Metabolic syndrome
• Pre-diabetes
• Pre-diabetic cardiomyopathy
• β-Adrenoceptors

• ceramide
• insulin resistance
• sphingolipid
• sphingosine 1-phosphate
• β-cell

• Animals
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/enzymology
• Diabetes Mellitus, Type 2/pathology
• Humans
• Hypoglycemic Agents/pharmacology
• Hypoglycemic Agents/therapeutic use
• Insulin Resistance/physiology
• Insulin-Secreting Cells/drug effects
• Insulin-Secreting Cells/enzymology
• Insulin-Secreting Cells/pathology
• Phosphotransferases (Alcohol Group Acceptor)/metabolism

• Rats
• cafeteria diet.
• high-carbohydrate diet
• high-fat diet
• metabolic alterations
• reference value

• Animals
• Diet/adverse effects
• Humans
• Metabolic Syndrome/diagnosis
• Metabolic Syndrome/etiology
• Rats
• Rodentia

Hepatic insulin resistance is a chief pathogenic determinant in the development of type 2 diabetes, which is often associated with abnormal hepatic lipid regulation. Sphingolipids are a class of essential lipids in the liver, where sphingosine kinase 2 (SphK2) is a key enzyme in their catabolic pathway. However, roles of SphK2 and its related sphingolipids in hepatic insulin resistance remain elusive. Here we generate liver-specific Sphk2 knockout mice, demonstrating that SphK2 in the liver is essential for insulin sensitivity and glucose homeostasis. We also identify sphingosine as a bona fide endogenous inhibitor of hepatic insulin signaling. These findings provide physiological insights into SphK2 and sphingosine, which could be therapeutic targets for the management of insulin resistance and diabetes.

Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.

• ceramide
• hepatocyte
• insulin resistance
• sphingolipids
• type 2 diabetes

Diabetic cardiomyopathy (DCM) is a complication of diabetes that can cause damage to myocardial structure and function. Metformin (Met) is a widely used type 2 diabetes treatment drug that exerts cardioprotective effects through multiple pathways. Prokineticin 2 (PK2) is a small-molecule secreted protein that plays pivotal parts in cardiomyocyte survival and angiogenesis. However, the role of Met in regulating the PK2 signaling pathway in DCM remains unclear. This experiment explored the effects of Met on high glucose (HG)-induced injury through the PK2/PKR pathway in vivo and in vitro. Cardiomyocytes isolated from adult or AKT-knockout mice were treated with HG (33 mmol/L) and PK2 or AKT1/2 kinase inhibitor (AKT inhibitor). Heart contraction properties based on cell shortening were evaluated; these properties included the resting cell length, peak shortening (PS), maximum speed of shortening/relengthening (±dL/dt), time to 90% relengthening (TR₉₀), and time to peak shortening (TPS). Mice with streptozotocin-induced diabetes were treated with Met to evaluate cardiac function, myocardial structure, and the PK2/PKR and AKT/GSK3β pathways. Moreover, H9c2 cardiomyocytes were exposed to HG in the absence or presence of Met with or without the PK2 antagonist PKRA7 or the AKT inhibitor, and apoptotic proteins such as Bax and Bcl-2 and the PK2/PKR and AKT/GSK3β pathways were evaluated using western blot analysis. The prolongation of TR₉₀ and decreases in PS and ±dL/dt caused by HG were ameliorated by PK2 in cardiomyocytes, but the effects of PK2 were ameliorated or negated by the AKT inhibitor and in AKT-knockout mice. Diabetic mice showed metabolic abnormalities, aberrant myocardial enzyme levels, declines in myocardial systolic and diastolic function associated with myocardial fibrosis, and pronounced apoptosis, but these effects were greatly rescued by Met treatment. Moreover, PK2, PKR1, and PKR2 expression and p-AKT/AKT and p-GSK3β/GSK3β ratios were decreased in diabetic mice, and these decreases were attenuated by Met. Likewise, H9c2 cells exposed to HG showed reduced PK2/PKR expression and decreased p-AKT/AKT and p-GSK3β/GSK3β ratios, and these effects were nullified by Met. In addition, the effects of Met on cardiomyocytes exposed to HG were abolished after intervention with PKRA7 or the AKT inhibitor. These results suggest that Met can activate the PK2/PKR-mediated AKT/GSK3β pathway, thus improving cardiac function and alleviating apoptosis in DM mice.

• AKT/GSK3β signaling pathway
• apoptosis
• diabetic cardiomyopathy
• prokineticin 2
• prokineticin 2 receptors

Prokineticin 2 (PK2) is a small 8 kDa protein that participates in many physiological processes, such as angiogenesis, inflammation, and neurogenesis. This experiment investigated the effect of PK2 on high glucose/high palmitic acid-induced oxidative stress, apoptosis, and autophagy in cardiomyocytes and the AKT/GSK3β signalling pathway. H9c2 cells were exposed to normal and high concentrations (33 mM) of glucose and palmitic acid (150 μM) with or without PK2 (10 nM) for 48 h. Reactive oxygen species were detected using the fluorescent probes DCFH-DA and DHE. Changes in apoptosis were assessed using flow cytometry, and autophagosomes were detected using Ad-GFP-LC3. Apoptotic proteins, such as Cleaved Caspase3, Bax, and Bcl-2; autophagy proteins, including Beclin-1 and LC3B; and PK2/PKR/AKT/GSK3β signals were evaluated using western blotting. Cardiomyocytes exposed to high glucose/high palmitic acid exhibited increases in intracellular ROS, apoptosis, and autophagosomes, and these increases were robustly prevented by PK2. In addition, high glucose/high palmitic acid remarkably suppressed PK2, PKR1, and PKR2 expression and p-AKT/AKT and p-GSK3β/GSK3β ratios, and these effects were significantly prevented by PK2. Moreover, an AKT1/2 kinase inhibitor (AKT inhibitor, 10 μM) blocked the effects of PK2 on the changes in cardiomyocyte exposure to high glucose/high palmitic acid. These results suggest that PK2 attenuates high glucose/high palmitic acid-induced cardiomyocyte apoptosis by inhibiting oxidative stress and autophagosome accumulation and that this protective effect is most likely mediated by the AKT-related signalling pathway.