Luteolin Attenuates Diabetic Myocardial Hypertrophy by Inhibiting Proteasome Activity.

INTRODUCTION: Luteolin is a flavonoid polyphenolic compound exerting broad pharmacological and medicinal properties. Diabetes-related obesity increases the total blood volume and cardiac output and may increase the myocardial hypertrophy progression. However, the mechanism of luteolin in diabetic myocardial hypertrophy remains uncertain. Therefore, this study aimed to evaluate whether luteolin improved diabetic cardiomyopathy (DCM) by inhibiting the proteasome activity. METHODS: Cardiomyopathy was induced in streptozotocin-treated diabetes mellitus (DM) and db/db mice. Luteolin (20 mg kg-1·day-1) was administrated via gavage for 12 weeks. In vitro, high glucose and high insulin (HGI, glucose at 25.5 mM and insulin at 0.1 µM) inducing primary neonatal rat cardiomyocytes (NRCMs) were treated with or without luteolin for 48 h. Echocardiography, reverse transcription quantitative polymerase chain reaction, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate. RESULTS: Luteolin administration significantly prevented the onset of cardiac hypertrophy, fibrosis, and dysfunction in type 1 DM (T1DM) and type 2 DM (T2DM). Compared with DCM mice, luteolin groups showed lower serum triglyceride and total cholesterol levels. Furthermore, luteolin attenuated HGI-induced myocardial hypertrophy and reduced atrial natriuretic factor mRNA level in NRCMs. Proteasome activities were inhibited by luteolin in vitro. Luteolin also reduces the proteasome subunit levels (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome, as well as proteasome-regulated particles (Rpt) 1 and Rpt4 levels of 19S proteasome. Furthermore, luteolin treatment increased protein kinase B (AKT) and GSK-3α/ß (inactivation of GSK-3) phosphorylation. The phosphorylation level of AMPK activity was also reversed after the treatment with luteolin in comparison with the HGI-treated group. CONCLUSION: This study indicates that luteolin protected against DCM in mice, including T1DM and T2DM, by upregulating phosphorylated protein AMPK and AKT/GSK-3 pathways while decreasing the proteasome activity. These findings suggest that luteolin may be a potential therapeutic agent for DCM.

Isoform-Specific Role of GSK-3 in High Fat Diet Induced Obesity and Glucose Intolerance.

Obesity-associated metabolic disorders are rising to pandemic proportions; hence, there is an urgent need to identify underlying molecular mechanisms. Glycogen synthase kinase-3 (GSK-3) signaling is highly implicated in metabolic diseases. Furthermore, GSK-3 expression and activity are increased in Type 2 diabetes patients. However, the isoform-specific role of GSK-3 in obesity and glucose intolerance is unclear. Pharmacological GSK-3 inhibitors are not isoform-specific, and tissue-specific genetic models are of limited value to predict the clinical outcome of systemic inhibiion. To overcome these limitations, we created novel mouse models of ROSA26CreERT2-driven, tamoxifen-inducible conditional deletion of GSK-3 that allowed us to delete the gene globally in an isoform-specific and temporal manner. Isoform-specific GSK-3 KOs and littermate controls were subjected to a 16-week high-fat diet (HFD) protocol. On an HFD, GSK-3α KO mice had a significantly lower body weight and modest improvement in glucose tolerance compared to their littermate controls. In contrast, GSK-3ß-deletion-mediated improved glucose tolerance was evident much earlier in the timeline and extended up to 12 weeks post-HFD. However, this protective effect weakened after chronic HFD (16 weeks) when GSK-3ß KO mice had a significantly higher body weight compared to controls. Importantly, GSK-3ß KO mice on a control diet maintained significant improvement in glucose tolerance even after 16 weeks. In summary, our novel mouse models allowed us to delineate the isoform-specific role of GSK-3 in obesity and glucose tolerance. From a translational perspective, our findings underscore the importance of maintaining a healthy weight in patients receiving lithium therapy, which is thought to work by GSK-3 inhibition mechanisms.

[Therapeutic effect of Baimai Ointment on peripheral sensitization of chronic inflammatory pain in mice].

Chronic inflammatory pain is mainly manifested by peripheral sensitization. Baimai Ointment(BMO), a classical Tibetan medicine for external use, has good clinical efficacy in the treatment of chronic inflammatory pain, while its pharmacodynamics and mechanism for relieving peripheral sensitization remain unclear. This study established an animal model of chronic inflammatory pain induced by complete Freund's adjuvant to explore the mechanism of BMO in the treatment of chronic inflammatory pain by behavioral test, side effect assessment, network analysis, and experimental verification. The pharmacodynamics experiment showed that BMO increased the thresholds of mechanical pain sensitivity and thermal radiation pain sensitivity of chronic inflammatory pain mice in a dose-dependent manner, and had inhibitory effect on foot swelling, inflammatory mediator, and the expression of transient receptor potential vanilloid-1(TRPV1) and transient receptor potential A1(TRPA1). The results of body weight monitoring, pain sensitivity threshold detection in normal mice, rotarod performance test, and forced swimming test showed that BMO had no obvious toxic or side effect. The network analysis of 51 candidate active molecules selected according to the efficacy of BMO, content of main components, and ADME parameters showed that the inhibitory effect of BMO on chronic inflammatory pain was associated with the core regulatory elements of tumor necrosis factor(TNF) and T cell receptor signaling pathways. BMO down-regulated the protein levels of mitogen-activated protein kinase 14(MAPK14), MAPK1, and prostaglandin-endoperoxide synthase 2(PTGS2), and up-regulated the phosphorylation le-vel of glycogen synthase kinase 3 beta(GSK3 B) in the plantar tissue of mice. In conclusion, BMO can effectively relieve peripheral sensitization of chronic inflammatory pain without inducing tolerance and obvious toxic and side effects. The relevant mechanism may be related to the regulation of BMO on core regulatory elements of TNF and T cell receptor signaling pathways in surrounding tissues.

The role of glycogen synthase kinase-3beta in schizophrenia.

Glycogen synthase kinase (GSK)-3beta is recognized as a ubiquitous multifunctional enzyme involved in the modulation of many aspects of neuronal function. Inhibitory control of GSK-3beta has been identified to be crucial for the phosphoinositide 3'-kinase (PI3K)-protein kinase B (Akt)-mediated cell survival. Several lines of evidence converge in implicating abnormal GSK-3beta activity in the pathogenesis of schizophrenia. Preclinical evidence showing that both typical and atypical antipsychotics can indirectly inhibit the activity of GSK-3beta, has pointed to GSK-3beta as a possible therapeutic target for schizophrenia. It is well known that GSK-3beta can be indirectly inhibited via regulation of several intracellular signaling cascades, including the canonical Wnt, Reelin and tyrosine kinase receptor (Trk)-PI3K-Akt. Recently, direct inhibition of GSK-3beta has emerged as a possible option in the pharmacotherapy of several neuropsychiatric disorders. There is, however, a number of issues that need to be considered regarding therapeutic utility of GSK-3beta inhibitors. This article reviews the evidence supporting the possible role of aberrant GSK-3beta in the pathogenesis of schizophrenia and thus suggesting GSK-3beta to be a potential therapeutic target for this disorder.