Abstract P050: Novel Mechanism of Ser-496 ERK5 Phosphorylation and Association with p90RSK Is Critical for Regulating C Terminus of Hsc70-Interacting Protein (CHIP) Ubiquitin E3 Ligase Activity in Diabetes-Mediated Exacerbation of Cardiomyocyte Apoptosis and Left Ventricular Dysfunction After Myocardial Infarction

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Nhat-Tu Le ◽  
Yuichiro Takei ◽  
Chang-Hoon Woo ◽  
Tetsuro Shishido ◽  
Yan Lu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Active Form ◽  
E3 Ligase ◽  
Left Ventricular ◽  
Ang Ii ◽  
Lv Dysfunction ◽  
On Chip

Rationale: Cardiac dysfunction is accelerated in DM patients after MI. Previously, we reported the critical role of ERK5 and CHIP association on CHIP Ub E3 ligase activity, which inhibits inducible cAMP early repressor (ICER)-mediated apoptosis and left ventricle (LV) dysfunction after MI in DM (DM + MI). Yet the regulatory mechanism of ERK5-CHIP has not been established. Objective: Since we found that p90RSK activation was increased in DM heart, we investigated whether p90RSK activation may inhibit ERK5-mediated CHIP activation, and subsequent ICER induction and apoptosis. Methods and Results: The inhibition of p90RSK activation prevented the reduction of ERK5-CHIP binding, CHIP activity, as well as ICER induction and cardiac apoptosis both in vitro after angiotensin II (ang II) stimulation and in vivo after DM + MI. p90RSK and CHIP share a same binding site with ERK5 C-terminal domain (aa571–807), and overexpression of both p90RSK and ERK5 (aa571–807) fragment, but not kinase dead mutant of p90RSK, inhibited ERK5-CHIP association, suggesting the critical role of p90RSK activation on ERK5-CHIP interaction, and competitive nature of p90RSK and CHIP against ERK5 association. Furthermore. LC-MS/MS analysis identified ERK5-S496 as being directly phosphorylated by p90RSK, and ERK5 S496A mutant significantly impaired ang II-mediated inhibition of CHIP Ub ligase activity, suggesting the critical role of Ser-496 phoaphorylation of ERK5 on CHIP activity. Therefore, p90RSK activation is critical for both p90RSK-ERK5 association as well as ERK5-Ser496 phosphorylation, and following disruption of ERK5-CHIP interaction and subsequent inhibition of CHIP Ub ligase activity. The reduction of CHIP Ub ligase activity and LV dysfunction were accelerated both in cardio-specific ERK5 knock out and wild type p90RSK transgenic mice (WT-p90RSK-Tg). Furthermore, double transgenic mice of WT-p90RSK and constitutively active form of MEK5α (specific ERK5 activator) inhibited single WT-p90RSK-Tg-medaited reduction of CHIP Ub ligase activity, LV dysfunction, and improved mortality after MI. Conclusions: These data strongly suggested that p90RSK activation accelerated cardiac dysfunction and apoptosis after DM + MI via inhibiting ERK5-CHIP module.

scholarly journals Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH

2009 ◽  
Vol 297 (1) ◽  
pp. H153-H162 ◽  
Author(s):  
Sabrina Serpillon ◽  
Beverly C. Floyd ◽  
Rakhee S. Gupte ◽  
Shimran George ◽  
Mark Kozicky ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Rat Heart ◽  
Mitochondrial Respiratory Chain ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Posterior Wall Thickness ◽  
Patients With Diabetes ◽  
Protein Kinase C Inhibitor ◽  
Glucose 6 Phosphate Dehydrogenase

Increased oxidative stress is a known cause of cardiac dysfunction in animals and patients with diabetes, but the sources of reactive oxygen species [e.g., superoxide anion (O2−)] and the mechanisms underlying O2− production in diabetic hearts are not clearly understood. Our aim was to determine whether NADPH oxidase (Nox) is a source of O2− and whether glucose-6-phosphate dehydrogenase (G6PD)-derived NADPH plays a role in augmenting O2− generation in diabetes. We assessed cardiac function, Nox and G6PD activities, NADPH levels, and the activities of antioxidant enzymes in heart homogenates from young (9–11 wk old) Zucker lean and obese (fa/fa) rats. We found that myocardial G6PD activity was significantly higher in fa/fa than in lean rats, whereas superoxide dismutase and glutathione peroxidase activities were decreased ( P < 0.05). O2− levels were elevated (70–90%; P < 0.05) in the diabetic heart, and this elevation was blocked by the Nox inhibitor gp-91ds-tat (50 μM) or by the mitochondrial respiratory chain inhibitors antimycin (10 μM) and rotenone (50 μM). Inhibition of G6PD by 6-aminonicotinamide (5 mM) and dihydroepiandrosterone (100 μM) also reduced ( P < 0.05) O2− production. Notably, the activities of Nox and G6PD in the fa/fa rat heart were inhibited by chelerythrine, a protein kinase C inhibitor. Although we detected no changes in stroke volume, cardiac output, or ejection fraction, left ventricular diameter was slightly increased during diastole and systole, and left ventricular posterior wall thickness was decreased during systole ( P < 0.05) in Zucker fa/fa rats. Our findings suggest that in a model of severe hyperlipidema and hyperglycemia Nox-derived O2− generation in the myocardium is fueled by elevated levels of G6PD-derived NADPH. Similar mechanisms were found to activate O2− production and induce endothelial dysfunction in aorta. Thus G6PD may be a useful therapeutic target for treating the cardiovascular disease associated with type 2 diabetes, if second-generation drugs specifically reducing the activity of G6PD to near normal levels are developed.

Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Okumura ◽  
Yunzhe Bai ◽  
Meihua Jin ◽  
Sayaka Suzuki ◽  
Akiko Kuwae ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Proinflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

scholarly journals The SUMO E3 Ligase Activity of Pc2 Is Coordinated through a SUMO Interaction Motif

2010 ◽  
Vol 30 (9) ◽  
pp. 2193-2205 ◽  
Author(s):  
Shen-hsi Yang ◽  
Andrew D. Sharrocks
Keyword(s):  
Protein Modification ◽  
Binding Proteins ◽  
Noncovalent Interactions ◽  
Active Form ◽  
Embryonic Stem ◽  
E3 Ligase ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Sumo Conjugation

ABSTRACT Protein modification by SUMO conjugation has emerged to be an important regulatory event. Recently, the mechanisms through which SUMO elicits its effects on target proteins have been elucidated. One of these is the noncovalent association between SUMO and coregulatory proteins via SUMO interaction motifs (SIMs). We therefore searched for additional binding proteins to elucidate how SUMO acts as a signal to potentiate novel noncovalent interactions with SUMO-binding proteins. We identified an E3 ligase, Pc2, as a SUMO-binding protein with two functionally distinct SIMs. Here, we focus on the role of SIM2 and demonstrate that it is crucial for many of the documented Pc2 functions, which converge on determining its E3 ligase activity. One role of SUMO binding in this context is the subnuclear partitioning of the active form of Ubc9 (SUMO∼Ubc9) by Pc2. The significance of the SIM2-dependent functions of Pc2 is demonstrated in the control of the precise expression of lineage-specific genes during embryonic stem cell differentiation.

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

2018 ◽  
Vol 47 (5) ◽  
pp. 361-371 ◽  
Author(s):  
Qing Kuang ◽  
Ning Xue ◽  
Jing Chen ◽  
Ziyan Shen ◽  
Xiaomeng Cui ◽  
...  
Keyword(s):  
Renal Function ◽  
Hydrogen Sulfide ◽  
Cardiac Dysfunction ◽  
Mononuclear Cells ◽  
Troponin T ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Mrna Levels ◽  
Ventricular Ejection Fraction

Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H2S) level. Nevertheless, the role of H2S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H2S in patients with different stages of CKD, and to identify the role of H2S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H2S was measured with spectrophotometry. Sulfhemoglobin, the integration of H2S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H2S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H2S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H2S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H2S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H2S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative ­correlation between plasma H2S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H2S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H2S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD ­patients.

Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ellen E Gillis ◽  
Jennifer C Sullivan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Critical Role ◽  
High Dose ◽  
Ang Ii ◽  
Osmotic Minipump ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

Abstract 3474: Cardiac -Specific SOCS3 Dificient Mice Shows Resistance to Lipopolysaccharide-Induced Cardiac Dysfunction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Futamata Nobuyoshi ◽  
Hldeo Yasukawa ◽  
Toyoharu Ohba ◽  
Kazutoshi Mawatari ◽  
Daisuke Fukui ◽  
...  
Keyword(s):  
Western Blot ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Left Ventricular Ejection ◽  
Cytokine Signaling ◽  
Rt Pcr ◽  
Lv Dysfunction ◽  
Stat3 Signaling ◽  
Cardiomyocyte Survival

Background : Lypopolysaccharide (LPS)-induced left ventricular (LV) dysfunction is a well-established model for sepsis-induced acute heart failure. STAT3 signaling in the heart has been shown to promote cardiomyocyte survival during LPS-induced LV dysfunction. Little is known, however, about the role of negative regulation of STAT3 signaling during LPS-induced LV dysfunction. Suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of gp130 cytokine-induced STAT3 signaling that plays an important role in cardiomyocyte survival. In this study, we determined whether STAT3 signaling and its negative regulator SOCS3 would play a role in LPS-induced LV dysfunction. Methods and Results : We examined the activation of STAT3 and inductions of gp130 cytokines and SOCS3 in the wild-type (WT) mice hearts after LPS injection by western blot and real-time PCR (RT-PCR). RT-PCR revealed that gp130 cytokines were markedly increased after AMI. Western blot revealed that STAT3 was markedly phosphorylated and SOCS3 was induced in WT mice hearts after LPS injection. To investigate the role of STAT3 signaling and SOCS3 in LPS-induced LV dysfunction, we generated cardiac-specific SOCS3 knockout mice (SOCS3-CKO). Left ventricular ejection fraction (LVEF) of SOCS3-CKO mice was similar to that of WT mice at baseline (64.2 ± 6.1 vs. 62.4 ± 4.4%). LPS (30mg/kg) elicited a significant and robust reduction of LVEF in both SOCS3-CKO mice and WT mice 3 hr after LPS injection (18 ± 4.5 vs. 16 ± 5.2%, p <0.01). LVEF in WT mice was further reduced 6 hr after LPS injection. On the other hand, interestingly, LVEF was restored to the baseline in SOCS3-CKO mice 6 hr after LPS injection (10.4 ± 3.9 vs. 62.2 ± 8.1%, p <0.01). Also the duration and intensity of STAT3 phosphorylation after LPS injection was greater in SOCS3-CKO mice than WT mice. Furthermore, SOCS3-CKO mice showed greater survival rate than WT mice after LPS injection ( p <0.01). Conclusion : Our data show that the deletion of SOCS3 in cardiomyocytes prevents the LPS-induced LV dysfunction in mice, possibly by augmenting the STAT3-mediated gp130 cytokine signaling.

scholarly journals Advanced cardiac magnetic resonance imaging in takotsubo cardiomyopathy

2020 ◽  
Vol 93 (1115) ◽  
pp. 20200514
Author(s):  
Vineeta Ojha ◽  
Rishabh Khurana ◽  
Kartik P Ganga ◽  
Sanjeev Kumar
Keyword(s):  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Takotsubo Cardiomyopathy ◽  
Left Ventricular ◽  
Diagnostic Modality ◽  
Coronary Syndrome ◽  
Lv Dysfunction ◽  
Reversible Condition

Takotsubo cardiomyopathy (TC) is a reversible condition in which there is transient left ventricular (LV) dysfunction characterised most commonly by basal hyperkinesis and mid-apical LV ballooning and hypokinesia. It is said to be triggered by stress and mimics, such as acute coronary syndrome (ACS) clinically. Diagnosis is usually suspected on echocardiography due to the characteristic contraction pattern in a patient with symptoms and signs of ACS but normal coronary arteries on catheter angiography. Cardiac magnetic resonance (CMR), with its latest advancements, is the diagnostic modality of choice for diagnosis, prognosis and follow-up of patients. The advances in CMR (including T1, T2, ECV mapping and threshold-based late gadolinium enhancement (LGE) measurements have revolutionised the role of CMR in tissue characterisation and prognostication in patients with TC. In this review, we highlight the current role of CMR in management of TC and enumerate the CMR findings in TC as well the current advances in the field of CMR, which could help in prognosticating these patients.

scholarly journals Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 409 ◽  
Author(s):  
Manuela Antoniel ◽  
Francesco Traina ◽  
Luciano Merlini ◽  
Davide Andrenacci ◽  
Domenico Tigani ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Critical Role ◽  
Active Form ◽  
Congenital Muscular Dystrophy ◽  
Cell Polarization ◽  
Pcr Analysis ◽  
Matrix Remodeling ◽  
Collagen Vi

Mutations in collagen VI genes cause two major clinical myopathies, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), and the rarer myosclerosis myopathy. In addition to congenital muscle weakness, patients affected by collagen VI-related myopathies show axial and proximal joint contractures, and distal joint hypermobility, which suggest the involvement of tendon function. To gain further insight into the role of collagen VI in human tendon structure and function, we performed ultrastructural, biochemical, and RT-PCR analysis on tendon biopsies and on cell cultures derived from two patients affected with BM and UCMD. In vitro studies revealed striking alterations in the collagen VI network, associated with disruption of the collagen VI-NG2 (Collagen VI-neural/glial antigen 2) axis and defects in cell polarization and migration. The organization of extracellular matrix (ECM) components, as regards collagens I and XII, was also affected, along with an increase in the active form of metalloproteinase 2 (MMP2). In agreement with the in vitro alterations, tendon biopsies from collagen VI-related myopathy patients displayed striking changes in collagen fibril morphology and cell death. These data point to a critical role of collagen VI in tendon matrix organization and cell behavior. The remodeling of the tendon matrix may contribute to the muscle dysfunction observed in BM and UCMD patients.

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

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