Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1

2019 ◽  
Vol 11 (488) ◽  
pp. eaau7116 ◽  
Author(s):  
Shiming Peng ◽  
Wen Xiao ◽  
Dapeng Ju ◽  
Baofa Sun ◽  
Nannan Hou ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Fasting Blood Glucose ◽  
Reduced Body ◽  
Forkhead Box ◽  
Obesity And Diabetes ◽  
Approved Drugs ◽  
Blood Glucose Concentrations ◽  
Precise Molecular Mechanism

Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 (FOXO1) mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis.

scholarly journals SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

2016 ◽  
Vol 56 (4) ◽  
pp. 301-309 ◽  
Author(s):  
Ping Li ◽  
Yan Hao ◽  
Feng-Hui Pan ◽  
Min Zhang ◽  
Jian-Qiang Ma ◽  
...  
Keyword(s):  
Small Intestine ◽  
Hba1c Level ◽  
Metabolic Disorders ◽  
Fasting Blood Glucose ◽  
Glucose Absorption ◽  
Favorable Effect ◽  
Rt Pcr ◽  
Treatment Of Diabetes

This study investigates the effectiveness and mechanisms of a serum- and glucocorticoid-inducible kinase 1 (SGK1) inhibitor in counteracting hyperglycemia. In an in vivo experiment, we demonstrated that after an 8-week treatment with an SGK1 inhibitor, the fasting blood glucose and HbA1c level significantly decreased in db/db mice. RT-PCR and western blot analyses revealed that intestinal SGK1 and sodium glucose co-transporter 1 (SGLT1) expression were enhanced in db/db mice. Treatment with an SGK1 inhibitor decreased excessive SGLT1 expression in the intestine of db/db mice. In vitro experiments with intestinal IEC-6 cells showed that the co-administration of an SGK1 inhibitor partly reversed the SGLT1 expression and glucose absorption that were induced by dexamethasone. In conclusion, this study revealed that the favorable effect of an SGK1 inhibitor on hyperglycemia is partly due to decreased glucose absorption through SGLT1 in the small intestine. These data collectively suggest that SGK1 may be a potent target for the treatment of diabetes and other metabolic disorders.

scholarly journals ­Myostain is Involved in GINSENOSIDE-Rb1-mediated anti-obesity

2021 ◽  
Author(s):  
Hong-Shi Li ◽  
Jiang-Ying Kuang ◽  
Gui-Jun Liu ◽  
Wei-Jie Wu ◽  
Xian-Lun Yin ◽  
...  
Keyword(s):  
Active Component ◽  
C2c12 Cells ◽  
Ginsenoside Rb1 ◽  
Obese Mice ◽  
Reduced Body ◽  
Obesity And Diabetes ◽  
The World ◽  
Treatment Of Obesity ◽  
Myoblast Cells

Abstract Obesity, as one of the major public health problems in the world, has attracted more and more attention. Rb1 is the most abundant active component of Panax ginseng and it has been reported to have benefit effects on obesity and diabetes. But the mechanisms of Rb1 in regulation of obesity are not very clear. In this study, by use of obese mice, we found that Rb1 not only reduced body weight but also decreased myostain (MSTN) expression,which plays a vital part in the regulation of obesity. In vitro, we found that Rb1 treatment also decreased MSTN expression in differentiated C2C12 cells (Myoblast cells) and 3T3-L1 cells (adipocytes). Fndc5, as the downstream of MSTN, was increased after Rb1 treatment. ConclusionsOur results showed that Rb1 may ameliorate obesity in part through MSTN/Fndc5 signaling pathway. Our study provides important experimental evidences for the treatment of obesity by Rb1.

scholarly journals Tr1 Cells as a Key Regulator for Maintaining Immune Homeostasis in Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun Song ◽  
Ning Wang ◽  
Lihua Chen ◽  
Liang Fang
Keyword(s):  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Immune Homeostasis ◽  
Forkhead Box P3 ◽  
Forkhead Box ◽  
Distinct Subset ◽  
Regulatory Capacity ◽  
Tr1 Cells

The immune system is composed of effectors and regulators. Type 1 regulatory T (Tr1) cells are classified as a distinct subset of T cells, and they secret high levels of IL-10 but lack the expression of the forkhead box P3 (Foxp3). Tr1 cells act as key regulators in the immune network, and play a central role in maintaining immune homeostasis. The regulatory capacity of Tr1 cells depends on many mechanisms, including secretion of suppressive cytokines, cell-cell contacts, cytotoxicity and metabolic regulation. A breakdown of Tr1-cell-mediated tolerance is closely linked with the pathogenesis of various diseases. Based on this observation, Tr1-cell therapy has emerged as a successful treatment option for a number of human diseases. In this review, we describe an overview of Tr1 cell identification, functions and related molecular mechanisms. We also discuss the current protocols to induce/expand Tr1 cells in vitro for clinical application, and summarize the recent progress of Tr1 cells in transplantation.

Plasminogen Activation in Diabetes Mellitus: Normalization of Blood Sugar Levels Improves Impaired Enzyme Kinetics In Vitro

1985 ◽  
Vol 54 (02) ◽  
pp. 413-414 ◽  
Author(s):  
Margarethe Geiger ◽  
Bernd R Binder
Keyword(s):  
Plasminogen Activator ◽  
Blood Sugar ◽  
Metabolic Disorders ◽  
Normal Values ◽  
Diabetic Patients ◽  
Type I ◽  
Plasminogen Activation ◽  
Lag Period ◽  
Sugar Levels

SummaryWe have demonstrated previously that fibrin enhanced plasmin formation by the vascular plasminogen activator was significantly impaired, when components isolated from the plasma of three uncontrolled diabetic patients (type I) were used to study plasminogen activation in vitro. In the present study it can be demonstrated that functional properties of the vascular plasminogen activators as well as of the plasminogens from the same three diabetic patients are significantly improved after normalization of blood sugar levels and improvement of HbAlc values. Most pronounced the Km of diabetic vascular plasminogen activator in the presence of fibrin returned to normal values, and for diabetic plasminogen the prolonged lag period until maximal plasmin formation occurred was shortened to almost control values. From these data we conclude that the observed abnormalities of in vitro fibrinolysis are not primarily associated with the diabetic disease, but might be secondary to metabolic disorders caused by diabetes.

Let-7e-5p Regulates GLP-1 Content and Basal Release From Enteroendocrine L Cells From DIO Male Mice

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Sandra Handgraaf ◽  
Rodolphe Dusaulcy ◽  
Florian Visentin ◽  
Jacques Philippe ◽  
Yvan Gosmain
Keyword(s):  
Compensatory Mechanism ◽  
L Cells ◽  
Low Fat Diet ◽  
Obesity And Diabetes ◽  
Basal Release ◽  
Glucagon Like Peptide 1 ◽  
Cell Transcriptome ◽  
Microarray Analyses

Abstract Characterization of enteroendocrine L cells in diabetes is critical for better understanding of the role of glucagon-like peptide-1 (GLP-1) in physiology and diabetes. We studied L-cell transcriptome changes including microRNA (miRNA) dysregulation in obesity and diabetes. We evaluated the regulation of miRNAs through microarray analyses on sorted enteroendocrine L cells from control and obese glucose-intolerant (I-HFD) and hyperglycemic (H-HFD) mice after 16 weeks of respectively low-fat diet (LFD) or high-fat diet (HFD) feeding. The identified altered miRNAs were studied in vitro using the mouse GLUTag cell line to investigate their regulation and potential biological functions. We identified that let-7e-5p, miR-126a-3p, and miR-125a-5p were differentially regulated in L cells of obese HFD mice compared with control LFD mice. While downregulation of let-7e-5p expression was observed in both I-HFD and H-HFD mice, levels of miR-126a-3p increased and of miR-125a-5p decreased significantly only in I-HFD mice compared with controls. Using miRNA inhibitors and mimics we observed that modulation of let-7e-5p expression affected specifically GLP-1 cellular content and basal release, whereas Gcg gene expression and acute GLP-1 secretion and cell proliferation were not affected. In addition, palmitate treatment resulted in a decrease of let-7e-5p expression along with an increase in GLP-1 content and release, suggesting that palmitate acts on GLP-1 through let-7e-5p. By contrast, modulation of miR-125a-5p and miR-126a-3p in the same conditions did not affect content or secretion of GLP-1. We conclude that decrease of let-7e-5p expression in response to palmitate may constitute a compensatory mechanism contributing to maintaining constant glycemia in obese mice.

scholarly journals Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer K. Dowling ◽  
Remsha Afzal ◽  
Linden J. Gearing ◽  
Mariana P. Cervantes-Silva ◽  
Stephanie Annett ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Mitochondrial Dynamics ◽  
Interleukin 10 ◽  
Metabolic Reprogramming ◽  
In Vivo Model ◽  
Macrophage Polarisation ◽  
Inflammatory Status ◽  
Inflammatory Macrophages

AbstractMitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Dasol Kim ◽  
Hui-Yun Hwang ◽  
Eun Sun Ji ◽  
Jin Young Kim ◽  
Jong Shin Yoo ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Elongation Factor ◽  
Dependent Manner ◽  
Diet Induced Obesity ◽  
Metabolic Dysregulation ◽  
Autophagy Induction ◽  
Transcription Factor Eb ◽  
Mitochondrial Elongation

AbstractDisorders of autophagy, a key regulator of cellular homeostasis, cause a number of human diseases. Due to the role of autophagy in metabolic dysregulation, there is a need to identify autophagy regulators as therapeutic targets. To address this need, we conducted an autophagy phenotype-based screen and identified the natural compound kaempferide (Kaem) as an autophagy enhancer. Kaem promoted autophagy through translocation of transcription factor EB (TFEB) without MTOR perturbation, suggesting it is safe for administration. Moreover, Kaem accelerated lipid droplet degradation in a lysosomal activity-dependent manner in vitro and ameliorated metabolic dysregulation in a diet-induced obesity mouse model. To elucidate the mechanism underlying Kaem’s biological activity, the target protein was identified via combined drug affinity responsive target stability and LC–MS/MS analyses. Kaem directly interacted with the mitochondrial elongation factor TUFM, and TUFM absence reversed Kaem-induced autophagy and lipid degradation. Kaem also induced mitochondrial reactive oxygen species (mtROS) to sequentially promote lysosomal Ca2+ efflux, TFEB translocation and autophagy induction, suggesting a role of TUFM in mtROS regulation. Collectively, these results demonstrate that Kaem is a potential therapeutic candidate/chemical tool for treating metabolic dysregulation and reveal a role for TUFM in autophagy for metabolic regulation with lipid overload.

scholarly journals Forkhead box B2 inhibits the malignant characteristics of the pancreatic cancer cell line Panc‐1 in vitro

2019 ◽  
Vol 24 (10) ◽  
pp. 674-681
Author(s):  
Hiroki Fukuchi ◽  
Yukinobu Hayashida ◽  
Kunio Inoue ◽  
Yoshifusa Sadamura
Keyword(s):  
Pancreatic Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Forkhead Box

The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling

2021 ◽  
Author(s):  
Junchao Wang ◽  
Wenjuan Xu ◽  
Rongjuan Wang ◽  
Rongrong Cheng ◽  
Zhengquan Tang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Metabolic Disorders ◽  
Therapeutic Effects ◽  
Akkermansia Muciniphila ◽  
Intestinal Mucus ◽  
Obesity And Diabetes

Akkermansia muciniphila is a probiotic inhabiting host intestinal mucus layers and displays evident easing or therapeutic effects on host enteritis and metabolic disorders such as obesity and diabetes. The outer...

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