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Bhuvaneswari D, Riitvek B, Lakshmi BS. Multi Targeted Activity of Cocculus hirsutus through Modulation of DPP-IV and PTP-1B Leading to Enhancement of Glucose Uptake and Attenuation of Lipid Accumulation. Appl Biochem Biotechnol 2025; 197:2493-2507. [PMID: 39760988 DOI: 10.1007/s12010-024-05142-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/24/2024] [Indexed: 01/07/2025]
Abstract
Multi-targeted therapies are gaining attention in the management of multifactorial diseases due to their poly pharmacology, enhanced potency and reduced toxicity. Metabolic disorders like Type 2 diabetes mellitus (T2DM) and obesity necessitate multi-targeted therapy to improve insulin sensitivity, regulate glucose homeostasis and support weight loss. Medicinal plants rich in bioactive compounds exhibit multi-targetted action with minimal side effects. In the current study, Cocculus hirsutus methanol extract (CME) and its hydromethanolic fraction (HMF) were investigated for their multi-target potential. Significant inhibition of Dipeptidyl peptidase IV (DPP-IV), a key enzyme in glucose metabolism was observed due to CME (54%) and HMF (70%) at 10 µg/ml and 1 µg/ml respectively. Protein Tyrosine Phosphatase 1B (PTP-1B), involved in the regulation of insulin signalling, was also inhibited by CME (67%) and HMF (73%) at 10 µg/ml concentration. An increase in glucose uptake was observed due to CME (62% and 65%) and HMF (63% and 68%) in 3T3-L1 adipocytes and L6 myotubes at 100 ng/ml. Further, investigation of HMF showed a decrease in lipid accumulation by 63% at 1 µg/ml in 3T3-L1 cells. Interestingly, HMF improved insulin sensitivity by upregulating GLUT4 expression (p < 0.05) via the PI3K/AKT pathway in both 3T3-L1 adipocytes and L6 myotubes. An inhibition in lipid accumulation was also observed by suppression of Peroxisome proliferator-activated receptor γ (PPARγ) (p < 0.05), a key regulator of adipogenesis in 3T3-L1 adipocytes. Gas chromatography-mass spectrometry analysis of the HMF showed the major component to be 3-methylmannoside (26.52%).
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Affiliation(s)
- D Bhuvaneswari
- Tissue Culture and Drug Discovery Laboratory, Department of Biotechnology, Anna University, Chennai, 600 025, India
| | - B Riitvek
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA
| | - B S Lakshmi
- Tissue Culture and Drug Discovery Laboratory, Department of Biotechnology, Anna University, Chennai, 600 025, India.
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Rajala R, Griffin CT. A novel function for endothelial protease-activated receptors in modulating insulin receptor activity with implications for diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.21.644607. [PMID: 40196641 PMCID: PMC11974755 DOI: 10.1101/2025.03.21.644607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Thrombin, a serine protease with increased activity in diabetics, signals through protease-activated receptors 1 and 4 (PAR1/PAR4) on endothelial cells (ECs). While studying the roles of endothelial PAR1/4 in diabetic pathology, we found that mice with inducible deletion of both receptors on ECs ( Par1/4 iECko ) displayed increased insulin sensitivity and were protected against streptozotocin (STZ)-induced diabetes. Concordantly, we found that cultured primary ECs with PAR1/4 deficiency had increased basal activity/phosphorylation of the insulin receptor (IR) and insulin transcytosis. This elevated IR activity correlated with reduced activity of protein tyrosine phosphatase 1B (PTP1B), which is a negative regulator of IR activity. Lastly, Par1/4 iECko mice with additional deletion of one allele of the IR gene demonstrated restoration of diabetic phenotypes after STZ treatment, indicating that these phenotypes are driven by heightened IR activity. These findings establish a novel link between endothelial PAR signaling and IR regulation, underscoring the critical role of ECs in metabolic homeostasis and identifying a potential therapeutic target for diabetes. GRAPHICAL ABSTRACT
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Bennett AM, Tiganis T. Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics. Annu Rev Physiol 2025; 87:301-324. [PMID: 39531392 DOI: 10.1146/annurev-physiol-022724-105540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
The increased prevalence of chronic metabolic disorders, including obesity and type 2 diabetes and their associated comorbidities, are among the world's greatest health and economic challenges. Metabolic homeostasis involves a complex interplay between hormones that act on different tissues to elicit changes in the storage and utilization of energy. Such processes are mediated by tyrosine phosphorylation-dependent signaling, which is coordinated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Perturbations in the functions of PTPs can be instrumental in the pathophysiology of metabolic diseases. The goal of this review is to highlight key advances in our understanding of how PTPs control body weight and glucose metabolism, as well as their contributions to obesity and type 2 diabetes. The emerging appreciation of the integrated functions of PTPs in metabolism, coupled with significant advances in pharmaceutical strategies aimed at targeting this class of enzymes, marks the advent of a new frontier in combating metabolic disorders.
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Affiliation(s)
- Anton M Bennett
- Yale Center for Molecular and Systems Metabolism, New Haven, Connecticut, USA
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA;
| | - Tony Tiganis
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia;
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Congur I, Mingrone G, Guan K. Targeting endoplasmic reticulum stress as a potential therapeutic strategy for diabetic cardiomyopathy. Metabolism 2025; 162:156062. [PMID: 39515414 DOI: 10.1016/j.metabol.2024.156062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/02/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Endoplasmic reticulum (ER) is an essential organelle involved in vesicular transport, calcium handling, protein synthesis and folding, and lipid biosynthesis and metabolism. ER stress occurs when ER homeostasis is disrupted by the accumulation of unfolded and/or misfolded proteins in the ER lumen. Adaptive pathways of the unfolded protein response (UPR) are activated to maintain ER homeostasis. In obesity and type 2 diabetes mellitus (T2DM), accumulating data indicate that persistent ER stress due to maladaptive UPR interacts with insulin/leptin signaling, which may be the potential and central mechanistic link between obesity-/T2DM-induced metabolic dysregulation (chronic hyperglycemia, dyslipidemia and lipotoxicity in cardiomyocytes), insulin/leptin resistance and the development of diabetic cardiomyopathy (DiabCM). Meanwhile, these pathological conditions further exacerbate ER stress. However, their interrelationships and the underlying molecular mechanisms are not fully understood. A deeper understanding of ER stress-mediated pathways in DiabCM is needed to develop novel therapeutic strategies. The aim of this review is to discuss the crosstalk between ER stress and leptin/insulin signaling and their involvement in the development of DiabCM focusing on mitochondria-associated ER membranes and chronic inflammation. We also present the current direction of drug development and important considerations for translational research into targeting ER stress for the treatment of DiabCM.
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Affiliation(s)
- Irem Congur
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Germany
| | - Geltrude Mingrone
- Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, United Kingdom; Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Kaomei Guan
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Germany.
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Sakaguchi M. The role of insulin signaling with FOXO and FOXK transcription factors. Endocr J 2024; 71:939-944. [PMID: 38987195 PMCID: PMC11778369 DOI: 10.1507/endocrj.ej24-0205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 06/05/2024] [Indexed: 07/12/2024] Open
Abstract
Insulin is an essential hormone for animal activity and survival, and it controls the metabolic functions of the entire body. Throughout the evolution of metazoan animals and the development of their brains, a sustainable energy supply has been essential to overcoming the competition for survival under various environmental stresses. Managing energy for metabolism, preservation, and consumption inevitably involves high oxidative stress, causing tissue damage in various organs. In both mice and humans, excessive dietary intake can lead to insulin resistance in various organs, ultimately displaying metabolic syndrome and type 2 diabetes. Insulin signals require thorough regulation to maintain metabolism across diverse environments. Recent studies demonstrated that two types of forkhead-box family transcription factors, FOXOs and FOXKs, are related to the switching of insulin signals during fasting and feeding states. Insulin signaling plays a role in supporting higher activity during periods of sufficient food supply and in promoting survival during times of insufficient food supply. The insulin receptor depends on the tyrosine phosphatase feedback of insulin signaling to maintain adipocyte insulin responsiveness. α4, a regulatory subunit of protein phosphatase 2A (PP2A), has been shown to play a crucial role in modulating insulin signaling pathways by regulating the phosphorylation status of key proteins involved in these pathways. This short review summarizes the current understanding of the molecular mechanism related to the regulation of insulin signals.
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Affiliation(s)
- Masaji Sakaguchi
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Ryu B, Ponce-Zea JE, Mai VH, Lee M, Hyun Sung S, Won Chin Y, Keun Oh W. Inhibition of protein tyrosine phosphatase 1B by serratane triterpenes from Huperzia serrata and their molecular docking study. Bioorg Med Chem Lett 2024; 111:129904. [PMID: 39069105 DOI: 10.1016/j.bmcl.2024.129904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/23/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitory compounds from the natural resources, two new serratane triterpenes, 3-O-dihydro-p-coumaroyltohogenol (1) and 21-O-acetyltohogenol (2), along with four known serratane triterpenes (3-6), were isolated from the whole plant of Huperzia serrata. The chemical structures of compounds 1 and 2 were determined by NMR study, HRMS analysis, and chemical modification. All isolates were evaluated for their PTP1B inhibitory activities. Among the isolates, compounds 1, 3, 5 and 6 exhibit moderate inhibitory activities against PTP1B. Kinetic studies demonstrated that they are competitive inhibitors. Molecular docking studies support these experimental results by showing that compounds 1, 3, 5 and 6 interact with the active site of PTP1B, clarifying the structure-activity relationship. This study suggests that serratane triterpenes from H. serrata have potential as starting skeletons for anti-diabetes or anti-obesity agents.
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Affiliation(s)
- Byeol Ryu
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
| | - Jorge-Eduardo Ponce-Zea
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
| | - Van-Hieu Mai
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
| | - Mina Lee
- College of Pharmacy, Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungangno, Suncheon 57922, Jeonnam, Republic of Korea
| | - Sang Hyun Sung
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
| | - Young Won Chin
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
| | - Won Keun Oh
- Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
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Gallero S, Persson KW, Henríquez-Olguín C. Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species. FEBS Lett 2024; 598:2145-2159. [PMID: 38803005 DOI: 10.1002/1873-3468.14937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/10/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024]
Abstract
Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.
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Affiliation(s)
- Samantha Gallero
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
| | - Kaspar W Persson
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
| | - Carlos Henríquez-Olguín
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
- Exercise Science Laboratory, Faculty of Medicine, Universidad Finis Terrae, Santiago, Chile
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Sun Y, Dinenno FA, Tang P, Kontaridis MI. Protein tyrosine phosphatase 1B in metabolic and cardiovascular diseases: from mechanisms to therapeutics. Front Cardiovasc Med 2024; 11:1445739. [PMID: 39238503 PMCID: PMC11374623 DOI: 10.3389/fcvm.2024.1445739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/05/2024] [Indexed: 09/07/2024] Open
Abstract
Protein Tyrosine Phosphatase 1B (PTP1B) has emerged as a significant regulator of metabolic and cardiovascular disease. It is a non-transmembrane protein tyrosine phosphatase that negatively regulates multiple signaling pathways integral to the regulation of growth, survival, and differentiation of cells, including leptin and insulin signaling, which are critical for development of obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Given PTP1B's central role in glucose homeostasis, energy balance, and vascular function, targeted inhibition of PTP1B represents a promising strategy for treating these diseases. However, challenges, such as off-target effects, necessitate a focus on tissue-specific approaches, to maximize therapeutic benefits while minimizing adverse outcomes. In this review, we discuss molecular mechanisms by which PTP1B influences metabolic and cardiovascular functions, summarize the latest research on tissue-specific roles of PTP1B, and discuss the potential for PTP1B inhibitors as future therapeutic agents.
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Affiliation(s)
- Yan Sun
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY, United States
| | - Frank A Dinenno
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY, United States
| | - Peiyang Tang
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY, United States
| | - Maria I Kontaridis
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY, United States
- Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, United States
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States
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9
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Coronell-Tovar A, Pardo JP, Rodríguez-Romero A, Sosa-Peinado A, Vásquez-Bochm L, Cano-Sánchez P, Álvarez-Añorve LI, González-Andrade M. Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs. FEBS Lett 2024; 598:1811-1838. [PMID: 38724486 DOI: 10.1002/1873-3468.14901] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 08/13/2024]
Abstract
Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.
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Affiliation(s)
- Andrea Coronell-Tovar
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Juan P Pardo
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | | | - Alejandro Sosa-Peinado
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Luz Vásquez-Bochm
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Patricia Cano-Sánchez
- Instituto de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Laura Iliana Álvarez-Añorve
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Martin González-Andrade
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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Bauer I, Rimbach G, Cordeiro S, Bosy-Westphal A, Weghuber J, Ipharraguerre IR, Lüersen K. A comprehensive in-vitro/ in-vivo screening toolbox for the elucidation of glucose homeostasis modulating properties of plant extracts (from roots) and its bioactives. Front Pharmacol 2024; 15:1396292. [PMID: 38989154 PMCID: PMC11233739 DOI: 10.3389/fphar.2024.1396292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/10/2024] [Indexed: 07/12/2024] Open
Abstract
Plant extracts are increasingly recognized for their potential in modulating (postprandial) blood glucose levels. In this context, root extracts are of particular interest due to their high concentrations and often unique spectrum of plant bioactives. To identify new plant species with potential glucose-lowering activity, simple and robust methodologies are often required. For this narrative review, literature was sourced from scientific databases (primarily PubMed) in the period from June 2022 to January 2024. The regulatory targets of glucose homeostasis that could be modulated by bioactive plant compounds were used as search terms, either alone or in combination with the keyword "root extract". As a result, we present a comprehensive methodological toolbox for studying the glucose homeostasis modulating properties of plant extracts and its constituents. The described assays encompass in-vitro investigations involving enzyme inhibition (α-amylase, α-glucosidase, dipeptidyl peptidase 4), assessment of sodium-dependent glucose transporter 1 activity, and evaluation of glucose transporter 4 translocation. Furthermore, we describe a patch-clamp technique to assess the impact of extracts on KATP channels. While validating in-vitro findings in living organisms is imperative, we introduce two screenable in-vivo models (the hen's egg test and Drosophila melanogaster). Given that evaluation of the bioactivity of plant extracts in rodents and humans represents the current gold standard, we include approaches addressing this aspect. In summary, this review offers a systematic guide for screening plant extracts regarding their influence on key regulatory elements of glucose homeostasis, culminating in the assessment of their potential efficacy in-vivo. Moreover, application of the presented toolbox might contribute to further close the knowledge gap on the precise mechanisms of action of plant-derived compounds.
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Affiliation(s)
- Ilka Bauer
- Division of Food Sciences, Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
| | - Gerald Rimbach
- Division of Food Sciences, Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
| | - Sönke Cordeiro
- Institute of Physiology, University of Kiel, Kiel, Germany
| | - Anja Bosy-Westphal
- Division of Human Nutrition, Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
| | - Julian Weghuber
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Wels, Austria
- FFoQSI—Austrian Competence Centre for Feed and Food Quality, Safety & Innovation, Tulln, Austria
| | - Ignacio R. Ipharraguerre
- Division of Food Sciences, Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
| | - Kai Lüersen
- Division of Food Sciences, Institute of Human Nutrition and Food Science, University of Kiel, Kiel, Germany
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Messeha SS, Agarwal M, Gendy SG, Mehboob SB, Soliman KFA. The Anti-Obesogenic Effects of Muscadine Grapes through Ciliary Neurotrophic Factor Receptor (Cntfr) and Histamine Receptor H1 (Hrh1) Genes in 3T3-L1 Differentiated Mouse Cells. Nutrients 2024; 16:1817. [PMID: 38931172 PMCID: PMC11206641 DOI: 10.3390/nu16121817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Obesity and type 2 diabetes are prevalent metabolic diseases that have significant links to several chronic diseases, including cancer, diabetes, hypertension, and cardiovascular disease. Muscadine grape extracts have shown the potential to reduce adiposity and improve insulin sensitivity and glucose control. Thus, this study was designed to determine the potential of muscadine grape berries extract (Pineapple and Southern Home) for its antiobesity properties in 3T3-L1 cells as a model for obesity research. The current study's data indicated the total phenolic content (TPC) and 2,2-diphenyl-1-picrylhydraziyl (DPPH) activity were higher in cultivar (CV) Southern Home, meanwhile, elevated the total flavonoid content (TFC) in Pineapple. Both extracts were safe across the tested range (0-5 mg/mL). A noticeable reduction in lipid accumulation was also found in extract-treated cells. In preadipocytes and adipocytes, the tested extracts showed significant alterations in various genes involved in glucose homeostasis and obesity. The most remarkable findings of the current study are the upregulation of two genes, Cntfr (+712.715-fold) and Hrh1 (+270.11-fold) in CV Pineapple extract-treated adipocytes 3T3-L1 and the high fold increase in Ramp3 induced by both Pineapple and Southern Home in pre-adipose cells. Furthermore, the tested extracts showed a potential to alter the mRNA of various genes, including Zfp91, B2m, Nr3c1, Insr, Atrn, Il6ra, Hsp90ab1, Sort1, and Npy1r. In conclusion, the data generated from the current study suggested that the two extracts under investigation are considered potential candidates for controlling insulin levels and managing obesity.
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Affiliation(s)
- Samia S. Messeha
- College of Science and Technology, Florida A&M University, Tallahassee, FL 32307, USA;
- College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, New Pharmacy Building, 1415 ML King Blvd., Tallahassee, FL 32307, USA
| | - Meenakshi Agarwal
- Center for Viticulture & Small Fruit Research, Florida A&M University, Tallahassee, FL 32317, USA;
| | - Sherif G. Gendy
- School of Allied Health Sciences, Florida A&M University, Tallahassee, FL 32307, USA;
| | - Sheikh B. Mehboob
- Center for Viticulture & Small Fruit Research, Florida A&M University, Tallahassee, FL 32317, USA;
| | - Karam F. A. Soliman
- College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, New Pharmacy Building, 1415 ML King Blvd., Tallahassee, FL 32307, USA
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12
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Zhang Y, Liu H, Lv T, Xiao M, Gao G. Protein Tyrosine Phosphatase 1B Inhibitors of Pueraria lobata Based on the Spectrum-Effect Relationship by Q-Marker Selection. Molecules 2024; 29:2731. [PMID: 38930797 PMCID: PMC11207073 DOI: 10.3390/molecules29122731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/24/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Pueraria lobata (P. lobata), a traditional anti-diabetic medicine mainly composed of flavonoids and isoflavones, has a long history in diabetes treatment in China. However, the anti-diabetic active component is still unclear. Recently, protein tyrosine phosphatase 1B (PTP1B) has been a hot therapeutic target by negatively regulating insulin signaling pathways. In this study, the spectrum-effect relationship analysis method was first used to identify the active components of P. lobata that inhibit PTP1B. The fingerprints of 12 batches of samples were established using high-performance liquid chromatography (HPLC), and sixty common peaks were identified. Meanwhile, twelve components were identified by a comparison with the standards. The inhibition of PTP1B activity was studied in vitro by using the p-nitrophenol method, and the partial least squares discriminant analysis, grey relational analysis, bivariate correlation analysis, and cluster analysis were used to analyze the bioactive compounds in P. lobata. Peaks 6, 9 (glycitin), 11 (genistin), 12 (4'-methoxypuerarin), 25, 34, 35, 36, 53, and 59 were considered as potentially active substances that inhibit PTP1B. The in vitro PTP1B inhibitory activity was confirmed by glycitin, genistin, and 4'-methoxypuerarin. The IC50s of the three compounds were 10.56 ± 0.42 μg/mL, 16.46 ± 0.29 μg/mL, and 9.336 ± 0.56 μg/mL, respectively, indicating the obvious PTP1B inhibitory activity. In brief, we established an effective method to identify PTP1B enzyme inhibitors in P. lobata, which is helpful in clarifying the material basis of P. lobata on diabetes. Additionally, it is evident that the spectrum-effect relationship method serves as an efficient approach for identifying active compounds, and this study can also serve as a reference for screening bioactive constituents in traditional Chinese medicine.
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Affiliation(s)
- Yong Zhang
- School of Pharmacy, Jining Medical University, Rizhao 276826, China;
| | - Haipeng Liu
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; (H.L.); (T.L.); (M.X.)
| | - Tianci Lv
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; (H.L.); (T.L.); (M.X.)
| | - Mengqian Xiao
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; (H.L.); (T.L.); (M.X.)
| | - Guihua Gao
- School of Pharmacy, Jining Medical University, Rizhao 276826, China;
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Delibegović M, Dall'Angelo S, Dekeryte R. Protein tyrosine phosphatase 1B in metabolic diseases and drug development. Nat Rev Endocrinol 2024; 20:366-378. [PMID: 38519567 DOI: 10.1038/s41574-024-00965-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 03/25/2024]
Abstract
Protein tyrosine phosphatase 1B (PTP1B), a non-transmembrane phosphatase, has a major role in a variety of signalling pathways, including direct negative regulation of classic insulin and leptin signalling pathways, and is implicated in the pathogenesis of several cardiometabolic diseases and cancers. As such, PTP1B has been a therapeutic target for over two decades, with PTP1B inhibitors identified either from natural sources or developed throughout the years. Some of these inhibitors have reached phase I and/or II clinical trials in humans for the treatment of type 2 diabetes mellitus, obesity and/or metastatic breast cancer. In this Review, we summarize the cellular processes and regulation of PTP1B, discuss evidence from in vivo preclinical and human studies of the association between PTP1B and different disorders, and discuss outcomes of clinical trials. We outline challenges associated with the targeting of this phosphatase (which was, until the past few years, viewed as difficult to target), the current state of the field of PTP1B inhibitors (and dual phosphatase inhibitors) and future directions for manipulating the activity of this key metabolic enzyme.
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Affiliation(s)
- Mirela Delibegović
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK.
| | - Sergio Dall'Angelo
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK
| | - Ruta Dekeryte
- Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK
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14
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Ferreira V, Folgueira C, Montes-San Lorenzo Á, Rodríguez-López A, Gonzalez-Iglesias E, Zubiaur P, Abad-Santos F, Sabio G, Rada P, Valverde ÁM. Estrogens prevent the hypothalamus-periphery crosstalk induced by olanzapine intraperitoneal treatment in female mice: Effects on brown/beige adipose tissues and liver. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167227. [PMID: 38733774 DOI: 10.1016/j.bbadis.2024.167227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 04/19/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024]
Abstract
Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS). Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17β-estradiol (E2) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E2 prevented OLA-induced phospho-JNK in hypothalamic neurons. These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.
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Affiliation(s)
- Vítor Ferreira
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Cintia Folgueira
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Ángela Montes-San Lorenzo
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Andrea Rodríguez-López
- Clinical Pharmacology Department, School of Medicine, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain
| | - Eva Gonzalez-Iglesias
- Clinical Pharmacology Department, School of Medicine, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain
| | - Pablo Zubiaur
- Clinical Pharmacology Department, School of Medicine, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain
| | - Francisco Abad-Santos
- Clinical Pharmacology Department, School of Medicine, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Patricia Rada
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
| | - Ángela M Valverde
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
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15
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Schwartz L, Salamon K, Simoni A, Eichler T, Jackson AR, Murtha M, Becknell B, Kauffman A, Linn-Peirano S, Holdsworth N, Tyagi V, Tang H, Rust S, Cortado H, Zabbarova I, Kanai A, Spencer JD. Insulin receptor signaling engages bladder urothelial defenses that limit urinary tract infection. Cell Rep 2024; 43:114007. [PMID: 38517889 PMCID: PMC11094371 DOI: 10.1016/j.celrep.2024.114007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 02/10/2024] [Accepted: 03/11/2024] [Indexed: 03/24/2024] Open
Abstract
Urinary tract infections (UTIs) commonly afflict people with diabetes. To better understand the mechanisms that predispose diabetics to UTIs, we employ diabetic mouse models and altered insulin signaling to show that insulin receptor (IR) shapes UTI defenses. Our findings are validated in human biosamples. We report that diabetic mice have suppressed IR expression and are more susceptible to UTIs caused by uropathogenic Escherichia coli (UPEC). Systemic IR inhibition increases UPEC susceptibility, while IR activation reduces UTIs. Localized IR deletion in bladder urothelium promotes UTI by increasing barrier permeability and suppressing antimicrobial peptides. Mechanistically, IR deletion reduces nuclear factor κB (NF-κB)-dependent programming that co-regulates urothelial tight junction integrity and antimicrobial peptides. Exfoliated urothelial cells or urine samples from diabetic youths show suppressed expression of IR, barrier genes, and antimicrobial peptides. These observations demonstrate that urothelial insulin signaling has a role in UTI prevention and link IR to urothelial barrier maintenance and antimicrobial peptide expression.
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Affiliation(s)
- Laura Schwartz
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children's, Columbus, OH 43205, USA
| | - Kristin Salamon
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Aaron Simoni
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Tad Eichler
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Ashley R Jackson
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children's, Columbus, OH 43205, USA
| | - Matthew Murtha
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Brian Becknell
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children's, Columbus, OH 43205, USA
| | - Andrew Kauffman
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA; Tulane University, New Orleans, LA 70118, USA
| | - Sarah Linn-Peirano
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA; Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, OH 43210, USA
| | - Natalie Holdsworth
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA; Ohio University Heritage College of Osteopathic Medicine, Athens, OH 45701, USA
| | - Vidhi Tyagi
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Hancong Tang
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Steve Rust
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Hanna Cortado
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA
| | - Irina Zabbarova
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Anthony Kanai
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - John David Spencer
- The Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH 43205, USA; Division of Nephrology and Hypertension, Nationwide Children's, Columbus, OH 43205, USA.
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16
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Perez-Quintero LA, Abidin BM, Tremblay ML. Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP. Front Med (Lausanne) 2024; 11:1364778. [PMID: 38707187 PMCID: PMC11066278 DOI: 10.3389/fmed.2024.1364778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/27/2024] [Indexed: 05/07/2024] Open
Abstract
In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.
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Affiliation(s)
- Luis Alberto Perez-Quintero
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Belma Melda Abidin
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Michel L. Tremblay
- Rosalind and Morris Goodman Cancer Institute, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
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Thiyagarajan G, Muthukumaran P, Prabhu D, Balasubramanyam M, Baddireddi LS. Syzygium cumini ameliorates high fat diet induced glucose intolerance, insulin resistance, weight gain, hepatic injury and nephrotoxicity through modulation of PTP1B and PPARγ signaling. ENVIRONMENTAL TOXICOLOGY 2024; 39:1086-1098. [PMID: 37815491 DOI: 10.1002/tox.23989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/04/2023] [Accepted: 09/21/2023] [Indexed: 10/11/2023]
Abstract
Metabolic disorders are majorly associated with insulin resistance and an impaired glucose tolerance. Since, many of the currently available drugs exhibit adverse effects and are resistant to therapies, natural products are a promising alternate in the alleviation of complex metabolic disorders. In the current study, Syzygium cumini methanolic extract (SCE) was investigated for its anti-diabetic and anti-adipogenic potential using C57BL/6 mice fed on high fat diet (HFD). The HFD fed obese mice were treated with 200 mg/kg SCE and compared with positive controls Metformin, Pioglitazone and Sodium Orthovanadate. The biometabolites in SCE were characterized using Fourier transform infrared and gas chromatography and mass spectroscopy. A reduction in blood glucose levels with improved insulin sensitivity and glucose tolerance was observed in SCE-treated HFD obese mice. Histopathological and biochemical investigations showed a reduction in hepatic injury and nephrotoxicity in SCE-administered HFD mice. Results showed inhibition of PTP1B and an upregulation of IRS1 and PKB-mediated signaling in skeletal muscle. A significant decrease in lipid markers such as TC, TG, LDL-c and VLDL-c levels were observed with increased HDL-c in SCE-treated HFD mice. A significant decrease in weight and adiposity was observed in SCE-administered HFD mice in comparison to controls. This decrease could be due to the partial agonism of PPARγ and an increased expression of adiponectin, an insulin sensitizer. Hence, the dual-modulatory effect of SCE, partly due to the presence of 26% Pyrogallol, could be useful in the management of diabetes and its associated maladies.
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Affiliation(s)
- Gopal Thiyagarajan
- Tissue Culture and Drug Discovery Laboratory, Centre for Food Technology, Department of Biotechnology, Anna University, Chennai, India
- Centre for Laboratory Animal Technology and Research, Sathyabama Institute of Science and Technology, Chennai, India
| | - Padmanaban Muthukumaran
- Tissue Culture and Drug Discovery Laboratory, Centre for Food Technology, Department of Biotechnology, Anna University, Chennai, India
| | - Durai Prabhu
- Department of Cell and Molecular Biology, Madras Diabetes Research Foundation, Chennai, India
| | | | - Lakshmi Subhadra Baddireddi
- Tissue Culture and Drug Discovery Laboratory, Centre for Food Technology, Department of Biotechnology, Anna University, Chennai, India
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18
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Datta R, Mukherjee D, Podolsky MJ, Yang CD, Alba DL, Singh S, Arnold TD, Koliwad S, Lizama CO, Atabai K. PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the β5 integrin. J Biol Chem 2024; 300:105631. [PMID: 38199575 PMCID: PMC10850974 DOI: 10.1016/j.jbc.2024.105631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 12/14/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Integrins are cell adhesion receptors that dimerize to mediate cell-cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvβ5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin β5 complexes with the insulin receptor beta (IRβ) in skeletal muscle, resulting in dephosphorylation of IRβ and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between β5 and IRβ impacts IRβ phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the β5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRβ resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The β5-PTP1B complex is recruited by MFGE8 to IRβ leading to termination of canonical insulin signaling. β5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and β5 in regulating insulin signaling.
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Affiliation(s)
- Ritwik Datta
- Cardiovascular Research Institute, University of California, San Francisco, California, USA
| | - Dibyanti Mukherjee
- Department of Pediatrics, University of California, San Francisco, California, USA
| | - Michael J Podolsky
- Cardiovascular Research Institute, University of California, San Francisco, California, USA
| | - Christopher D Yang
- Cardiovascular Research Institute, University of California, San Francisco, California, USA
| | - Diana L Alba
- Diabetes Center, University of California, San Francisco, California, USA; Division of Endocrinology, Department of Medicine, University of California, San Francisco, California, USA
| | - Sukhmani Singh
- Division of Endocrinology, Department of Medicine, University of California, San Francisco, California, USA
| | - Thomas D Arnold
- Department of Pediatrics, University of California, San Francisco, California, USA
| | - Suneil Koliwad
- Diabetes Center, University of California, San Francisco, California, USA; Division of Endocrinology, Department of Medicine, University of California, San Francisco, California, USA
| | - Carlos O Lizama
- Cardiovascular Research Institute, University of California, San Francisco, California, USA
| | - Kamran Atabai
- Cardiovascular Research Institute, University of California, San Francisco, California, USA; Diabetes Center, University of California, San Francisco, California, USA; Lung Biology Center, University of California, San Francisco, California, USA.
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Danao KR, Rokde VV, Nandurkar DM, Mahajan UN. Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment. Curr Diabetes Rev 2024; 21:e130224226925. [PMID: 38351692 DOI: 10.2174/0115733998280245240130075909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. METHODS A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. RESULTS As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. CONCLUSION Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.
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Affiliation(s)
- Kishor R Danao
- Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra 440037, India
| | - Vijayshri V Rokde
- Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra 440037, India
| | - Deweshri M Nandurkar
- Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra 440037, India
| | - Ujwala N Mahajan
- Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur, Maharashtra 440037, India
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Sakaguchi M. Adipose Tissue Plasticity and Insulin Signaling in the Pathogenesis of Type 2 Diabetes. Diabetol Int 2024; 15:28-33. [PMID: 38264220 PMCID: PMC10800324 DOI: 10.1007/s13340-023-00676-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/13/2023] [Indexed: 01/25/2024]
Abstract
Obesity is a major cause of various metabolic disorders, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases, in modern times. Fat tissue originally evolved as an organ to prepare for food shortages. However, when individuals consume excessive calories and engage in insufficient physical activity, it can lead to the excessive accumulation of lipids in white adipose tissue, potentially causing problems. In response to this excessive lipid accumulation extending to other tissues, insulin resistance is triggered in the body as a physiological response to prevent harmful effects. Additionally, in mammals, brown adipose tissue has evolved to generate energy and maintain body temperature. These inconspicuous defense mechanisms function coordinately to protect against systemic metabolic abnormalities affecting multiple organs. Understanding the dynamic nature of adipose tissues is now crucial for elucidating the details of the molecular abnormalities in obesity-associated metabolic diseases. This review outlines adipocyte plasticity and function with a focus on the physiological relevance and new pathways of insulin signaling.
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Affiliation(s)
- Masaji Sakaguchi
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuoku, Kumamoto 860-8556 Japan
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21
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Engin A. The Mechanism of Leptin Resistance in Obesity and Therapeutic Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:463-487. [PMID: 39287862 DOI: 10.1007/978-3-031-63657-8_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Leptin resistance is induced via leptin signaling blockade by chronic overstimulation of the leptin receptor and intracellular signaling defect or increased hypothalamic inflammation and suppressor of cytokine signaling (SOCS)-3 expression. High-fat diet triggers leptin resistance induced by at least two independent causes: first, the limited ability of peripheral leptin to activate hypothalamic signaling transducers and activators of transcription (STAT) signaling and secondly a signaling defect in leptin-responsive hypothalamic neurons. Central leptin resistance is dependent on decreased leptin transport efficiency across the blood brain barrier (BBB) rather than hypothalamic leptin insensitivity. Since the hypothalamic phosphorylated STAT3 (pSTAT3) represents a sensitive and specific readout of leptin receptor-B signaling, the assessment of pSTAT3 levels is the gold standard. Hypertriglyceridemia is one of important factors to inhibit the transport of leptin across BBB in obesity. Mismatch between high leptin and the amount of leptin receptor expression in obesity triggers brain leptin resistance via increasing hypothalamic inflammation and SOCS-3 expression. Therapeutic strategies that regulate the passage of leptin to the brain include the development of modifications in the structure of leptin analogues as well as the synthesis of new leptin receptor agonists with increased BBB permeability. In the hyperleptinemic state, polyethylene glycol (PEG)-modified leptin is unable to pass through the BBB. Peripheral histone deacetylase (HDAC) 6 inhibitor, tubastatin, and metformin increase central leptin sensitization. While add-on therapy with anagliptin, metformin and miglitol reduce leptin concentrations, the use of long-acting leptin analogs, and exendin-4 lead to the recovery of leptin sensitivity. Contouring surgery with fat removal, and bariatric surgery independently of the type of surgery performed provide significant improvement in leptin concentrations. Although approaches to correcting leptin resistance have shown some success, no clinically effective application has been developed to date. Due to the impairment of central and peripheral leptin signaling, as well as the extensive integration of leptin-sensitive metabolic pathways with other neurons, the effectiveness of methods used to eliminate leptin resistance is extremely limited.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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22
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Bhardwaj A, Antonelli M, Ueberheide B, Neel BG. Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.05.552118. [PMID: 37808759 PMCID: PMC10557583 DOI: 10.1101/2023.08.05.552118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ∼600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD -deleted HER2+ cell-derived xenografts phenocopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning "cold" tumors "hot". Our findings also reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders.
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Datta R, Podolsky MJ, Yang CD, Alba DL, Singh S, Koliwad S, Lizama CO, Atabai K. MFGE8 inhibits insulin signaling through PTP1B. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.30.542928. [PMID: 37398282 PMCID: PMC10312531 DOI: 10.1101/2023.05.30.542928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvβ5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, β5 complexes with the insulin receptor beta (IRβ) in skeletal muscle resulting in dephosphorylation of IRβ and reduction of insulin-stimulated glucose uptake. Here we investigate the mechanism by which the interaction between β5 and IRβ impacts IRβ phosphorylation status. We show that β5 blockade inhibits and MFGE8 promotes PTP1B binding to and dephosphorylation of IRβ resulting in reduced or increased insulin-stimulated myotube glucose uptake respectively. The β5-PTP1B complex is recruited by MFGE8 to IRβ leading to termination of canonical insulin signaling. β5 blockade enhances insulin-stimulated glucose uptake in wild type but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and β5 in regulating insulin signaling.
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Affiliation(s)
- Ritwik Datta
- Cardiovascular Research Institute, University of California, San Francisco, CA 94158
| | - Michael J Podolsky
- Cardiovascular Research Institute, University of California, San Francisco, CA 94158
| | - Christopher D Yang
- Cardiovascular Research Institute, University of California, San Francisco, CA 94158
| | - Diana L. Alba
- Diabetes Center, University of California, San Francisco, CA 94143
- Divisions of Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143
| | - Sukhmani Singh
- Divisions of Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143
| | - Suneil Koliwad
- Diabetes Center, University of California, San Francisco, CA 94143
- Divisions of Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143
| | - Carlos O Lizama
- Cardiovascular Research Institute, University of California, San Francisco, CA 94158
| | - Kamran Atabai
- Cardiovascular Research Institute, University of California, San Francisco, CA 94158
- Diabetes Center, University of California, San Francisco, CA 94143
- Lung Biology Center, University of California, San Francisco, CA 94158
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24
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Maccari R, Ottanà R. Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine. Int J Mol Sci 2023; 24:ijms24119621. [PMID: 37298571 DOI: 10.3390/ijms24119621] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is an enzyme crucially implicated in aberrations of various signaling pathways that underlie the development of different human pathologies, such as obesity, diabetes, cancer, and neurodegenerative disorders. Its inhibition can prevent these pathogenetic events, thus providing a useful tool for the discovery of novel therapeutic agents. The search for allosteric PTP1B inhibitors can represent a successful strategy to identify drug-like candidates by offering the opportunity to overcome some issues related to catalytic site-directed inhibitors, which have so far hampered the development of drugs targeting this enzyme. In this context, trodusquemine (MSI-1436), a natural aminosterol that acts as a non-competitive PTP1B inhibitor, appears to be a milestone. Initially discovered as a broad-spectrum antimicrobial agent, trodusquemine exhibited a variety of unexpected properties, ranging from antidiabetic and anti-obesity activities to effects useful to counteract cancer and neurodegeneration, which prompted its evaluation in several preclinical and clinical studies. In this review article, we provide an overview of the main findings regarding the activities and therapeutic potential of trodusquemine and their correlation with PTP1B inhibition. We also included some aminosterol analogues and related structure-activity relationships that could be useful for further studies aimed at the discovery of new allosteric PTP1B inhibitors.
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Affiliation(s)
- Rosanna Maccari
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Rosaria Ottanà
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
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25
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Patanè GT, Putaggio S, Tellone E, Barreca D, Ficarra S, Maffei C, Calderaro A, Laganà G. Catechins and Proanthocyanidins Involvement in Metabolic Syndrome. Int J Mol Sci 2023; 24:ijms24119228. [PMID: 37298181 DOI: 10.3390/ijms24119228] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Recent studies on natural antioxidant compounds have highlighted their potentiality against various pathological conditions. The present review aims to selectively evaluate the benefits of catechins and their polymeric structure on metabolic syndrome, a common disorder characterized by a cluster of three main risk factors: obesity, hypertension, and hyperglycemia. Patients with metabolic syndrome suffer chronic low inflammation state and oxidative stress both conditions effectively countered by flavanols and their polymers. The mechanism behind the activity of these molecules has been highlighted and correlated with the characteristic features present on their basic flavonoidic skelethon, as well as the efficient doses needed to perform their activity in both in vitro and in vivo studies. The amount of evidence provided in this review offers a starting point for flavanol dietary supplementation as a potential strategy to counteract several metabolic targets associated with metabolic syndrome and suggests a key role of albumin as flavanol-delivery system to the different target of action inside the organism.
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Affiliation(s)
- Giuseppe Tancredi Patanè
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Stefano Putaggio
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Ester Tellone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Davide Barreca
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Silvana Ficarra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Carlo Maffei
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Antonella Calderaro
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Giuseppina Laganà
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy
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26
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Ferreira V, Folgueira C, García-Altares M, Guillén M, Ruíz-Rosario M, DiNunzio G, Garcia-Martinez I, Alen R, Bookmeyer C, Jones JG, Cigudosa JC, López-Larrubia P, Correig-Blanchar X, Davis RJ, Sabio G, Rada P, Valverde ÁM. Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition. Redox Biol 2023; 63:102741. [PMID: 37230004 DOI: 10.1016/j.redox.2023.102741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/27/2023] Open
Abstract
Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.
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Affiliation(s)
- Vitor Ferreira
- Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Cintia Folgueira
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain
| | - María García-Altares
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain; Rovira I Virgili University, Department of Electronic Engineering, Tarragona, Spain
| | - Maria Guillén
- Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain
| | | | - Giada DiNunzio
- Center for Neurosciences and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | - Irma Garcia-Martinez
- Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Rosa Alen
- Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Christoph Bookmeyer
- Rovira I Virgili University, Department of Electronic Engineering, Tarragona, Spain
| | - John G Jones
- Center for Neurosciences and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal
| | | | - Pilar López-Larrubia
- Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain
| | - Xavier Correig-Blanchar
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain; Rovira I Virgili University, Department of Electronic Engineering, Tarragona, Spain; Institut D'Investigacio Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Roger J Davis
- Program in Molecular Medicine, Chan Medical School, University of Massachusetts, Worcester, USA
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain
| | - Patricia Rada
- Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
| | - Ángela M Valverde
- Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
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27
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Tonks NK. Protein Tyrosine Phosphatases: Mighty oaks from little acorns grow. IUBMB Life 2023; 75:337-352. [PMID: 36971473 PMCID: PMC10254075 DOI: 10.1002/iub.2716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 02/23/2023] [Indexed: 03/29/2023]
Abstract
In October 2020, we were finally able to gather for a celebration of Eddy Fischer's 100th birthday. As with many other events, COVID had disrupted and restricted preparations for the gathering, which ultimately was held via ZOOM. Nevertheless, it was a wonderful opportunity to share a day with Eddy, an exceptional scientist and true renaissance man, and to appreciate his stellar contributions to science. Eddy Fischer, together with Ed Krebs, was responsible for the discovery of reversible protein phosphorylation, which launched the entire field of signal transduction. The importance of this seminal work is now being felt throughout the biotechnology industry with the development of drugs that target protein kinases, which have transformed the treatment of a wide array of cancers. I was privileged to have worked with Eddy both as a postdoc and a junior faculty member, during which time we laid the foundations for our current understanding of the protein tyrosine phosphatase (PTP) family of enzymes and their importance as critical regulators of signal transduction. This tribute to Eddy is based upon the talk I presented at the event, giving a personal perspective on Eddy's influence on my career, our early research efforts together in this area, and how the field has developed since then.
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Affiliation(s)
- Nicholas K Tonks
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
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28
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Ali MY, Park SE, Seong SH, Zamponi GW, Jung HA, Choi JS. Ursonic acid from Artemisia montana exerts anti-diabetic effects through anti-glycating properties, and by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant C2C12 cells. Chem Biol Interact 2023; 376:110452. [PMID: 36933777 DOI: 10.1016/j.cbi.2023.110452] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Artemisia is one of the largest genera in the plant family Asteraceae and has long been used in traditional medicine for its antitussive, analgesic, antihypertensive, antitoxic, antiviral, antimalarial, and anti-inflammatory properties. However, the anti-diabetic activity of Artemisia montana has not been broadly studied. The goal of this study was to determine whether extracts of the aerial parts of A. montana and its main constituents inhibit protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase activities. We isolated nine compounds from A. montana including ursonic acid (UNA) and ursolic acid (ULA), which significantly inhibited PTP1B with IC50 values of 11.68 and 8.73 μM, respectively. In addition, UNA showed potent inhibitory activity against α-glucosidase (IC50 = 61.85 μM). Kinetic analysis of PTP1B and α-glucosidase inhibition revealed that UNA was a non-competitive inhibitor of both enzymes. Docking simulations of UNA demonstrated negative binding energies and close proximity to residues in the binding pockets of PTP1B and α-glucosidase. Molecular docking simulations between UNA and human serum albumin (HSA) revealed that UNA binds tightly to all three domains of HSA. Furthermore, UNA significantly inhibited fluorescent AGE formation (IC50 = 4.16 μM) in a glucose-fructose-induced HSA glycation model over the course of four weeks. Additionally, we investigated the molecular mechanisms underlying the anti-diabetic effects of UNA in insulin-resistant C2C12 skeletal muscle cells and discovered that UNA significantly increased glucose uptake and decreased PTP1B expression. Further, UNA increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. These findings clearly demonstrate that UNA from A. montana shows great potential for treatment of diabetes and its complications.
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Affiliation(s)
- Md Yousof Ali
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Se Eun Park
- Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea
| | - Su Hui Seong
- Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea; Division of Natural Products Research, Honam National Institute of Biological Resource, Mokpo, 58762, Republic of Korea
| | - Gerald W Zamponi
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Hyun Ah Jung
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju, 54896, Republic of Korea.
| | - Jae Sue Choi
- Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea.
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29
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Lopez DL, Casillas OE, Jaramillo HJ, Romero-Garcia T, Vazquez-Jimenez JG. AT1 receptor downregulation: A mechanism for improving glucose homeostasis. World J Diabetes 2023; 14:170-178. [PMID: 37035227 PMCID: PMC10075037 DOI: 10.4239/wjd.v14.i3.170] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/13/2023] [Accepted: 02/23/2023] [Indexed: 03/15/2023] Open
Abstract
There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-II enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1 receptor could have beneficial effects in treating metabolic syndrome and type 2 diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.
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Affiliation(s)
- Diana L Lopez
- Department of Internal Medicine, General Hospital of Mexicali, Mexicali 21000, Baja California, Mexico
| | - Oscar E Casillas
- Faculty of Medicine, Autonomous University of Baja California, Mexicali 21000, Baja California, Mexico
| | - Hiram J Jaramillo
- Department of Internal Medicine, General Hospital of Mexicali, Mexicali 21000, Baja California, Mexico
| | - Tatiana Romero-Garcia
- Faculty of Sports, Autonomous University of Baja California, Mexicali 21289, Baja California, Mexico
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Espinosa-Jiménez T, Cano A, Sánchez-López E, Olloquequi J, Folch J, Bulló M, Verdaguer E, Auladell C, Pont C, Muñoz-Torrero D, Parcerisas A, Camins A, Ettcheto M. A novel rhein-huprine hybrid ameliorates disease-modifying properties in preclinical mice model of Alzheimer's disease exacerbated with high fat diet. Cell Biosci 2023; 13:52. [PMID: 36895036 PMCID: PMC9999531 DOI: 10.1186/s13578-023-01000-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/28/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, β-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions. In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition. RESULTS Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Aβ42 peptide levels and plaque formation. Moreover, we found a decreased inflammatory response together with an increase in different synaptic proteins, such as drebrin 1 (DBN1) or synaptophysin, and in neurotrophic factors, especially in BDNF levels, correlated with a recovery in the number of dendritic spines, which resulted in memory improvement. Notably, the improvement observed in this model can be attributed directly to a protein regulation at central level, since no peripheral modification of those alterations induced by HFD consumption was observed. CONCLUSIONS Our results suggest that RHE-HUP could be a new candidate for the treatment of AD, even for individuals with high risk due to peripheral metabolic disturbances, given its multi-target profile which allows for the improvement of some of the most important hallmarks of the disease.
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Affiliation(s)
- Triana Espinosa-Jiménez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain.,Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Amanda Cano
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.,Ace Alzheimer Center Barcelona-International University of Catalunya (UIC), Barcelona, Spain.,Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, Barcelona, Spain
| | - Elena Sánchez-López
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.,Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, Barcelona, Spain.,Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, 08034, Barcelona, Spain
| | - Jordi Olloquequi
- Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.,Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Talca, Chile
| | - Jaume Folch
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Institut d'Investigació Sanitària Pere Virgili (IISPV), 43201, Reus, Spain.,Nutrition and Metabolic Health Research Group, Institute of Health Pere Virgili-IISPV, 43201, Reus, Spain
| | - Mònica Bulló
- Institut d'Investigació Sanitària Pere Virgili (IISPV), 43201, Reus, Spain.,Nutrition and Metabolic Health Research Group, Institute of Health Pere Virgili-IISPV, 43201, Reus, Spain.,CIBER Physiology of Obesity and Nutrition (CIBEROBN), Carlos III Health Institute, 28029, Madrid, Spain
| | - Ester Verdaguer
- Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
| | - Carme Auladell
- Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
| | - Caterina Pont
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Diego Muñoz-Torrero
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.,Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona, Spain
| | - Antoni Parcerisas
- Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain.,Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.,Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Miren Ettcheto
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain. .,Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain. .,Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain. .,Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII 27/31, 08028, Barcelona, Spain.
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Zhang C, Yang X, Meng X, Wu L, Liu X, Gao J, Liu S, Wu J, Huang D, Wang Z, Su X. Discovery of Novel PTP1B Inhibitors with Once-Weekly Therapeutic Potential for Type 2 Diabetes: Design, Synthesis, and In Vitro and In Vivo Investigations of BimBH3 Peptide Analogues. J Med Chem 2023; 66:3030-3044. [PMID: 36749220 DOI: 10.1021/acs.jmedchem.2c02003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Poor medication adherence in patients with type 2 diabetes mellitus has become one of the main causes of suboptimal glycemic control. Once-weekly drugs can markedly improve the convenience, adherence, and quality of life of T2DM patients; thus, they are clinically needed and preferred. PTP1B plays a negative role in both insulin and leptin signaling pathways, which makes it an important target for diabetes. Herein, we design and synthesize 35 analogues of core BimBH3 peptide via lipidation/acylation strategy based on our previous work and evaluate their PTP1B inhibitory activity, obtaining the primary structure-activity relationship. Five compounds with good PPT1B inhibitory activity, target selectivity, and significantly improved stability were selected for molecular docking study and searching candidate molecules with long-acting antidiabetic potential. The in vivo anti-T2DM evaluation validated the once-weekly therapeutic potential of analogues 19, 26, 27, 31, and 33, which were comparable with semaglutide and therefore presented as promising drug candidates.
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Affiliation(s)
- Chuanliang Zhang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.,School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Xianmin Yang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Xinjia Meng
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.,Marine Biomedical Research Institute, Ocean University of China, Qingdao 266071, China
| | - Xiaochun Liu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.,Marine Biomedical Research Institute, Ocean University of China, Qingdao 266071, China
| | - Jiangming Gao
- Marine Biomedical Research Institute, Ocean University of China, Qingdao 266071, China
| | - Shan Liu
- Marine Biomedical Research Institute, Ocean University of China, Qingdao 266071, China
| | - Juan Wu
- Marine Biomedical Research Institute, Ocean University of China, Qingdao 266071, China
| | - Dingmin Huang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Zhenwei Wang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Xianbin Su
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
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Choi M, Kwon H, Pak Y. Caveolin-2 in association with nuclear lamina controls adipocyte hypertrophy. FASEB J 2023; 37:e22745. [PMID: 36637913 DOI: 10.1096/fj.202201028rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 01/14/2023]
Abstract
Here, we identify that Caveolin-2 (Cav-2), an integral membrane protein, controls adipocyte hypertrophy in association with nuclear lamina. In the hypertrophy stage of adipogenesis, pY19-Cav-2 association with lamin A/C facilitated the disengagement of CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) from lamin A/C and repressed Cav-2 promoter at the nuclear periphery for epigenetic activation of Cav-2, and thereby promoted C/EBPα and PPARγ-induced adipocyte hypertrophy. Stable expression of Cav-2 was required and retained by phosphorylation, deubiquitination, and association with lamin A/C for the adipocyte hypertrophy. However, obese adipocytes exhibited augmented Cav-2 stability resulting from the up-regulation of lamin A/C over lamin B1, protein tyrosine phosphatase 1B (PTP1B), and nuclear deubiquitinating enzyme (DUB), Uchl5. Our findings show a novel epigenetic regulatory mechanism of adipocyte hypertrophy by Cav-2 at the nuclear periphery.
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Affiliation(s)
- Moonjeong Choi
- Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju, South Korea
| | - Hayeong Kwon
- Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju, South Korea
| | - Yunbae Pak
- Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju, South Korea
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33
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The PTP1B selective inhibitor MSI-1436 mitigates Tunicamycin-induced ER stress in human hepatocarcinoma cell line through XBP1 splicing modulation. PLoS One 2023; 18:e0278566. [PMID: 36649358 PMCID: PMC9844924 DOI: 10.1371/journal.pone.0278566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 11/18/2022] [Indexed: 01/18/2023] Open
Abstract
Protein tyrosine phosphatase PTP1B is considered as a key metabolic enzyme that has been reported to be associated with insulin resistance onset, and underlying cellular metabolic malfunctions, including ER stress and mitochondrial failure. In this study, effects of selective PTP1B inhibition using MSI-1436 on cellular apoptosis, oxidative stress, mitochondrial dysfunction and ER stress have been assessed using an in vitro model of Tunicamycin induced ER stress in HepG2 cell line. Inhibition of PTP1B using MSI-1436 significantly increased cell viability and reduced the number of apoptotic cells as well as the expression of key apoptosis initiators and effectors. MSI-1436 further mitigated ER stress, by downregulating the expression of IRE1, ATF6 and PERK transcripts, all being key ER stress sensors. Interestingly, MSI-1436 inhibited the XBP1 splicing, and thus its UPR-associated transcriptional activity. PTP1B inhibition further enabled to restore proper mitochondrial biogenesis, by improving transmembrane potential, and diminishing intracellular ROS while restoring of endogenous antioxidant enzymes genes expression. PTP1B inhibition using MSI-1436 could improve cellular apoptosis and metabolic integrity through the mitigation of ER and mitochondrial stress signalling pathways, and excessive ROS accumulation. This strategy may be useful for the treatment of metabolic disorders including IR, NAFLD and diabetes.
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Zhang Z, Shang ZP, Jiang Y, Qu ZX, Yang RY, Zhang J, Lin YX, Zhao F. Selective Inhibition of PTP1B by New Anthraquinone Glycosides from Knoxia valerianoides. JOURNAL OF NATURAL PRODUCTS 2022; 85:2836-2844. [PMID: 36399709 DOI: 10.1021/acs.jnatprod.2c00879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is highly validated as a therapeutic target for type 2 diabetes. However, active site-directed PTP1B inhibitors generally suffer from poor selectivity and bioavailability. Inspired by the identification of a unique anthraquinone-coumarin hybrid from Knoxia valerianoides exhibiting good specificity for PTP1B over the highly homologous T-cell protein tyrosine phosphatase (TCPTP), further chemical investigation of this plant species led to the isolation of nine new anthraquinone glycosides (1-9) and two known ones (10 and 11). Structures were characterized by a combination of spectroscopic analyses and chemical methods. All compounds showed PTP1B inhibitory activities with IC50 values ranging from 1.05 to 13.74 μM. Compounds 4 and 8 exhibited greater than 64-fold selectivity over TCPTP. Enzyme kinetic studies revealed that compounds 4 and 7 behaved as mixed-type inhibitors. Docking studies predicted similar binding modes of these compounds at the allosteric site positioned between helices α3 and α6.
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Affiliation(s)
- Zheng Zhang
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
| | - Zhi-Peng Shang
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
| | - Yan Jiang
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
| | - Zhao-Xia Qu
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
| | - Ren-Yong Yang
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
| | - Jing Zhang
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
| | - Ye-Xi Lin
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
| | - Feng Zhao
- The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, School of Pharmacy, Binzhou Medical University, Yantai 264003, People's Republic of China
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Zhu J, An Y, Wang X, Huang L, Kong W, Gao M, Wang J, Sun X, Zhu S, Xie Z. The natural product rotundic acid treats both aging and obesity by inhibiting PTP1B. LIFE MEDICINE 2022; 1:372-386. [PMID: 39872740 PMCID: PMC11749463 DOI: 10.1093/lifemedi/lnac044] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 10/20/2022] [Indexed: 01/30/2025]
Abstract
The occurrence of obesity is associated with age. But their interplay remains mysterious. Here, we discovered that rotundic acid (RA), a plant-derived pentacyclic triterpene, was a powerful agent for both anti-aging and treating obesity. Considering that obese individuals decrease the appetite-suppressing and energy-expenditure-enhancing functions of leptin leading to obesity, we found RA was a leptin sensitizer, evidenced by observations that RA enhanced the leptin sensitivity to normal diet-induced obese (DIO) mice, and had minimal or no use to normal lean mice, leptin receptor-deficient (db/db) mice, and leptin-deficient (ob/ob) mice. Simultaneously, RA significantly increased energy expenditure, BAT thermogenesis, and glucose metabolism in DIO mice, as the results of enhancing leptin sensitivity. Regarding mode of action, we demonstrated that RA is a noncompetitive inhibitor of leptin negative regulators protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP through interaction with their C-terminus, thus leading to weight loss through enhancing leptin sensitivity. Besides, we showed that deletion of yPTP1 in yeast completely abolished the lifespan extension effect of RA, celstrol, and withaferin A, while these compounds exhibited PTP1B inhibition activity. Furthermore, PTP1B knockdown extend lifespan in yeast and human cells, indicating PTP1B is an important factor regulating cellular aging.
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Affiliation(s)
- Jie Zhu
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yongpan An
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Xin Wang
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Liting Huang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Weikaixin Kong
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland
| | - Miaomiao Gao
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Jingxiang Wang
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Xinpei Sun
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Sujie Zhu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Zhengwei Xie
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
- Peking University - Yunnan Baiyao International Medical Research Center, Peking University Health Science Center, Beijing 100191, China
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Association between PTPN1 polymorphisms and obesity-related phenotypes in European adolescents: influence of physical activity. Pediatr Res 2022:10.1038/s41390-022-02377-1. [PMID: 36369476 DOI: 10.1038/s41390-022-02377-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/06/2022] [Accepted: 10/23/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND To study the associations of Protein Tyrosine Phosphatase-N1 (PTPN1) polymorphisms with obesity-related phenotypes in European adolescents, and the influence of physical activity on these relationships. METHODS Five polymorphisms of PTPN1 were genotyped in 1057 European adolescents (12-18 years old). We measured several phenotypes related to obesity, such as adiposity markers, and biochemical and clinical parameters. Physical activity was objectively measured by accelerometry. RESULTS The T, A, T, T and G alleles of the rs6067472, rs10485614, rs2143511, rs6020608 and rs968701 polymorphisms, respectively, were associated with lower levels of obesity-related phenotypes (i.e., body mass index, body fat percentage, hip circumference, fat mass index, systolic blood pressure and leptin) in European adolescents. In addition, the TATTG haplotype was associated with lower body fat percentage and fat mass index compared to the AACCA haplotype. Finally, when physical activity levels were considered, alleles of the rs6067472, rs2143511, rs6020608 and rs968701 polymorphisms were only associated with lower adiposity in active adolescents. CONCLUSIONS PTPN1 polymorphisms were associated with adiposity in European adolescents. Specifically, alleles of these polymorphisms were associated with lower adiposity only in physically active adolescents. Therefore, meeting the recommendations of daily physical activity may reduce obesity risk by modulating the genetic predisposition to obesity. IMPACT Using gene-phenotype and gene*environment analyses, we detected associations between polymorphisms of the Protein Tyrosine Phosphatase-N1 (PTPN1) gene and obesity-related phenotypes, suggesting a mechanism that can be modulated by physical activity. This study shows that genetic variability of PTPN1 is associated with adiposity, while physical activity seems to modulate the genetic predisposition. This brings insights about the mechanisms by which physical activity positively influences obesity.
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Thareja S, Verma SK, Jain AK, Kumar M, Bhardwaj TR. Rational Design and Synthesis of Novel Biphenyl Thiazolidinedione Conjugates as Inhibitors of Protein Tyrosine Phosphatase 1B for the Management of Type 2 Diabetes. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Im ST, Kim HS, Jung WK, Lee SH. Ishophloroglucin A, a potent PTP1B inhibitor isolated from brown alga Ishige okamurae inhibits adipogenesis in 3T3-L1 adipocytes. Fitoterapia 2022; 163:105342. [PMID: 36330897 DOI: 10.1016/j.fitote.2022.105342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/23/2022] [Accepted: 10/23/2022] [Indexed: 11/28/2022]
Abstract
Ishophloroglucin A (IPA) is one of the most abundant and active compounds in Ishige okamurae and is known to be a potential therapeutic candidate for the improvement of metabolic diseases. However, IPA on the inhibitory effects of protein tyrosine phosphatase 1B (PTP1B) and adipogenesis have not been determined. In this study, we investigated the effects of IPA on the inhibition of PTP1B, the effects on adipogenesis, and its mechanisms of action in 3 T3-L1 adipocytes. The IC50 value of IPA against PTP1B was 0.43 μM, which evidenced the higher inhibition activity than that of ursolic acid, a known PTP1B inhibitor. For further insight, we predicted the 3D structure of PTP1B and used a docking algorithm to simulate the binding between PTP1B and IPA. Molecular docking studies revealed a high and stable binding affinity between IPA and PTP1B and indicated that the IPA could interacts with the amino acid residues located in a region to the active site of PTP1B. Further studies showed that IPA concentrations between 6.25 μM and 25 μM dose-dependently attenuated adipogenesis, which was accompanied by a reduction in adipogenesis-related factors, including PPARγ, C/EBPα, SREBP-1c, and FABP4. Our findings suggested that IPA may be a promising natural compound for the treatment of obesity and related diseases.
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Affiliation(s)
- Seung Tae Im
- Department of Medical Science, Soonchunhyang University, Asan 31538, Republic of Korea
| | - Hyun-Soo Kim
- National Marine Biodiversity Institute of Korea, Seocheon 33662, Republic of Korea
| | - Won-Kyo Jung
- Major of Biomedical Engineering, Division of Smart Healthcare and New-senior Healthcare Innovation Center (BK21 Plus), Pukyong National University, Busan 48513, Republic of Korea; Research Center for Marine-Integrated Bionics Technology and Marine Integrated Biomedical Technology Center, Pukyong National University, Busan 48513, Republic of Korea.
| | - Seung-Hong Lee
- Department of Medical Science, Soonchunhyang University, Asan 31538, Republic of Korea; Department of Pharmaceutical Engineering, Soonchunhyang University, Asan 31538, Republic of Korea.
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39
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Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling. Nat Commun 2022; 13:6092. [PMID: 36241662 PMCID: PMC9568526 DOI: 10.1038/s41467-022-33842-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 10/05/2022] [Indexed: 02/03/2023] Open
Abstract
Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated serine/threonine phosphorylation despite a decrease in the protein phosphatase 2A (PP2A) levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor tyrosine phosphorylation. This occurs through decreased association of α4 with Y-box protein 1, resulting in the enhancement of the tyrosine phosphatase protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, adipocyte-specific knockout of α4 in male mice results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /Y-box protein 1(YBX1)-mediated pathway of insulin receptor signaling is involved in maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.
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40
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Ren X, Sun Y, Guo Q, Liu H, Jiang H, He X, Li X, Shi X, Xiu Z, Dong Y. Ameliorating Effect of the Total Flavonoids of Morus nigra L. on Prediabetic Mice Based on Regulation of Inflammation and Insulin Sensitization. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:12484-12501. [PMID: 36150176 DOI: 10.1021/acs.jafc.2c04970] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Prediabetes is a critical stage characterized by insulin resistance. Morus nigra L., an edible plant, is widely used in food and nutritive supplements and exhibits various pharmacological activities; however, its therapeutic effects and mechanisms on prediabetes have rarely been reported. In this research, the major components of total flavonoids of M. nigra L. (TFM) were identified, and TFM treatment was found to reduce prediabetes progressing to type 2 diabetes mellitus (T2DM) from 93.75 to 18.75%. The microbiota and next-generation sequencing combined with western blotting in vivo and in vitro demonstrated that TFM and its components ameliorated insulin resistance mediated by the suppressor of cytokine signaling and protein tyrosine phosphatase 1B, which benefited by maintaining intestinal homeostasis and restraining plasma levels of inflammatory factors. This study confirmed the T2DM prevention effect of TFM and revealed the underlying mechanism, setting the stage for the design of functional foods for diabetes prevention.
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Affiliation(s)
- Xinxiu Ren
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Yu Sun
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Qinfeng Guo
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Haodong Liu
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Hui Jiang
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Xiaoshi He
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Xia Li
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Xuan Shi
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Zhilong Xiu
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Yuesheng Dong
- School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China
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Protein tyrosine phosphatase 1B (PTP1B) as a potential therapeutic target for neurological disorders. Biomed Pharmacother 2022; 155:113709. [PMID: 36126456 DOI: 10.1016/j.biopha.2022.113709] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.
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Ureña-Vacas I, González-Burgos E, Divakar PK, Gómez-Serranillos MP. Lichen Depsidones with Biological Interest. PLANTA MEDICA 2022; 88:855-880. [PMID: 34034351 DOI: 10.1055/a-1482-6381] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Depsidones are some of the most abundant secondary metabolites produced by lichens. These compounds have aroused great pharmacological interest due to their activities as antioxidants, antimicrobial, and cytotoxic agents. Hence, this paper aims to provide up-to-date knowledge including an overview of the potential biological interest of lichen depsidones. So far, the most studied depsidones are fumarprotocetraric acid, lobaric acid, norstictic acid, physodic acid, salazinic acid, and stictic acid. Their pharmacological activities have been mainly investigated in in vitro studies and, to a lesser extent, in in vivo studies. No clinical trials have been performed yet. Depsidones are promising cytotoxic agents that act against different cell lines of animal and human origin. Moreover, these compounds have shown antimicrobial activity against both Gram-positive and Gram-negative bacteria and fungi, mainly Candida spp. Furthermore, depsidones have antioxidant properties as revealed in oxidative stress in vitro and in vivo models. Future research should be focused on further investigating the mechanism of action of depsidones and in evaluating new potential actions as well as other depsidones that have not been studied yet from a pharmacological perspective. Likewise, more in vivo studies are prerequisite, and clinical trials for the most promising depsidones are encouraged.
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Affiliation(s)
- Isabel Ureña-Vacas
- Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
| | - Elena González-Burgos
- Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
| | - Pradeep Kumar Divakar
- Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
| | - M Pilar Gómez-Serranillos
- Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
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Cellular and Molecular Mechanisms and Effects of Berberine on Obesity-Induced Inflammation. Biomedicines 2022; 10:biomedicines10071739. [PMID: 35885044 PMCID: PMC9312506 DOI: 10.3390/biomedicines10071739] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 11/30/2022] Open
Abstract
Obesity represents chronic low-grade inflammation that precipitates type 2 diabetes, cardiovascular disease, and cancer. Berberine (BBR) has been reported to exert anti-obesity and anti-inflammatory benefits. We aimed to demonstrate the underlying immune-modulating mechanisms of anti-obesity effects of BBR. First, we performed in silico study to identify therapeutic targets, describe potential pathways, and simulate BBR docking at M1 and M2 adipose tissue macrophages (ATMs), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, and C-X-C motif chemokine receptor 4 (CXCR4). Next, in vivo, we divided 20 C58BL/6 mice into four groups: normal chow, control (high fat diet (HFD)), HFD + BBR 100 mg/kg, and HFD + metformin (MET) 200 mg/kg. We evaluated body weight, organ weight, fat area in tissues, oral glucose and fat tolerance tests, HOMA-IR, serum lipids levels, population changes in ATMs, M1 and M2 subsets, and gene expression of TNF-α, CCL2, CCL3, CCL5, and CXCR4. BBR significantly reduced body weight, adipocyte size, fat deposition in the liver, HOMA-IR, triglycerides, free fatty acids, ATM infiltration, all assessed gene expression, and enhanced the CD206+ M2 ATMs population. In conclusion, BBR treats obesity and its associated metabolic dysfunctions, by modulating ATM recruitment and polarization via chemotaxis inhibition.
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Coulis G, Londhe AD, Sagabala RS, Shi Y, Labbé DP, Bergeron A, Sahadevan P, Nawaito SA, Sahmi F, Josse M, Vinette V, Guertin MC, Karsenty G, Tremblay ML, Tardif JC, Allen BG, Boivin B. Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy. Sci Signal 2022; 15:eabn6875. [PMID: 35439023 DOI: 10.1126/scisignal.abn6875] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393 and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy.
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Affiliation(s)
- Gérald Coulis
- Department of Nanobioscience, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12203, USA.,Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | - Avinash D Londhe
- Department of Nanobioscience, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12203, USA
| | - R Sudheer Sagabala
- Department of Nanobioscience, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12203, USA
| | - Yanfen Shi
- Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | - David P Labbé
- Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC H3G 1Y6, Canada.,Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.,Department of Surgery, Division of Urology, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Alexandre Bergeron
- Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.,Department of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Pramod Sahadevan
- Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Sherin A Nawaito
- Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.,Pharmacology and Physiology, Université de Montréal, Montréal, QC H3C 3J7, Canada.,Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Fatiha Sahmi
- Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
| | - Marie Josse
- Department of Nanobioscience, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12203, USA
| | - Valérie Vinette
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.,Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
| | | | - Gérard Karsenty
- Department of Genetics and Development, Columbia University, New York, NY 10032, USA
| | - Michel L Tremblay
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.,Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Jean-Claude Tardif
- Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.,Department of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Bruce G Allen
- Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.,Department of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.,Pharmacology and Physiology, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Benoit Boivin
- Department of Nanobioscience, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12203, USA.,Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.,Department of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
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45
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Rath P, Ranjan A, Ghosh A, Chauhan A, Gurnani M, Tuli HS, Habeeballah H, Alkhanani MF, Haque S, Dhama K, Verma NK, Jindal T. Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship. Molecules 2022; 27:molecules27072212. [PMID: 35408611 PMCID: PMC9000704 DOI: 10.3390/molecules27072212] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/10/2022] [Accepted: 03/17/2022] [Indexed: 11/17/2022] Open
Abstract
The increase in the number of cases of type 2 diabetes mellitus (T2DM) and the complications associated with the side effects of chemical/synthetic drugs have raised concerns about the safety of the drugs. Hence, there is an urgent need to explore and identify natural bioactive compounds as alternative drugs. Protein tyrosine phosphatase 1B (PTP1B) functions as a negative regulator and is therefore considered as one of the key protein targets modulating insulin signaling and insulin resistance. This article deals with the screening of a database of polyphenols against PTP1B activity for the identification of a potential inhibitor. The research plan had two clear objectives. Under first objective, we conducted a quantitative structure–activity relationship analysis of flavonoids with PTP1B that revealed the strongest correlation (R2 = 93.25%) between the number of aromatic bonds (naro) and inhibitory concentrations (IC50) of PTP1B. The second objective emphasized the binding potential of the selected polyphenols against the activity of PTP1B using molecular docking, molecular dynamic (MD) simulation and free energy estimation. Among all the polyphenols, silydianin, a flavonolignan, was identified as a lead compound that possesses drug-likeness properties, has a higher negative binding energy of −7.235 kcal/mol and a pKd value of 5.2. The free energy-based binding affinity (ΔG) was estimated to be −7.02 kcal/mol. MD simulation revealed the stability of interacting residues (Gly183, Arg221, Thr263 and Asp265). The results demonstrated that the identified polyphenol, silydianin, could act as a promising natural PTP1B inhibitor that can modulate the insulin resistance.
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Affiliation(s)
- Prangya Rath
- Amity Institute of Environmental Sciences, Amity University, Noida 201303, India; (P.R.); (M.G.)
| | - Anuj Ranjan
- Academy of Biology and Biotechnology, Southern Federal University, 344006 Rostov-on-Don, Russia
- Correspondence: (A.R.); (A.G.); Tel.: +91-999-090-7571 (A.R.); +91-967-862-9146 (A.G.)
| | - Arabinda Ghosh
- Microbiology Division, Department of Botany, Gauhati University, Guwahati 781014, India
- Correspondence: (A.R.); (A.G.); Tel.: +91-999-090-7571 (A.R.); +91-967-862-9146 (A.G.)
| | - Abhishek Chauhan
- Amity Institute of Environmental Toxicology Safety and Management, Amity University, Noida 201303, India; (A.C.); (T.J.)
| | - Manisha Gurnani
- Amity Institute of Environmental Sciences, Amity University, Noida 201303, India; (P.R.); (M.G.)
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India;
| | - Hamza Habeeballah
- Faculty of Applied Medical Sciences, King Abdulaziz University, Rabigh Branch, Rabigh 25732, Saudi Arabia;
| | - Mustfa F. Alkhanani
- Emergency Service Department, College of Applied Sciences, AlMaarefa University, Riyadh 11597, Saudi Arabia;
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia;
- Faculty of Medicine, Bursa Uludağ University Görükle Campus, Nilüfer 16059, Turkey
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, India;
| | - Naval Kumar Verma
- Homeopathy, Ministry of Ayush, Ayush Bhawan, B Block, GPO Complex INA, New Delhi 110023, India;
| | - Tanu Jindal
- Amity Institute of Environmental Toxicology Safety and Management, Amity University, Noida 201303, India; (A.C.); (T.J.)
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46
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ETS proto-oncogene 1 modulates PTP1B expression to participate in high glucose-mediated endothelial inflammation. Acta Biochim Biophys Sin (Shanghai) 2022; 54:565-573. [PMID: 35607953 PMCID: PMC9827757 DOI: 10.3724/abbs.2022021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Hyperglycemia-induced endothelial inflammation participates in the pathogenesis of cardiovascular complications in diabetics. Previous studies showed that protein tyrosine phosphatase 1B (PTP1B) and ETS proto-oncogene 1 (ets1) are involved in hyperglycemia-induced endothelial inflammation. In this study, we hypothesized that ets1 modulates PTP1B expression, thus playing a crucial role in hyperglycemia-induced vascular endothelial inflammation. Our results indicated that high glucose increases monocyte/endothelial adhesion, vascular cell adhesion molecule-1 (VCAM-1) expression and p65 phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose-mediated endothelial inflammation is reversed by PTP1B silencing. In addition, high glucose increases ets1 expression in HUVECs. silencing reverses high glucose-mediated endothelial inflammation. Furthermore, the effect of ets1 overexpression is similar to that of high glucose treatment, which is counteracted by si-PTP1B. The results from ChIP assays indicated that ets1 occupies the PTP1B promoter region. Ets1 overexpression enhances PTP1B promoter activity, which is disappeared after specific binding site mutation. experiments demonstrated that the expressions of VCAM-1, PTP1B, and ets1, as well as the phosphorylation of p65 are augmented in the aorta of diabetic rats. In conclusion, ets1 contributes to hyperglycemia-mediated endothelial inflammation via upregulation of PTP1B expression.
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47
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Friend or foe? Unraveling the complex roles of protein tyrosine phosphatases in cardiac disease and development. Cell Signal 2022; 93:110297. [PMID: 35259455 PMCID: PMC9038168 DOI: 10.1016/j.cellsig.2022.110297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 02/14/2022] [Accepted: 02/27/2022] [Indexed: 11/21/2022]
Abstract
Regulation of protein tyrosine phosphorylation is critical for most, if not all, fundamental cellular processes. However, we still do not fully understand the complex and tissue-specific roles of protein tyrosine phosphatases in the normal heart or in cardiac pathology. This review compares and contrasts the various roles of protein tyrosine phosphatases known to date in the context of cardiac disease and development. In particular, it will be considered how specific protein tyrosine phosphatases control cardiac hypertrophy and cardiomyocyte contractility, how protein tyrosine phosphatases contribute to or ameliorate injury induced by ischaemia / reperfusion or hypoxia / reoxygenation, and how protein tyrosine phosphatases are involved in normal heart development and congenital heart disease. This review delves into the newest developments and current challenges in the field, and highlights knowledge gaps and emerging opportunities for future research.
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48
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Chen XY, Wang C, Huang YZ, Zhang LL. Nonalcoholic fatty liver disease shows significant sex dimorphism. World J Clin Cases 2022; 10:1457-1472. [PMID: 35211584 PMCID: PMC8855265 DOI: 10.12998/wjcc.v10.i5.1457] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/02/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which has been renamed metabolic dysfunction-associated fatty liver disease, is a growing global medical problem. The incidence of NAFLD and its associated end-stage liver disease is increasing each year, and many research advancements have been achieved to date. This review focuses on the current knowledge of the sex differences in NAFLD and does not elaborate on areas without differences. Studies have revealed significant sex differences in the prevalence, influencing factors, pathophysiology, complications and therapies of NAFLD. Men have a higher incidence than women. Compared with women, men exhibit increased visceral fat deposition, are more susceptible to leptin resistance, lack estrogen receptors, and tend to synthesize fatty acids into fat storage. Male patients will experience more severe hepatic fibrosis and a higher incidence of liver cancer. However, once NAFLD occurs, women show a faster progression of liver fibrosis, higher levels of liver cell damage and inflammation and are less likely to undergo liver transplantation than men. In general, men have more risk factors and more severe pathophysiological reactions than women, whereas the development of NAFLD is faster in women, and the treatments for women are more limited than those for men. Thus, whether sex differences should be considered in the individualized prevention and treatment of NAFLD in the future is worth considering.
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Affiliation(s)
- Xing-Yu Chen
- The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
| | - Cong Wang
- The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
| | - Yi-Zhou Huang
- The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
| | - Li-Li Zhang
- The Second Affiliated Hospital, Chongqing Medical University, Chongqing 404100, China
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49
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Protein tyrosine phosphatases in skeletal development and diseases. Bone Res 2022; 10:10. [PMID: 35091552 PMCID: PMC8799702 DOI: 10.1038/s41413-021-00181-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/29/2021] [Accepted: 09/14/2021] [Indexed: 12/24/2022] Open
Abstract
Skeletal development and homeostasis in mammals are modulated by finely coordinated processes of migration, proliferation, differentiation, and death of skeletogenic cells originating from the mesoderm and neural crest. Numerous molecular mechanisms are involved in these regulatory processes, one of which is protein posttranslational modifications, particularly protein tyrosine phosphorylation (PYP). PYP occurs mainly through the action of protein tyrosine kinases (PTKs), modifying protein enzymatic activity, changing its cellular localization, and aiding in the assembly or disassembly of protein signaling complexes. Under physiological conditions, PYP is balanced by the coordinated action of PTKs and protein tyrosine phosphatases (PTPs). Dysregulation of PYP can cause genetic, metabolic, developmental, and oncogenic skeletal diseases. Although PYP is a reversible biochemical process, in contrast to PTKs, little is known about how this equilibrium is modulated by PTPs in the skeletal system. Whole-genome sequencing has revealed a large and diverse superfamily of PTP genes (over 100 members) in humans, which can be further divided into cysteine (Cys)-, aspartic acid (Asp)-, and histidine (His)-based PTPs. Here, we review current knowledge about the functions and regulatory mechanisms of 28 PTPs involved in skeletal development and diseases; 27 of them belong to class I and II Cys-based PTPs, and the other is an Asp-based PTP. Recent progress in analyzing animal models that harbor various mutations in these PTPs and future research directions are also discussed. Our literature review indicates that PTPs are as crucial as PTKs in supporting skeletal development and homeostasis.
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Yang XT, Li TZ, Geng CA, Liu P, Chen JJ. Synthesis and biological evaluation of (20 S,24 R)-epoxy-dammarane-3β,12β,25-triol derivatives as α-glucosidase and PTP1B inhibitors. Med Chem Res 2022; 31:350-367. [PMID: 35035203 PMCID: PMC8749348 DOI: 10.1007/s00044-021-02836-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/07/2021] [Indexed: 11/27/2022]
Abstract
The dammarane triterpenoid (20S,24R)-epoxy-dammarane-3β,12β,25-triol obtained from Cyclocarya paliurus in our previous study showed inhibitory activity on α-glucosidase in vitro with an inhibitory ratio of 32.2% at the concentration of 200 μM. In order to reveal the structure-activity relationships (SARs) and get more active compounds, 42 derivatives of (20S,24R)-epoxy-dammarane-3β,12β,25-triol were synthesized by chemical modification on the hydroxyls (C-3 and C-12), rings A and E, and assayed for their α-glucosidase and PTP1B inhibitory activities. Two compounds (8, 26) increased activity against α-glucosidase, and four compounds (8, 15, 26, 42) significantly inhibited PTP1B. It was noted that compounds 8 and 26 could inhibit both α-glucosidase and PTP1B as dual-target inhibitors with IC50 values of 489.8, 467.7 μM (α-glucosidase) and 319.7, 269.1 μM (PTP1B). Compound 26 was revealed to be a mix-type inhibitor on α-glucosidase and a noncompetitive-type inhibitor on PTP1B based on enzyme kinetic study. Furthermore, compound 42 could selectively inhibited PTP1B as a mix-type inhibitor with IC50 value of 134.9 μM, which was 2.5-fold higher than the positive control, suramin sodium (IC50 339.0 μM), but not inhibit α-glucosidase. ![]()
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Affiliation(s)
- Xiao-Tong Yang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences; Yunnan Key Laboratory of Natural Medicinal Chemistry, 650201 Kunming, People's Republic of China
| | - Tian-Ze Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences; Yunnan Key Laboratory of Natural Medicinal Chemistry, 650201 Kunming, People's Republic of China
| | - Chang-An Geng
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences; Yunnan Key Laboratory of Natural Medicinal Chemistry, 650201 Kunming, People's Republic of China
| | - Pei Liu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences; Yunnan Key Laboratory of Natural Medicinal Chemistry, 650201 Kunming, People's Republic of China
| | - Ji-Jun Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences; Yunnan Key Laboratory of Natural Medicinal Chemistry, 650201 Kunming, People's Republic of China.,University of Chinese Academy of Sciences, 100049 Beijing, People's Republic of China
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