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Butanda-Nuñez A, Rodríguez-Cortés O, Ramos-Martínez E, Cerbón MA, Escobedo G, Chavarría A. Silybin restores glucose uptake after tumour necrosis factor-alpha and lipopolysaccharide stimulation in 3T3-L1 adipocytes. Adipocyte 2024; 13:2374062. [PMID: 38953241 PMCID: PMC11221471 DOI: 10.1080/21623945.2024.2374062] [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: 04/12/2023] [Accepted: 06/25/2024] [Indexed: 07/03/2024] Open
Abstract
Obesity is associated with a low-grade chronic inflammatory process characterized by higher circulating TNFα levels, thus contributing to insulin resistance. This study evaluated the effect of silybin, the main bioactive component of silymarin, which has anti-inflammatory properties, on TNFα levels and its impact on glucose uptake in the adipocyte cell line 3T3-L1 challenged with two different inflammatory stimuli, TNFα or lipopolysaccharide (LPS). Silybin's pre-treatment effect was evaluated in adipocytes pre-incubated with silybin (30 or 80 µM) before challenging with the inflammatory stimuli (TNFα or LPS). For the post-treatment effect, the adipocytes were first challenged with the inflammatory stimuli and then post-treated with silybin. After treatments, TNFα production, glucose uptake, and GLUT4 protein expression were determined. Both inflammatory stimuli increased TNFα secretion, diminished GLUT4 expression, and significantly decreased glucose uptake. Silybin 30 µM only reduced TNFα secretion after the LPS challenge. Silybin 80 µM as post-treatment or pre-treatment decreased TNFα levels, improving glucose uptake. However, glucose uptake enhancement induced by silybin did not depend on GLUT4 protein expression. These results show that silybin importantly reduced TNFα levels and upregulates glucose uptake, independently of GLUT4 protein expression.
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Affiliation(s)
- Alejandra Butanda-Nuñez
- Unidad de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Octavio Rodríguez-Cortés
- Laboratorio 103, SEPI, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Espiridión Ramos-Martínez
- Unidad de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Marco Antonio Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Galileo Escobedo
- Laboratorio de Proteómica y Metabolómica, Hospital General de México “Dr. Eduardo Liceaga”, Mexico City, Mexico
| | - Anahí Chavarría
- Unidad de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Wang Y, Rong X, Guan H, Ouyang F, Zhou X, Li F, Tan X, Li D. The Potential Effects of Isoleucine Restricted Diet on Cognitive Impairment in High-Fat-Induced Obese Mice via Gut Microbiota-Brain Axis. Mol Nutr Food Res 2023; 67:e2200767. [PMID: 37658490 DOI: 10.1002/mnfr.202200767] [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: 11/06/2022] [Revised: 05/15/2023] [Indexed: 09/03/2023]
Abstract
SCOPE Obesity induced by high-fat diet (HFD) can cause lipid metabolism disorders and cognitive impairment. Isoleucine restriction can effectively alleviate lipid metabolism disorders caused by HFD but the underlying mechanisms on cognition are unknown. METHODS AND RESULTS Thirty 3-month-old C57BL/6J mice are divided equally into the following groups: the control group, HFD group, and HFD Low Ile group (67% reduction in isoleucine in high fat feeds). Feeding for 11 weeks with behavioral testing, which shows that isoleucine restriction attenuates HFD-induced cognitive dysfunction. As observed by staining, isoleucine restriction inhibits HFD-induced neuronal damage and microglia activation. Furthermore, isoleucine restriction significantly increases the relative abundance of gut microbiota, decreases the proportion of Proteobacteria, and reduces the levels of lipopolysaccharide (LPS) in serum and brain. Isoleucine restriction reduces protein expression of TLR4/MyD88/NF-κB signaling pathway and inhibits upregulation of proinflammatory cytokine genes and protein expression in mice brain. In addition, isoleucine restriction significantly improves insulin resistance in the brain as well as synaptic plasticity impairment. CONCLUSION Isoleucine restriction may be a potential intervention to reduce HFD-induced cognitive impairment by altering gut microbiota, reducing neuroinflammation, insulin resistance, and improving synaptic plasticity in mice brain.
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Affiliation(s)
- Yuli Wang
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
| | - Xue Rong
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
| | - Hui Guan
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
| | - Fangxin Ouyang
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
| | - Xing Zhou
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
| | - Feng Li
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
| | - Xintong Tan
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
| | - Dapeng Li
- College of Food Science and Engineering, Shandong Agricultural University Key Laboratory of Food Nutrition and Human Health in Universities of Shandong, Taian, 271018, China
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Newborns from Mothers Who Intensely Consumed Sucralose during Pregnancy Are Heavier and Exhibit Markers of Metabolic Alteration and Low-Grade Systemic Inflammation: A Cross-Sectional, Prospective Study. Biomedicines 2023; 11:biomedicines11030650. [PMID: 36979631 PMCID: PMC10045555 DOI: 10.3390/biomedicines11030650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/16/2023] [Accepted: 02/19/2023] [Indexed: 02/24/2023] Open
Abstract
Robust data in animals show that sucralose intake during gestation can predispose the offspring to weight gain, metabolic disturbances, and low-grade systemic inflammation; however, concluding information remains elusive in humans. In this cross-sectional, prospective study, we examined the birth weight, glucose and insulin cord blood levels, monocyte subsets, and inflammatory cytokine profile in 292 neonates at term from mothers with light sucralose ingestion (LSI) of less than 60 mg sucralose/week or heavy sucralose intake (HSI) of more than 36 mg sucralose/day during pregnancy. Mothers in the LSI (n = 205) or HSI (n = 87) groups showed no differences in age, pregestational body mass index, blood pressure, and glucose tolerance. Although there were no differences in glucose, infants from HSI mothers displayed significant increases in birth weight and insulin compared to newborns from LSI mothers. Newborns from HSI mothers showed a substantial increase in the percentage of inflammatory nonclassical monocytes compared to neonates from LSI mothers. Umbilical cord tissue of infants from HSI mothers exhibited higher IL-1 beta and TNF-alpha with lower IL-10 expression than that found in newborns from LSI mothers. Present results demonstrate that heavy sucralose ingestion during pregnancy affects neonates’ anthropometric, metabolic, and inflammatory features.
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Ndlovu SS, Ghazi T, Chuturgoon AA. The Potential of Moringa oleifera to Ameliorate HAART-Induced Pathophysiological Complications. Cells 2022; 11:2981. [PMID: 36230942 PMCID: PMC9563018 DOI: 10.3390/cells11192981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 09/20/2022] [Indexed: 12/06/2022] Open
Abstract
Highly active antiretroviral therapy (HAART) comprises a combination of two or three antiretroviral (ARV) drugs that are administered together in a single tablet. These drugs target different steps within the human immunodeficiency virus (HIV) life cycle, providing either a synergistic or additive antiviral effect; this enhances the efficiency in which viral replication is suppressed. HIV cannot be completely eliminated, making HAART a lifetime treatment. With long-term HAART usage, an increasing number of patients experience a broadening array of complications, and this significantly affects their quality of life, despite cautious use. The mechanism through which ARV drugs induce toxicity is associated with metabolic complications such as mitochondrial dysfunction, oxidative stress, and inflammation. To address this, it is necessary to improve ARV drug formulation without compromising its efficacy; alternatively, safe supplementary medicine may be a suitable solution. The medicinal plant Moringa oleifera (MO) is considered one of the most important sources of novel nutritionally and pharmacologically active compounds that have been shown to prevent and treat various diseases. MO leaves are rich in polyphenols, vitamins, minerals, and tannins; studies have confirmed the therapeutic properties of MO. MO leaves provide powerful antioxidants, scavenge free radicals, promote carbohydrate metabolism, and repair DNA. MO also induces anti-inflammatory, hepatoprotective, anti-proliferative, and anti-mutagenic effects. Therefore, MO can be a source of affordable and safe supplement therapy for HAART-induced toxicity. This review highlights the potential of MO leaves to protect against HAART-induced toxicity in HIV patients.
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Affiliation(s)
| | - Terisha Ghazi
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
| | - Anil A. Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
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Infante M, Padilla N, Alejandro R, Caprio M, Della-Morte D, Fabbri A, Ricordi C. Diabetes-Modifying Antirheumatic Drugs: The Roles of DMARDs as Glucose-Lowering Agents. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:571. [PMID: 35629988 PMCID: PMC9143119 DOI: 10.3390/medicina58050571] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/14/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023]
Abstract
Systemic inflammation represents a shared pathophysiological mechanism which underlies the frequent clinical associations among chronic inflammatory rheumatic diseases (CIRDs), insulin resistance, type 2 diabetes (T2D), and chronic diabetes complications, including cardiovascular disease. Therefore, targeted anti-inflammatory therapies are attractive and highly desirable interventions to concomitantly reduce rheumatic disease activity and to improve glucose control in patients with CIRDs and comorbid T2D. Therapeutic approaches targeting inflammation may also play a role in the prevention of prediabetes and diabetes in patients with CIRDs, particularly in those with traditional risk factors and/or on high-dose corticosteroid therapy. Recently, several studies have shown that different disease-modifying antirheumatic drugs (DMARDs) used for the treatment of CIRDs exert antihyperglycemic properties by virtue of their anti-inflammatory, insulin-sensitizing, and/or insulinotropic effects. In this view, DMARDs are promising drug candidates that may potentially reduce rheumatic disease activity, ameliorate glucose control, and at the same time, prevent the development of diabetes-associated cardiovascular complications and metabolic dysfunctions. In light of their substantial antidiabetic actions, some DMARDs (such as hydroxychloroquine and anakinra) could be alternatively termed "diabetes-modifying antirheumatic drugs", since they may be repurposed for co-treatment of rheumatic diseases and comorbid T2D. However, there is a need for future randomized controlled trials to confirm the beneficial metabolic and cardiovascular effects as well as the safety profile of distinct DMARDs in the long term. This narrative review aims to discuss the current knowledge about the mechanisms behind the antihyperglycemic properties exerted by a variety of DMARDs (including synthetic and biologic DMARDs) and the potential use of these agents as antidiabetic medications in clinical settings.
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Affiliation(s)
- Marco Infante
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
- Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
- Section of Endocrinology, UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Via Cola di Rienzo 28, 00192 Rome, Italy
| | - Nathalia Padilla
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Colonia Centroamérica L-823, Managua 14048, Nicaragua;
| | - Rodolfo Alejandro
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
| | - Massimiliano Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Roma, Via di Val Cannuta 247, 00166 Rome, Italy;
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy;
| | - David Della-Morte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy;
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Department of Neurology, Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, 1120 NW 14th St., Miami, FL 33136, USA
| | - Andrea Fabbri
- Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Camillo Ricordi
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
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Tung YT, Zeng JL, Ho ST, Xu JW, Lin IH, Wu JH. Djulis Hull Improves Insulin Resistance and Modulates the Gut Microbiota in High-Fat Diet (HFD)-Induced Hyperglycaemia. Antioxidants (Basel) 2021; 11:45. [PMID: 35052549 PMCID: PMC8772896 DOI: 10.3390/antiox11010045] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/21/2021] [Accepted: 12/25/2021] [Indexed: 12/15/2022] Open
Abstract
In this study, we annotated the major flavonoid glycoside, rutin, of djulis hull crude extract using a Global Natural Products Social Molecular Networking (GNPS) library and its MS/MS spectra. To evaluate the protective effect of djulis hull crude extract and rutin on glucose tolerance, we fed mice a high-fat diet (HFD) for 16 weeks to induce hyperglycaemia. These results showed that crude extract significantly decreased HFD-induced elevation in the area under the curve (AUC) of weekly random blood glucose and oral glucose tolerance tests (OGTT), homeostasis model assessment (HOMA-IR), and advanced glycation end product (AGE) levels, and significantly increased pIRS1 and Glut4 protein expression in epididymal white adipose tissue (eWAT) and liver. Furthermore, the HFD-induced reduction in the activity of glutathione peroxidase (GPx) and catalase (CAT) was reversed by crude extract. In addition, ZO-1 and occludin protein expression in the colon was markedly downregulated in HFD-fed mice, resulting in decreased intestinal permeability and lipopolysaccharide (LPS) translocation, but were restored following crude extract. Moreover, the crude extract intervention had a profound effect on the alpha diversity and microbial community in the gut microbiota. Therefore, djulis hull crude extract could improve blood glucose and increase insulin receptor sensitivity in HFD-induced hyperglycaemia, which is likely due to its modulation of the gut microbiota, preservation of the integrity of the intestinal barrier to reduce body inflammation, increased antioxidant activity, and modulation of insulin signalling.
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Affiliation(s)
- Yu-Tang Tung
- Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 402, Taiwan;
- Nutrition Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Jun-Lan Zeng
- Department of Forestry, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.Z.); (J.-W.X.)
| | - Shang-Tse Ho
- Department of Wood Based Materials and Design, National Chiayi University, Chiayi 600, Taiwan;
| | - Jin-Wei Xu
- Department of Forestry, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.Z.); (J.-W.X.)
| | - I-Hsuan Lin
- Bioinformatics Core Facility, University of Manchester, Manchester M13 9PT, UK;
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Jyh-Horng Wu
- Department of Forestry, National Chung Hsing University, Taichung 402, Taiwan; (J.-L.Z.); (J.-W.X.)
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Recent advances in PTP1B signaling in metabolism and cancer. Biosci Rep 2021; 41:230148. [PMID: 34726241 PMCID: PMC8630396 DOI: 10.1042/bsr20211994] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/26/2021] [Accepted: 11/01/2021] [Indexed: 12/16/2022] Open
Abstract
Protein tyrosine phosphorylation is one of the major post-translational modifications in eukaryotic cells and represents a critical regulatory mechanism of a wide variety of signaling pathways. Aberrant protein tyrosine phosphorylation has been linked to various diseases, including metabolic disorders and cancer. Few years ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors, able to block the signals emanating from receptor tyrosine kinases. However, recent evidence demonstrates that misregulation of PTPs activity plays a critical role in cancer development and progression. Here, we will focus on PTP1B, an enzyme that has been linked to the development of type 2 diabetes and obesity through the regulation of insulin and leptin signaling, and with a promoting role in the development of different types of cancer through the activation of several pro-survival signaling pathways. In this review, we discuss the molecular aspects that support the crucial role of PTP1B in different cellular processes underlying diabetes, obesity and cancer progression, and its visualization as a promising therapeutic target.
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Painter JD, Akbari O. Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes. Front Immunol 2021; 12:727008. [PMID: 34489979 PMCID: PMC8416625 DOI: 10.3389/fimmu.2021.727008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/29/2021] [Indexed: 12/13/2022] Open
Abstract
Type 2 innate lymphoid cells (ILC2) are the innate counterparts of Th2 cells and are critically involved in the maintenance of homeostasis in a variety of tissues. Instead of expressing specific antigen receptors, ILC2s respond to external stimuli such as alarmins released from damage. These cells help control the delicate balance of inflammation in adipose tissue, which is a determinant of metabolic outcome. ILC2s play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM) through their protective effects on tissue homeostasis. A variety of crosstalk takes place between resident adipose cells and ILC2s, with each interaction playing a key role in controlling this balance. ILC2 effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile. Trafficking and maintenance of ILC2 populations are critical for tissue homeostasis. The metabolic environment and energy source significantly affect the number and function of ILC2s in addition to affecting their interactions with resident cell types. How ILC2s react to changes in the metabolic environment is a clear determinant of the severity of disease. Treating sources of metabolic instability via critical immune cells provides a clear avenue for modulation of systemic homeostasis and new treatments of T2DM.
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Affiliation(s)
- Jacob D Painter
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Viurcos-Sanabria R, Escobedo G. Immunometabolic bases of type 2 diabetes in the severity of COVID-19. World J Diabetes 2021; 12:1026-1041. [PMID: 34326952 PMCID: PMC8311488 DOI: 10.4239/wjd.v12.i7.1026] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/16/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 and type 2 diabetes (T2D) have now merged into an ongoing global syndemic that is threatening the lives of millions of people around the globe. For this reason, there is a deep need to understand the immunometabolic bases of the main etiological factors of T2D that affect the severity of COVID-19. Here, we discuss how hyperglycemia contributes to the cytokine storm commonly associated with COVID-19 by stimulating monocytes and macrophages to produce interleukin IL-1β, IL-6, and TNF-α in the airway epithelium. The main mechanisms through which hyperglycemia promotes reactive oxygen species release, inhibition of T cell activation, and neutrophil extracellular traps in the lungs of patients with severe SARS-CoV-2 infection are also studied. We further examine the molecular mechanisms by which proinflammatory cytokines induce insulin resistance, and their deleterious effects on pancreatic β-cell exhaustion in T2D patients critically ill with COVID-19. We address the effect of excess glucose on advanced glycation end product (AGE) formation and the role of AGEs in perpetuating pneumonia and acute respiratory distress syndrome. Finally, we discuss the contribution of preexisting endothelial dysfunction secondary to diabetes in the development of neutrophil trafficking, vascular leaking, and thrombotic events in patients with severe SARS-CoV-2 infection. As we outline here, T2D acts in synergy with SARS-CoV-2 infection to increase the progression, severity, and mortality of COVID-19. We think a better understanding of the T2D-related immunometabolic factors that contribute to exacerbate the severity of COVID-19 will improve our ability to identify patients with high mortality risk and prevent adverse outcomes.
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Affiliation(s)
| | - Galileo Escobedo
- Laboratorio de Proteómica, Dirección de Investigación, Hospital General de Mexico “Dr. Eduardo Liceaga”, Mexico City 06720, Mexico
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Shyur LF, Varga V, Chen CM, Mu SC, Chang YC, Li SC. Extract of white sweet potato tuber against TNF-α-induced insulin resistance by activating the PI3K/Akt pathway in C2C12 myotubes. BOTANICAL STUDIES 2021; 62:7. [PMID: 34003397 PMCID: PMC8131422 DOI: 10.1186/s40529-021-00315-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 05/11/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND White sweet potato (WSP; Ipomoea batatas L. Simon No. 1) has many potential beneficial effects on metabolic control and diabetes-related insulin resistance. The improvement of insulin resistance by WSP tuber extracts on glucose uptake were not investigated in C2C12 myoblast cells. RESULTS WSP tuberous ethanol extract (WSP-E) was partitioned with ethyl-acetate and water to obtain ethyl-acetate layer (WSP-EA) and water layer (WSP-EW). The WSP-EA shows the highest total phenolic contents and highest antioxidant activity by Folin-Ciocalteu and (2,2-diphenyl-1-picryl-hydrazyl-hydrate, DPPH) assay, respectively. After low concentration horse serum on differentiation inducement of C2C12 myoblasts into mature myotubes, the cells were treated with TNF-α to induce insulin resistance. WSP-EA and WSP-EW extracts increased the uptake of fluorescence glucose analogue (2-[N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino]-2-deoxy-D-glucose, 2-NBDG) in a dose-dependent manner as examined by flow cytometry. The WSP-EA enhanced glucose uptake by activation of phosphorylation of IR (pIR), IRS-1 (pIRS-1) and Akt (pAkt) involved in PI3K (phosphatidylinositol 3-kinase)/protein kinase B (Akt) pathway, also upregulated glucose transporter 4 (GLUT4) expression in myotubes. CONCLUSIONS WSP-EA enhanced the glucose uptake in C2C12 myotubes through upregulating the PI3K/Akt pathway. The in vitro data reveal that WSP tuber extracts has potential applications to improve insulin resistance in diabetes.
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Affiliation(s)
- Lie-Fen Shyur
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 11529 Taiwan
| | - Viola Varga
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031 Taiwan
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary
| | - Chiao-Ming Chen
- Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei, 10462 Taiwan
| | - Shu-Chi Mu
- School of Medicine, Fu-Jen Catholic University, New Taipei City, 24205 Taiwan
| | - Yu-Chih Chang
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 115 Taiwan
| | - Sing-Chung Li
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031 Taiwan
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Ortiz-Huidobro RI, Velasco M, Larqué C, Escalona R, Hiriart M. Molecular Insulin Actions Are Sexually Dimorphic in Lipid Metabolism. Front Endocrinol (Lausanne) 2021; 12:690484. [PMID: 34220716 PMCID: PMC8251559 DOI: 10.3389/fendo.2021.690484] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 05/31/2021] [Indexed: 12/14/2022] Open
Abstract
The increment in energy-dense food and low physical activity has contributed to the current obesity pandemic, which is more prevalent in women than in men. Insulin is an anabolic hormone that regulates the metabolism of lipids, carbohydrates, and proteins in adipose tissue, liver, and skeletal muscle. During obesity, nutrient storage capacity is dysregulated due to a reduced insulin action on its target organs, producing insulin resistance, an early marker of metabolic dysfunction. Insulin resistance in adipose tissue is central in metabolic diseases due to the critical role that this tissue plays in energy homeostasis. We focused on sexual dimorphism on the molecular mechanisms of insulin actions and their relationship with the physiology and pathophysiology of adipose tissue. Until recently, most of the physiological and pharmacological studies were done in males without considering sexual dimorphism, which is relevant. There is ample clinical and epidemiological evidence of its contribution to the establishment and progression of metabolic diseases. Sexual dimorphism is a critical and often overlooked factor that should be considered in design of sex-targeted therapeutic strategies and public health policies to address obesity and diabetes.
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Affiliation(s)
- Rosa Isela Ortiz-Huidobro
- Neurosciences Division, Department of Cognitive Neuroscience, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Myrian Velasco
- Neurosciences Division, Department of Cognitive Neuroscience, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Carlos Larqué
- Department of Embryology and Genetics, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Rene Escalona
- Department of Embryology and Genetics, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Marcia Hiriart
- Neurosciences Division, Department of Cognitive Neuroscience, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- *Correspondence: Marcia Hiriart,
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Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin. J Psychiatr Res 2021; 133:82-92. [PMID: 33316649 PMCID: PMC7855678 DOI: 10.1016/j.jpsychires.2020.12.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 11/20/2020] [Accepted: 12/01/2020] [Indexed: 12/13/2022]
Abstract
Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.
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13
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Zang L, Kothan S, Yang Y, Zeng X, Ye L, Pan J. Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro. Adipocyte 2020; 9:24-34. [PMID: 31989870 PMCID: PMC6999839 DOI: 10.1080/21623945.2020.1721235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 01/07/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
Insulin plays an important role during adipogenic differentiation of animal preadipocytes and the maintenance of mature phenotypes. However, its role and mechanism in dedifferentiation of adipocyte remains unclear. This study investigated the effects of insulin on dedifferentiation of mice adipocytes, and the potential mechanisms. The preadipocytes were isolated from the subcutaneous white adipose tissue of wild type (WT), TNFα gene mutant (TNFα-/-), leptin gene spontaneous point mutant (db/db) and TNFα-/-/db/db mice and were then induced for differentiation. Interestingly, dedifferentiation of these adipocytes occurred once removing exogenous insulin from the adipogenic medium. As characteristics of dedifferentiation of the adipocytes, downregulation of adipogenic markers, upregulation of stemness markers and loss of intracellular lipids were observed from the four genotypes. Notably, dedifferentiation was occurring earlier if the insulin signal was blocked. These dedifferentiated cells regained the potentials of the stem cell-like characteristics. There is no significant difference in the characteristics of the dedifferentiation between the adipocytes. Overall, the study provided evidence that insulin plays a negative regulatory role in the dedifferentiation of adipocytes. We also confirmed that both dedifferentiation of mouse adipocytes, and effect of the insulin on this process were independent of the cell genotypes, while it is a widespread phenomenon in the adipocytes.
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Affiliation(s)
- Liguo Zang
- Shandong Provincial Key Laboratory of Animal Resistant Biology, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Suchart Kothan
- Center of Radiation Research and Medical Imaging, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Yiyi Yang
- Shandong Provincial Key Laboratory of Animal Resistant Biology, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Xiangyi Zeng
- Shandong Provincial Key Laboratory of Animal Resistant Biology, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Lingmin Ye
- Shandong Provincial Key Laboratory of Animal Resistant Biology, College of Life Sciences, Shandong Normal University, Jinan, China
| | - Jie Pan
- Shandong Provincial Key Laboratory of Animal Resistant Biology, College of Life Sciences, Shandong Normal University, Jinan, China
- Center of Radiation Research and Medical Imaging, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
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Mohamad HE, Asker ME, Keshawy MM, Abdel Aal SM, Mahmoud YK. Infliximab ameliorates tumor necrosis factor-alpha exacerbated renal insulin resistance induced in rats by regulating insulin signaling pathway. Eur J Pharmacol 2020; 872:172959. [PMID: 32004528 DOI: 10.1016/j.ejphar.2020.172959] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/24/2020] [Accepted: 01/24/2020] [Indexed: 12/17/2022]
Abstract
Infliximab (IFX), a monoclonal antibody for tumor necrosis factor-alpha (TNF-α), is known to restore blood glucose homeostasis. However, its effects on improving renal insulin resistance (IR) are not yet studied. So we investigate the impact of infliximab on renal insulin signaling pathway in IR rat model regarding to metformin (MET). The induced IR was confirmed by a high oral glucose tolerance test, an elevation of lipid profile and the homeostatic model assessment of insulin resistance 2 (HOMA-IR 2) values. Subsequently, IR rats were concurrently treated with either MET (100 mg/kg/day) or IFX (one dose 5 mg/kg) besides IR and normal control (NC) groups. Four weeks later, IR control rats displayed hyperglycemia, hyperinsulinemia and elevation in HOMA-IR 2, renal function markers and renal tissue TNF-α, interleukins-1β and 6 (Il-1β, IL-6) and suppressor of cytokines signaling 3 (SOCS3) contents as well as glomerulosclerosis when compared to NC group. Additionally, the phosphorylation of renal insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were markedly impaired. Treatment with either MET or IFX significantly improved IR and kidney functions. The effects of the drugs were achieved by the downregulation of renal inflammatory cytokines and SOCS3 levels and the amelioration of the renal IRS1/PI3K/Akt pathway. In conclusion, MET and IFX ameliorated the TNF-α worsening effect on IR in rat renal tissues by regulating insulin signaling. Interestingly, infliximab was superior to metformin in regulating insulin signaling pathway. Therefore, infliximab could be used as an adjuvant therapy in improving renal IR.
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Affiliation(s)
- Hoda E Mohamad
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Mervat E Asker
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Mohammed M Keshawy
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Ismailia, 41522, Suez Canal University, Egypt
| | - Sara M Abdel Aal
- Department of Histology& Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Yasmin K Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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15
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Kumar A, Rana D, Rana R, Bhatia R. Protein Tyrosine Phosphatase (PTP1B): A promising Drug Target Against Life-threatening Ailments. Curr Mol Pharmacol 2020; 13:17-30. [DOI: 10.2174/1874467212666190724150723] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/26/2019] [Accepted: 07/11/2019] [Indexed: 12/14/2022]
Abstract
Background:Protein tyrosine phosphatases are enzymes which help in the signal transduction in diabetes, obesity, cancer, liver diseases and neurodegenerative diseases. PTP1B is the main member of this enzyme from the protein extract of human placenta. In phosphate inhibitors development, significant progress has been made over the last 10 years. In early-stage clinical trials, few compounds have reached whereas in the later stage trials or registration, yet none have progressed. Many researchers investigate different ways to improve the pharmacological properties of PTP1B inhibitors.Objective:In the present review, authors have summarized various aspects related to the involvement of PTP1B in various types of signal transduction mechanisms and its prominent role in various diseases like cancer, liver diseases and diabetes mellitus.Conclusion:There are still certain challenges for the selection of PTP1B as a drug target. Therefore, continuous future efforts are required to explore this target for the development of PTP inhibitors to treat the prevailing diseases associated with it.
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Affiliation(s)
- Ajay Kumar
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
| | - Divya Rana
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
| | - Rajat Rana
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
| | - Rohit Bhatia
- Department of Pharmaceutical Analysis, Indo-Soviet Friendship College of Pharmacy (ISFCP), Moga-142001, India
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16
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Inhibition of tumor necrosis factor-α enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance. Mol Cell Biochem 2020; 466:45-54. [PMID: 31933108 DOI: 10.1007/s11010-020-03686-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 01/04/2020] [Indexed: 01/25/2023]
Abstract
Insulin resistance (IR) has emerged as one of the main risk factors for renal fibrosis (RF) that represents a common stage in almost all chronic kidney disease. The present study aims to investigate the inhibitory effect of empagliflozin (EMPA "a sodium-glucose co-transporter 2 inhibitor") and infliximab [IFX "a tumor necrosis factor-α (TNF-α) antibody"] on RF in rats with induced IR. IR was induced by adding 10% fructose in drinking water for 20 weeks. Thereafter, fructose-induced IR rats were concurrently treated with EMPA (30 mg/kg), IFX (1 dose 5 mg/kg), or EMPA + IFX for 4 weeks, in addition to IR control group (received 10% fructose in water) and normal control (NC) group. Rats with IR displayed hyperglycemia, deterioration in kidney functions, glomerulosclerosis, and collagen fiber deposition in renal tissues as compared to NC. This was associated with downregulation of the renal sirtuin 1 (Sirt 1) expression along with higher renal tissue TNF-α and transforming growth factor-β1 (TGF-β1) levels. Both EMPA and IFX significantly modulated the aforementioned fibrotic cytokines, upregulated the renal Sirt 1 expression, and attenuated RF compared to IR control group. Of note, IFX effect was superior to that of EMPA. However, the combination of EMPA and IFX alleviated RF to a greater extent surpassing the monotherapy. This may be attributed to the further upregulation of renal Sirt 1 in addition to the downregulation of fibrotic cytokines. These findings suggest that the combination of EMPA and IFX offers additional benefits and may represent a promising therapeutic option for RF.
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Vega-Galaviz D, Vecchyo-Tenorio GD, Alcántara-Suárez R, Méndez-García LA, Sánchez-Del Real AL, Villalobos-Molina R, Fragoso JM, León-Cabrera S, Ostoa-Saloma P, Pérez-Tamayo R, Escobedo G. M2 macrophage immunotherapy abolishes glucose intolerance by increasing IL-10 expression and AKT activation. Immunotherapy 2020; 12:9-24. [PMID: 31914828 DOI: 10.2217/imt-2019-0080] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Aim: Glucose intolerance associates with M1/M2 macrophage unbalance. We thus wanted to examine the effect of M2 macrophage administration on mouse model of glucose intolerance. Materials & methods: C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks and then received thrice 20 mg/kg streptozotocin (HFD-GI). Bone marrow-derived stem cells were collected from donor mice and differentiated/activated into M2 macrophages for intraperitoneal administration into HFD-GI mice. Results: M2 macrophage treatment abolished glucose intolerance independently of obesity. M2 macrophage administration increased IL-10 in visceral adipose tissue and serum, but showed no effect on serum insulin. While nitric oxide synthase-2 and arginase-1 remained unaltered, M2 macrophage treatment restored AKT phosphorylation in visceral adipose tissue. Conclusion: M2 macrophage treatment abolishes glucose intolerance by increasing IL-10 and phosphorylated AKT.
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Affiliation(s)
- Diana Vega-Galaviz
- Laboratory for Proteomics & Metabolomics, Research Division, General Hospital of Mexico 'Dr. Eduardo Liceaga', 06720 Mexico City, Mexico
| | - Georgina Del Vecchyo-Tenorio
- Laboratory for Proteomics & Metabolomics, Research Division, General Hospital of Mexico 'Dr. Eduardo Liceaga', 06720 Mexico City, Mexico.,Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Raúl Alcántara-Suárez
- Laboratory for Proteomics & Metabolomics, Research Division, General Hospital of Mexico 'Dr. Eduardo Liceaga', 06720 Mexico City, Mexico
| | - Lucia A Méndez-García
- Laboratory for Proteomics & Metabolomics, Research Division, General Hospital of Mexico 'Dr. Eduardo Liceaga', 06720 Mexico City, Mexico
| | - Ana L Sánchez-Del Real
- Laboratory for Proteomics & Metabolomics, Research Division, General Hospital of Mexico 'Dr. Eduardo Liceaga', 06720 Mexico City, Mexico
| | - Rafael Villalobos-Molina
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico.,Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - José M Fragoso
- Departamento de Biología Molecular, Instituto Nacional de Cardiología 'Ignacio Chávez', Mexico City, Mexico
| | - Sonia León-Cabrera
- Carrera de Médico Cirujano, Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala 54090, Mexico
| | - Pedro Ostoa-Saloma
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico
| | - Ruy Pérez-Tamayo
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Galileo Escobedo
- Laboratory for Proteomics & Metabolomics, Research Division, General Hospital of Mexico 'Dr. Eduardo Liceaga', 06720 Mexico City, Mexico
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