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Jiang M, Li Z, Qin X, Chen L, Zhu G. Regulatory Role of Flavonoid Baicalin from Scutellaria baicalensis on AMPK: A Review. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2025; 53:771-801. [PMID: 40374371 DOI: 10.1142/s0192415x25500296] [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: 05/17/2025]
Abstract
AMP-activated protein kinase (AMPK) is a ubiquitous sensor of cellular energy and nutrient status in eukaryotic cells. It serves an essential function in the modulation of energy balance and metabolism homeostasis through its regulation of carbohydrate metabolism, lipid metabolism and protein metabolism. The dysregulation of AMPK is closely related to a series of systemic diseases, affecting multiple organs and tissues. Baicalin is a natural compound derived from the dry raw root of Scutellaria baicalensis, and it has been found to exhibit several potential pharmacological actions. These include hepatoprotective effects, anti-inflammation effects and anti-tumor effects. These biological activities are related to the regulatory effect of baicalin on the host metabolism, which is closely associated with AMPK modulation. In this review, we provide an overview of the regulatory effect of baicalin on AMPK and its upstream and downstream signaling pathways. The pharmacological properties and underlying mechanism of baicalin for regulating AMPK were summarized with regards to four aspects: regulatory effect of baicalin on AMPK in lipid metabolism and glucose metabolism, regulatory effect of baicalin on AMPK in its pharmacological effect of anti-tumor and anti-inflammation. As a natural compound, baicalin has the potential for the management of certain AMPK-related diseases.
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Affiliation(s)
- Ming Jiang
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Zhuoneng Li
- Centers for Disease Control and Prevention of Wuhan, Wuhan, China
| | - Xu Qin
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Guangxun Zhu
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
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Udom GJ, Oritsemuelebi B, Frazzoli C, Bocca B, Ruggieri F, Orisakwe OE. [Heavy metals and derangement in carbohydrate metabolism in eye diseases: a systematic review]. Vestn Oftalmol 2025; 141:89-100. [PMID: 40353546 DOI: 10.17116/oftalma202514102189] [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: 05/14/2025]
Abstract
PURPOSE To uncover the negative impacts of heavy metals on carbohydrate metabolism, their mechanisms and contributory factors, as well as their role on the etiopathogenesis, pathophysiology, and progression of eye diseases. MATERIAL AND METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), various databases were searched (e.g., Scopus, PubMed, etc.) to collect evidence on the link and role of heavy metals in carbohydrate metabolism and pathogenesis of eye diseases. Included studies were appraised for quality using the Critical Appraisal Skills Programme checklists and extracted data were analyzed using the narrative synthesis method. RESULTS Of the 128 papers retrieved, 24 papers met the inclusion criteria. Heavy metals are associated with the onset and progression of diabetes and eye diseases secondary to diabetes (age-related macular degeneration, cataract, and diabetic retinopathy) majorly via toxic interference (induction, inhibition and/or deactivation) of glucose metabolizing enzymes and oxidative stress. The etiology of DR is intricate and includes the simultaneous disruption of several metabolic and signaling mechanisms within the retinal neurovascular unit. The retina is more susceptible to metal-induced toxicities due to the high affinity of heavy metals to melanin content of the retinal epithelium. CONCLUSION This study emphasizes the harmful effects of chronic and intermittent exposure to heavy metals, suggesting no safe exposure levels. To prevent eye diseases secondary to heavy metals-induced altered carbohydrate metabolism, metal chelators, low glycemic diets, and lifestyle modifications should be exploited among vulnerable populations.
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Affiliation(s)
- G J Udom
- Kampala International University, Ishaka, Uganda
- Federal University Oye-Ekiti, Oye-Ekiti, Nigeria
| | | | - C Frazzoli
- Istituto Superiore di Sanità, Rome, Italy
| | - B Bocca
- stituto Superiore di Sanità, Rome, Italy
| | - F Ruggieri
- stituto Superiore di Sanità, Rome, Italy
| | - O E Orisakwe
- African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR) - University of Port Harcourt, Port Harcourt, Nigeria
- Advanced Research Centre, European University of Lefke, Lefke, Turkey
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Pramanik R, Dey A, Chakrabarty AK, Banerjee D, Narwaria A, Sharma S, Rai RK, Katiyar CK, Dubey SK. Diabetes mellitus and Alzheimer's disease: Understanding disease mechanisms, their correlation, and promising dual activity of selected herbs. JOURNAL OF ETHNOPHARMACOLOGY 2024; 333:118402. [PMID: 38821139 DOI: 10.1016/j.jep.2024.118402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 05/12/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE This review explores the link between Type 2 Diabetes Mellitus (T2DM) and diabetes-induced Alzheimer's disease (AD). It emphasizes the shared pathophysiological links and mechanisms between the two conditions, focusing on reduced insulin levels and receptors, impaired glucose metabolism, insulin resistance, mitochondrial dysfunction, and oxidative damage in AD-affected brains-paralleling aspects of T2DM. The review suggests AD as a "diabetes of the brain," supported by cognitive enhancement through antidiabetic interventions. It focuses on the traditionally used Indian herbs as a means to manage both conditions while addressing developmental challenges. AIM OF THE STUDY This study explores the DM-AD connection, reviewing medicinal herbs with protective potential for both ailments, considering traditional uses and developmental challenges. MATERIALS AND METHODS Studied research, reviews, and ethnobotanical and scientific data from electronic databases and traditional books. RESULTS The study analyzes the pathophysiological links between DM and AD, emphasizing their interconnected factors. Eight Ayurvedic plants with dual protective effects against T2DM and AD are thoroughly reviewed with preclinical/clinical evidence. Historical context, phytoconstituents, and traditional applications are explored. Innovative formulations using these plants are examined. Challenges stemming from phytoconstituents' physicochemical properties are highlighted, prompting novel formulation development, including nanotechnology-based delivery systems. The study uncovers obstacles in formulating treatments for these diseases. CONCLUSION The review showcases the dual potential of chosen medicinal herbs against both diseases, along with their traditional applications, endorsing their use. It addresses formulation obstacles, proposing innovative delivery technologies for herbal therapies, while acknowledging their constraints. The review suggests the need for heightened investment and research in this area.
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Affiliation(s)
- Rima Pramanik
- R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, 700056, India
| | - Anuradha Dey
- R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, 700056, India
| | | | - Dipankar Banerjee
- R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, 700056, India
| | - Avinash Narwaria
- R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, 700056, India
| | - Swapnil Sharma
- Department of Pharmacy, Banasthali Vidyapith, Banasthali, 304022, Rajasthan, India
| | - Rajiva Kumar Rai
- R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, 700056, India
| | - Chandra Kant Katiyar
- R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, 700056, India
| | - Sunil Kumar Dubey
- R&D Healthcare Division, Emami Ltd, 13, BT Road, Belgharia, Kolkata, 700056, India.
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Maiese K. The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk. Front Immunol 2023; 14:1273570. [PMID: 38022638 PMCID: PMC10663950 DOI: 10.3389/fimmu.2023.1273570] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.
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Affiliation(s)
- Kenneth Maiese
- Innovation and Commercialization, National Institutes of Health, Bethesda, MD, United States
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Melero R, Quiroz-Rodríguez ME, Lara-Hernández F, Redón J, Sáez G, Briongos-Figuero LS, Abadía-Otero J, Martín-Escudero JC, Chaves FJ, Ayala G, García-García AB. Genetic interaction in the association between oxidative stress and diabetes in the Spanish population. Free Radic Biol Med 2023; 205:62-68. [PMID: 37268047 DOI: 10.1016/j.freeradbiomed.2023.05.030] [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: 03/22/2023] [Revised: 05/24/2023] [Accepted: 05/30/2023] [Indexed: 06/04/2023]
Abstract
Oxidative stress (OS) is a relevant intermediate mechanism involved in Type 2 Diabetes Mellitus (T2D) development. To date, the interaction between OS parameters and variations in genes related to T2D has not been analyzed. AIMS To study the genetic interaction of genes potentially related to OS levels (redox homeostasis, renin-angiotensin-aldosterone system, endoplasmic stress response, dyslipidemia, obesity and metal transport) and OS and T2D risk in a general population from Spain (the Hortega Study) in relation to the risk of suffering from T2D. MATERIALS AND METHODS One thousand five hundred and two adults from the University Hospital Rio Hortega area were studied and 900 single nucleotide polymorphisms (SNPs) from 272 candidate genes were analyzed. RESULTS There were no differences in OS levels between cases and controls. Some polymorphisms were associated with T2D and with OS levels. Significant interactions were observed between OS levels and two polymorphisms in relation to T2D presence: rs196904 (ERN1 gene) and rs2410718 (COX7C gene); and between OS levels and haplotypes of the genes: SP2, HFF1A, ILI8R1, EIF2AK2, TXNRD2, PPARA, NDUFS2 and ERN1. CONCLUSIONS Our results indicate that genetic variations of the studied genes are associated with OS levels and that their interaction with OS parameters may contribute to the risk of developing T2D in the Spanish general population. These data support the importance of analyzing the influence of OS levels and their interaction with genetic variations in order to establish their real impact in T2D risk. Further studies are required to identify the real relevance of interactions between genetic variations and OS levels and the mechanisms involved in them.
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Affiliation(s)
- Rebeca Melero
- Genomics and Diabetes Unit, INCLIVA Biomedical Research Institute, 46010, Valencia, Spain
| | | | | | - Josep Redón
- Cardiometabolic Renal Risk Research Group, INCLIVA Biomedical Research Institute, University of Valencia, 46010, Valencia, Spain; CIBEROBN, ISCIII, 28029, Madrid, Spain
| | - Guillermo Sáez
- Department of Biochemistry and Molecular Biology, Faculty of Medicine and Odontology, University of Valencia, 46010, Valencia, Spain; Service of Clinical Analysis, University Hospital Dr. Peset-FISABIO, Spain
| | | | - Jessica Abadía-Otero
- Department of Internal Medicine, Rio Hortega University Hospital, 47012, Valladolid, Spain
| | - Juan Carlos Martín-Escudero
- Department of Internal Medicine, Rio Hortega University Hospital, 47012, Valladolid, Spain; Department of Medicine, Faculty of Medicine, University of Valladolid, 47002, Valladolid, Spain
| | - F Javier Chaves
- Genomics and Diabetes Unit, INCLIVA Biomedical Research Institute, 46010, Valencia, Spain; CIBERDEM, ISCIII, 28029, Madrid, Spain.
| | - Guillermo Ayala
- Department of Statistics and Operation Research, University of Valencia, 46100, Burjassot, Valencia, Spain
| | - Ana-Bárbara García-García
- Genomics and Diabetes Unit, INCLIVA Biomedical Research Institute, 46010, Valencia, Spain; CIBERDEM, ISCIII, 28029, Madrid, Spain
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Jiang W, Ding K, Yue R, Lei M. Therapeutic effects of icariin and icariside II on diabetes mellitus and its complications. Crit Rev Food Sci Nutr 2023; 64:5852-5877. [PMID: 36591787 DOI: 10.1080/10408398.2022.2159317] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Diabetes mellitus (DM) is a global health issue in the twenty-first century, and there are numerous challenges in preventing and alleviating its chronic complications. The herb Epimedium has beneficial therapeutic effects on various human diseases, including DM. Its major flavonoid component, icariin, has significant anti-DM activity and may help improve pancreatic β-cell dysfunction and insulin resistance. Furthermore, preclinical evidence has shown that icariin and its in vivo bioactive form, icariside II, have preventive and therapeutic effects on several diabetic complications, including diabetic cardiomyopathy, diabetic vascular endothelial disorder, diabetic nephropathy, and diabetic erectile dysfunction. In this review, we present the general and toxicological information concerning icariin and icariside II and review the anti-DM effects of icariin from a molecular perspective. Additionally, we discuss the potential benefits of icariin and icariside II on the important pathological mechanisms of various diabetic complications. Despite positive preclinical evidence, additional investigations are needed before relevant clinical studies can be conducted. Therefore, we conclude with suggestions for future research. Hopefully, this review will provide a comprehensive molecular perspective for future research and product development related to icariin and icariside II in treating DM and diabetic complications.
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Affiliation(s)
- Wei Jiang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kaixi Ding
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Rensong Yue
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ming Lei
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer's Disease-like Neuropathology in a Mouse Model for Down Syndrome. Antioxidants (Basel) 2023; 12:antiox12010111. [PMID: 36670973 PMCID: PMC9854894 DOI: 10.3390/antiox12010111] [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: 12/19/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023] Open
Abstract
Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer's disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS.
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Quintana-Pérez JC, García-Dolores F, Valdez-Guerrero AS, Alemán-González-Duhart D, Arellano-Mendoza MG, Rojas Hernández S, Olivares-Corichi IM, García Sánchez JR, Trujillo Ferrara JG, Tamay-Cach F. Modeling type 2 diabetes in rats by administering tacrolimus. Islets 2022; 14:114-127. [PMID: 35348048 PMCID: PMC8966987 DOI: 10.1080/19382014.2022.2051991] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The prevalence of diabetes is rapidly increasing. The current number of diagnosed cases is ~422 million, expected to reach ~640 million by 2040. Type 2 diabetes, which constitutes ~95% of the cases, is characterized by insulin resistance and a progressive loss of β-cell function. Despite intense research efforts, no treatments are yet able to cure the disease or halt its progression. Since all existing animal models of type 2 diabetes have serious drawbacks, one is needed that represents the complete pathogenesis, is low cost and non-obese, and can be developed relatively quickly. The aim of this study was to evaluate a low-cost, non-obese model of type 2 diabetes engendered by administering a daily high dose of tacrolimus (an immunosuppressant) to Wistar rats for 4 weeks. The biochemical and antioxidant markers were measured at basal and after the 4-week tacrolimus treatment. At week 4, the values of these parameters closely resembled those observed in human type 2 diabetes, including fasting blood glucose at 141.5 mg/dL, blood glucose greater than 200 mg/dL at 120 min of the glucose tolerance test, blood glucose at varied levels in the insulin tolerance test, and elevated levels of cholesterol and triglyceride. The tacrolimus treatment produced hypoinsulinemia and sustained hyperglycemia, probably explained by the alteration found in pancreatic β-cell function and morphology. This model should certainly be instrumental for evaluating possible type 2 diabetes treatments, and for designing new immunosuppressants that do not cause pancreatic damage, type 2 diabetes, or new-onset diabetes after transplantation (NODAT).
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Affiliation(s)
- JC Quintana-Pérez
- Laboratorio de Investigación en Bioquímica Aplicada, Sección de Estudios de Posgrado e Investigación y Departamento de Formación Básica Disciplinaria, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas,Miguel Hidalgo, Ciudad de México, México
| | - F García-Dolores
- Departamento de Patología, Instituto de Servicios Periciales y Ciencias Forenses, Tribunal Superior de Justicia de la Ciudad de México, Ciudad de México, México
| | - AS Valdez-Guerrero
- Laboratorio de Investigación en Bioquímica Aplicada, Sección de Estudios de Posgrado e Investigación y Departamento de Formación Básica Disciplinaria, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas,Miguel Hidalgo, Ciudad de México, México
| | - D Alemán-González-Duhart
- Laboratorio de Investigación en Bioquímica Aplicada, Sección de Estudios de Posgrado e Investigación y Departamento de Formación Básica Disciplinaria, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas,Miguel Hidalgo, Ciudad de México, México
| | - MG Arellano-Mendoza
- Laboratorio de Investigación en Enfermedades Crónico Degenerativas, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Miguel Hidalgo, Ciudad de México, México
| | - S Rojas Hernández
- Laboratorio de Inmunología Celular y Molecular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Miguel Hidalgo, Ciudad de México, México
| | - IM Olivares-Corichi
- Laboratorio de Estrés Oxidativo, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Ciudad de México, México
| | - JR García Sánchez
- Laboratorio de Estrés Oxidativo, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Ciudad de México, México
| | - JG Trujillo Ferrara
- Laboratorio de Investigación en Bioquímica Aplicada, Sección de Estudios de Posgrado e Investigación y Departamento de Formación Básica Disciplinaria, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas,Miguel Hidalgo, Ciudad de México, México
| | - F Tamay-Cach
- Laboratorio de Investigación en Bioquímica Aplicada, Sección de Estudios de Posgrado e Investigación y Departamento de Formación Básica Disciplinaria, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas,Miguel Hidalgo, Ciudad de México, México
- CONTACT F Tamay-Cach Laboratorio de Investigación en Bioquímica Aplicada, Sección de Estudios de Posgrado e Investigación y Departamento de Formación Básica Disciplinaria, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Casco de Santo Tomas, Miguel Hidalgo, Ciudad de México11340, México. JG TrujilloFerrara
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Oxidative Stress and Inflammatory Biomarkers in Patients with Diabetic Foot. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58121866. [PMID: 36557068 PMCID: PMC9785583 DOI: 10.3390/medicina58121866] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Background and Objectives: Diabetic foot (DF) development is driven by complex interactions of hyperglycemia, inflammation, and oxidative stress (OS). We aimed to investigate OS and inflammatory biomarkers in patients with DF and their potential to improve early diagnosis and management of DF. Materials and Methods: The prooxidant−antioxidant balance (PAB), superoxide dismutase (SOD), total oxidative status (TOS), total sulfhydryl groups (SHG), routine biochemical parameters, and complete blood count were determined in 42 patients with type-2 DM, of which 23 patients had DF, while 19 patients were without DF complications. The neutrophils-to-lymphocyte ratio (NLR) was evaluated as a biomarker of inflammation. Results: Patients with DF had significantly higher (p < 0.05) PAB levels (170 ± 33.9 U/L) compared to those without DF complications (142 ± 31.3 U/L). In addition, patients with DF had significantly reduced SOD activities (p < 0.01). NLR values were significantly higher in the DF group (median: 2.8; interquartile range: 2.0−4.3) than in the group without DF (median: 1.4; interquartile range: 1.4−2.1; p < 0.01). A positive correlation was found between the PAB and NLR index (r = 0.449; p < 0.05). The diagnostic accuracy of both PAB (AUC = 0.741; p < 0.01) and NLR (AUC = 0.760; p < 0.01) was estimated as acceptable. Conclusions: In conclusion, the development of DF is associated with enhanced OS and inflammation processes. PAB and NLR could be useful non-invasive biomarkers of DF development.
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Lv B, Yang X, An T, Wu Y, He Z, Li B, Wang Y, Tan F, Wang T, Zhu J, Hu Y, Liu X, Jiang G. Combined analysis of whole-exome sequencing and RNA sequencing in type 2 diabetes mellitus patients with thirst and fatigue. Diabetol Metab Syndr 2022; 14:111. [PMID: 35941691 PMCID: PMC9358875 DOI: 10.1186/s13098-022-00884-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 07/28/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The principal objective of this study was to gain a better understanding of the mechanisms of type 2 diabetes mellitus (T2DM) patients with fatigue (D-T2DM) through exome and transcriptome sequencing. METHODS After whole-exome sequencing on peripheral blood of 6 D-T2DM patients, the consensus mutations were screen out and analyzed by a series of bioinformatics analyses. Then, we combined whole-exome sequencing and transcriptome sequencing results to find the important genes that changed at both the DNA and RNA levels. RESULTS The results showed that a total of 265,393 mutation sites were found in D-T2DM patients compared with normal individuals, 235 of which were consensus mutations shared with D-T2DM patients. These genes significantly enriched in HIF-1 signaling pathway and sphingolipid signaling pathway. At the RNA level, a total of 375 genes were identified to be differentially expressed. After the DNA-RNA joint analysis, eight genes were screened that changed at both DNA and RNA levels. Among these genes, FUS and LMNA were related to carbohydrate metabolism, energy metabolism, and mitochondrial function. Subsequently, we predicted the herbs, including Qin Pi and Hei Zhi Ma, that might play a therapeutic role in D-T2DM through the SymMap database. CONCLUSION These findings have significant implications for understanding the mechanisms of D-T2DM and provide potential targets for D-T2DM diagnosis and treatment.
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Affiliation(s)
- Bohan Lv
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Xiuyan Yang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Tian An
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Yanxiang Wu
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Zhongchen He
- Department of Endocrinology, Beijing He Ping li Hospital, Beijing, China
| | - Bowu Li
- Department of Endocrinology, Beijing He Ping li Hospital, Beijing, China
| | - Yijiao Wang
- Department of Endocrinology, Beijing He Ping li Hospital, Beijing, China
| | - Fang Tan
- Department of Endocrinology, Beijing He Ping li Hospital, Beijing, China
| | - Tingye Wang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Jiajian Zhu
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Yuanyuan Hu
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaokun Liu
- Department of Cardiology, Gongren Hospital of Tangshan City, Tangshan, China
| | - Guangjian Jiang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
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11
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Mohseni-Moghaddam P, Ghobadian R, Khaleghzadeh-Ahangar H. Dementia in Diabetes mellitus and Atherosclerosis; Two Interrelated Systemic Diseases. Brain Res Bull 2022; 181:87-96. [DOI: 10.1016/j.brainresbull.2022.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 12/18/2021] [Accepted: 01/24/2022] [Indexed: 12/06/2022]
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12
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Cai J, Li Y, Liu S, Liu Q, Zhang J, Wei Y, Mo X, Lin Y, Tang X, Mai T, Mo C, Luo T, Huang S, Lu H, Zhang Z, Qin J. Associations between multiple heavy metals exposure and glycated hemoglobin in a Chinese population. CHEMOSPHERE 2022; 287:132159. [PMID: 34509013 DOI: 10.1016/j.chemosphere.2021.132159] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Heavy metals may play an important role as environmental risk factors in diabetes mellitus. This study aimed to explore the association of HbA1c with As, Cd, Cu, Ni, Pb, and Zn in single-metal exposure and multi-metal co-exposure models. METHODS A cross-sectional study involving 3472 participants was conducted. Plasma concentrations of heavy metals were determined by inductively coupled plasma mass spectrometry. We estimated the association of each metal with HbA1c by linear regression. Potential heterogeneities by sex, age, and smoking were investigated, and metal mixtures and interactions were assessed by the Bayesian kernel machine regression (BKMR). RESULTS In linear regression, Cu (β = 0.324, p < 0.05) and Ni (β = -0.19, p < 0.05) showed significant association with HbA1c in all participants. In BKMR analyses, all exposure-response relationships were approximately linear. Cu was significantly and positively associated with HbA1c levels in overall participants, women, participants aged 60 years old and above, and nonsmokers. Ni was significantly and negatively associated with HbA1c levels in overall participants. We did not observe the overall effect of plasma metal mixtures on HbA1c or the interaction effect of the metals on HbA1c. CONCLUSION Cu was positively correlated with HbA1c, whereas Ni was negatively correlated with HbA1c, when evaluated individually or in a metal mixture. Additional studies are necessary to confirm these correlations and to control for exposure to different metals in the general population.
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Affiliation(s)
- Jiansheng Cai
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, PR China; Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - You Li
- Department of Environmental Health and Occupational Medicine, School of Public Health, Guilin Medical University, Guilin, PR China
| | - Shuzhen Liu
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Qiumei Liu
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Junling Zhang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Yanfei Wei
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Xiaoting Mo
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Yinxia Lin
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Xu Tang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Tingyu Mai
- Department of Environmental Health and Occupational Medicine, School of Public Health, Guilin Medical University, Guilin, PR China
| | - Chunbao Mo
- Department of Environmental Health and Occupational Medicine, School of Public Health, Guilin Medical University, Guilin, PR China
| | - Tingyu Luo
- Department of Environmental Health and Occupational Medicine, School of Public Health, Guilin Medical University, Guilin, PR China
| | - Shenxiang Huang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Huaxiang Lu
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China
| | - Zhiyong Zhang
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China; Department of Environmental Health and Occupational Medicine, School of Public Health, Guilin Medical University, Guilin, PR China.
| | - Jian Qin
- Department of Environmental and Occupational Health, School of Public Health, Guangxi Medical University, Shuangyong Road No.22, Nanning, 530021, Guangxi province, PR China.
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13
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De Sanctis V, Soliman A, Daar S, Tzoulis P, Yassin MA, Di Maio S, Kattamis C. Insulin-Like Growth Factor -1 (IGF-1) and Glucose Dysregulation in Young Adult Patients with β-Thalassemia Major: Causality or Potential Link? ACTA BIO-MEDICA : ATENEI PARMENSIS 2022; 93:e2022331. [PMID: 36533767 PMCID: PMC9828921 DOI: 10.23750/abm.v93i6.13288] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/04/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND Insulin-like growth factor-1 (IGF-1) has been shown to lower blood glucose through stimulating glucose transport to fat and muscle and inhibiting hepatic glucose output. Although previous cross-sectional reports reported an association between low circulating concentrations of IGF-1 and glucose dysregulation (GD), its role is still debated. AIMS OF STUDY The present retrospective study was designed to assess the circulating IGF-1 levels in β-thalassemia major (β -TM) patients with normal oral glucose tolerance test (NGT-OGTT) and (GD) referred for an endocrine evaluation to explore the potential link between low IGF-1 and GD. STUDY DESIGN AND METHODS Our study included 34 young adult patients with β-TM; 12 patients with NGT after OGTT, 7 with impaired glucose tolerance (IGT), 9 with impaired fasting glucose (IFG) plus IGT, and 6 patients with β-TM-related diabetes mellitus (β-TM- DM). RESULTS Twenty-two β-TM patients with GD or β-TM- DM and 1 patient with NGT had IGF-1 levels below the 2.5th percentile. Correlation of IGF-1 with fasting plasma glucose, HOMA-IR (homeostatic model assessment for insulin resistance) and OGIS (oral glucose insulin sensitivity) was found. Moreover, a negative correlation was documented between ALT and the Insulinogenic Index (IGI) and a positive correlation between serum ferritin and PG 2-h after OGTT. CONCLUSION This study reports for the first time an association between low levels of IGF-1 and GD in β-TM patients. Despite some limitations, our study can serve to generate proposals for more convenient and efficient methods to identify and treat early GD in patients with β-TM, and to conduct more extensive studies. www.actabiomedica.it).
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Affiliation(s)
- Vincenzo De Sanctis
- Coordinator of ICET-A Network (International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine) and Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy
| | - Ashraf Soliman
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar and Department of Pediatrics, Division of Endocrinology, Alexandria University Children’s Hospital, Alexandria, Egypt
| | - Shahina Daar
- Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman, Oman
| | - Ploutarchos Tzoulis
- Department of Metabolism and Experimental Therapeutics, Division of Medicine, University College London, London, UK
| | - Mohamed A. Yassin
- Hematology-Oncology Department, National Centre for Cancer Care and Research, Doha, Qatar
| | - Salvatore Di Maio
- Emeritus Director in Pediatrics, Children’s Hospital “Santobono-Pausilipon”, Naples, Italy
| | - Christos Kattamis
- First Department of Pediatrics, National Kapodistrian University of Athens, Greece
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14
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Barone E, Di Domenico F, Perluigi M, Butterfield DA. The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease. Free Radic Biol Med 2021; 176:16-33. [PMID: 34530075 PMCID: PMC8595768 DOI: 10.1016/j.freeradbiomed.2021.09.006] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/31/2021] [Accepted: 09/09/2021] [Indexed: 02/08/2023]
Abstract
Alzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resistance, as a risk factor for AD and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported in recent clinical and preclinical studies. Brain functions require continuous supply of glucose and oxygen and a tight regulation of metabolic processes. Loss of this metabolic regulation has been proposed to be a contributor to memory dysfunction associated with neurodegeneration. Within the above scenario, this review will focus on the interplay among oxidative stress (OS), insulin resistance and AMPK dysfunctions in the brain by highlighting how these neurotoxic events contribute to neurodegeneration. We provide an overview on the detrimental effects of OS on proteins regulating insulin signaling and how these alterations impact cell metabolic dysfunctions through AMPK dysregulation. Such processes, we assert, are critically involved in the molecular pathways that underlie AD.
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Affiliation(s)
- Eugenio Barone
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - Fabio Di Domenico
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - Marzia Perluigi
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - D Allan Butterfield
- Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506-0055, USA.
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Bilen A, Calik I, Yayla M, Dincer B, Tavaci T, Cinar I, Bilen H, Cadirci E, Halici Z, Mercantepe F. Does daily fasting shielding kidney on hyperglycemia-related inflammatory cytokine via TNF-α, NLRP3, TGF-β1 and VCAM-1 mRNA expression. Int J Biol Macromol 2021; 190:911-918. [PMID: 34492249 DOI: 10.1016/j.ijbiomac.2021.08.216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 02/08/2023]
Abstract
This study aimed to investigate the effects of blood glucose control and the kidneys' functions, depending on fasting, in the streptozotocin-induced diabetes model in rats via TNF-α, NLRP-3, TGF-β1 and VCAM-1 mRNA expression in the present study. 32 Wistar albino rats were allocated randomly into four main groups; H (Healthy, n = 6), HF (Healthy fasting, n = 6), D (Diabetes, n = 10), DF (Diabetes and fasting, n = 10). Blood glucose and HbA1c levels significantly increased in the D group compared to the healthy ones (p < 0.05). However, the fasting period significantly improved blood glucose and HbA1c levels 14 days after STZ induced diabetes in rats compared to the D group. Similar findings we obtained for serum (BUN-creatinine) and urine samples (creatinine and urea levels). STZ induced high glucose levels significantly up-regulated TNF-α, NLRP-3, TGF-β1 and VCAM-1 mRNA expression and fasting significantly decreased these parameters when compared to diabetic rats. Histopathological staining also demonstrated the protective effects of fasting on diabetic kidney tissue. In conclusion, intermittent fasting regulated blood glucose level as well as decreasing harmful effects of diabetes on kidney tissue. The fasting period significantly decreased the hyperglycemia-related inflammatory cytokine damage on kidneys and also reduced apoptosis in favor of living organisms.
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Affiliation(s)
- Arzu Bilen
- Department of Internal Medicine, Division of Endocrinology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Ilknur Calik
- Department of Pathology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Muhammed Yayla
- Department of Pharmacology, Faculty of Medicine, Kafkas University, Kars, Turkey
| | - Busra Dincer
- Department of Pharmacology, Faculty of Pharmacy, Erzincan Binali Yildirim University, Erzincan, Turkey
| | - Taha Tavaci
- Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Irfan Cinar
- Department of Pharmacology, Faculty of Medicine, Kastamonu University, Kastamonu, Turkey
| | - Habip Bilen
- Department of Internal Medicine, Division of Endocrinology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Elif Cadirci
- Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey; Ataturk University, Clinical Research, Development and Design Application and Research Center, Erzurum, Turkey
| | - Zekai Halici
- Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey; Ataturk University, Clinical Research, Development and Design Application and Research Center, Erzurum, Turkey
| | - Filiz Mercantepe
- Department of Internal Medicine, Division of Endocrinology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
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16
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Mahmoudi N, Kiasalari Z, Rahmani T, Sanaierad A, Afshin-Majd S, Naderi G, Baluchnejadmojarad T, Roghani M. Diosgenin Attenuates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats: Underlying Mechanisms. Neuropsychobiology 2021; 80:25-35. [PMID: 32526752 DOI: 10.1159/000507398] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 03/19/2020] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Prolonged diabetes mellitus causes impairments of cognition and attentional dysfunctions. Diosgenin belongs to a group of steroidal saponins with reported anti-diabetic and numerous protective properties. This research aimed to assess the effect of diosgenin on beneficially ameliorating learning and memory decline in a rat model of type 1 diabetes caused by streptozotocin (STZ) and to explore its modes of action including involvement in oxidative stress and inflammation. METHODS Rats were assigned to one of four experimental groups, comprising control, control under treatment with diosgenin, diabetic, and diabetic under treatment with diosgenin. Diosgenin was given daily p.o. (40 mg/kg) for 5 weeks. RESULTS The administration of diosgenin to the diabetic group reduced the deficits of functional performance in behavioral tests, consisting of Y-maze, passive avoidance, radial arm maze, and novel object discrimination tasks (recognitive). Furthermore, diosgenin treatment attenuated hippocampal acetylcholinesterase activity and malon-dialdehyde, along with improvement of antioxidants such as superoxide dismutase and glutathione. Meanwhile, the hippocampal levels of inflammatory indicators, namely interleukin 6, nuclear factor-κB, toll-like receptor 4, tumor necrosis factor α, and astrocyte-specific biomarker glial fibrillary acidic protein, were lower and, on the other hand, tissue levels of nuclear factor (erythroid-derived 2)-related factor 2 were elevated upon diosgenin administration. Besides, the mushroom-like spines of the pyramidal neurons of the hippocampal CA1 area decreased in the diabetic group, and this was alleviated following diosgenin medication. CONCLUSIONS Taken together, diosgenin is capable of ameliorating cognitive deficits in STZ-diabetic animals, partly due to its amelioration of oxidative stress, inflammation, astrogliosis, and possibly improvement of cholinergic function in addition to its neuroprotective potential.
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Affiliation(s)
- Narges Mahmoudi
- Department of Physiology, School of Medicine, Shahed University, Tehran, Iran
| | - Zahra Kiasalari
- Neurophysiology Research Center, Shahed University, Tehran, Iran
| | - Tayebeh Rahmani
- Department of Physiology, School of Medicine, Shahed University, Tehran, Iran
| | - Ashkan Sanaierad
- Department of Physiology, School of Medicine, Shahed University, Tehran, Iran
| | | | - Gholamali Naderi
- Department of Biochemistry, School of Medicine, Shahed University, Tehran, Iran
| | | | - Mehrdad Roghani
- Neurophysiology Research Center, Shahed University, Tehran, Iran,
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17
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Jukić I, Kolobarić N, Stupin A, Matić A, Kozina N, Mihaljević Z, Mihalj M, Šušnjara P, Stupin M, Ćurić ŽB, Selthofer-Relatić K, Kibel A, Lukinac A, Kolar L, Kralik G, Kralik Z, Széchenyi A, Jozanović M, Galović O, Medvidović-Kosanović M, Drenjančević I. Carnosine, Small but Mighty-Prospect of Use as Functional Ingredient for Functional Food Formulation. Antioxidants (Basel) 2021; 10:1037. [PMID: 34203479 PMCID: PMC8300828 DOI: 10.3390/antiox10071037] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 11/17/2022] Open
Abstract
Carnosine is a dipeptide synthesized in the body from β-alanine and L-histidine. It is found in high concentrations in the brain, muscle, and gastrointestinal tissues of humans and is present in all vertebrates. Carnosine has a number of beneficial antioxidant properties. For example, carnosine scavenges reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes created by peroxidation of fatty acid cell membranes during oxidative stress. Carnosine can oppose glycation, and it can chelate divalent metal ions. Carnosine alleviates diabetic nephropathy by protecting podocyte and mesangial cells, and can slow down aging. Its component, the amino acid beta-alanine, is particularly interesting as a dietary supplement for athletes because it increases muscle carnosine, and improves effectiveness of exercise and stimulation and contraction in muscles. Carnosine is widely used among athletes in the form of supplements, but rarely in the population of cardiovascular or diabetic patients. Much less is known, if any, about its potential use in enriched food. In the present review, we aimed to provide recent knowledge on carnosine properties and distribution, its metabolism (synthesis and degradation), and analytical methods for carnosine determination, since one of the difficulties is the measurement of carnosine concentration in human samples. Furthermore, the potential mechanisms of carnosine's biological effects in musculature, metabolism and on immunomodulation are discussed. Finally, this review provides a section on carnosine supplementation in the form of functional food and potential health benefits and up to the present, neglected clinical use of carnosine.
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Affiliation(s)
- Ivana Jukić
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
| | - Nikolina Kolobarić
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
| | - Ana Stupin
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Pathophysiology, Physiology and Immunology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 10E, HR-31000 Osijek, Croatia
| | - Anita Matić
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
| | - Nataša Kozina
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
| | - Zrinka Mihaljević
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
| | - Martina Mihalj
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Dermatology and Venereology, University Hospital Osijek, HR-31000 Osijek, Croatia
| | - Petar Šušnjara
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
| | - Marko Stupin
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department for Cardiovascular Disease, University Hospital Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia
| | - Željka Breškić Ćurić
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Internal Medicine, General Hospital Vinkovci, Zvonarska 57, HR-32100 Vinkovci, Croatia
| | - Kristina Selthofer-Relatić
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department for Cardiovascular Disease, University Hospital Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia
- Department for Internal Medicine, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia
| | - Aleksandar Kibel
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department for Cardiovascular Disease, University Hospital Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia
| | - Anamarija Lukinac
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Rheumatology, Clinical Immunology and Allergology, Clinical Hospital Center Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia
| | - Luka Kolar
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Internal Medicine, Vukovar General Hospital, HR-32000 Vukovar, Croatia
| | - Gordana Kralik
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Nutricin j.d.o.o. Darda, HR-31326 Darda, Croatia
| | - Zlata Kralik
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Animal Production and Biotechnology, Faculty of Agrobiotechnical Sciences, Josip Juraj Strossmayer University of Osijek, Vladimira Preloga 1, HR-31000 Osijek, Croatia
| | - Aleksandar Széchenyi
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia
| | - Marija Jozanović
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia
| | - Olivera Galović
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia
| | - Martina Medvidović-Kosanović
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia
| | - Ines Drenjančević
- Department of Physiology and Immunology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (I.J.); (N.K.); (A.S.); (A.M.); (N.K.); (Z.M.); (M.M.); (P.Š.); (M.S.); (A.K.)
- Scientific Center of Excellence for Personalized Health Care, Josip Juraj Strossmayer University of Osijek, Trg Svetog Trojstva 3, HR-31000 Osijek, Croatia; (Ž.B.Ć.); (K.S.-R.); (A.L.); (L.K.); (G.K.); (Z.K.); (A.S.); (M.J.); (O.G.); (M.M.-K.)
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Rojas M, Chávez-Castillo M, Bautista J, Ortega Á, Nava M, Salazar J, Díaz-Camargo E, Medina O, Rojas-Quintero J, Bermúdez V. Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. World J Diabetes 2021; 12:745-766. [PMID: 34168725 PMCID: PMC8192246 DOI: 10.4239/wjd.v12.i6.745] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/20/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
At present, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD.
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Affiliation(s)
- Milagros Rojas
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Mervin Chávez-Castillo
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Jordan Bautista
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Ángel Ortega
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Manuel Nava
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Edgar Díaz-Camargo
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Oscar Medina
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Joselyn Rojas-Quintero
- Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02155, United States
| | - Valmore Bermúdez
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia
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19
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Jing G, Wang H, Nan F, Liu Y, Zhang M. Naofucong Ameliorates High Glucose Induced Hippocampal Neuron Injury Through Suppressing P2X7/NLRP1/Caspase-1 Pathway. Front Pharmacol 2021; 12:647116. [PMID: 34093185 PMCID: PMC8173084 DOI: 10.3389/fphar.2021.647116] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 04/28/2021] [Indexed: 12/26/2022] Open
Abstract
P2X7/NLRP1/caspase-1 mediated neuronal injury plays an important role in diabetic cognitive impairment and eventually inflammatory cascade reaction. Chinese herbal compound Naofucong has been mainly used to treat cognitive disorders in Traditional Chinese Medicine The present study aimed to investigate whether its neuroprotective effects might be related to the inhibition of P2X7R/NLRP1/caspase-1 mediated neuronal injury or not. In this study, high glucose-induced HT22 hippocampal neurons were used to determine Naofucong-containing serum neuronal protective effects. Lentiviruses knock out of TXNIP and P2X7R was used to determine that protective effects of Naofucong was related to inflammatory response and P2X7/NLRP1/caspase-1 mediated neuronal injury. NAC was also used to inhibit oxidative stress, so as to determine that oxidative stress is an important starting factor for neuronal injury of HT22 cells cultured with high glucose. Naofucong decreased apoptosis, IL-1β and IL-18 levels in high glucose-induced HT22 hippocampal neuron cells. Naofucong suppressed NLRP1/caspase-1 mediated neuronal injury, and P2X7 was involved in process. HT22 cells cultured in high glucose had an internal environment with elevated oxidative stress, which could promote neuronal injury. The current study demonstrated that Naofucong could significantly improve high glucose-induced HT22 hippocampal neuron injury, which might be related to suppress P2X7R/NLRP1/caspase-1 pathway, which provides novel evidence to support the future clinical use of Naofucong.
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Affiliation(s)
- Guangchan Jing
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Huanyuan Wang
- Acupuncture and Tuina Department, Qilu Hospital of Shandong University, Jinan, China
| | - Fengwei Nan
- Department of Endocrinology, Kaifeng Hospital of Traditional Chinese Medicine, Kaifeng, China
| | - Yuqin Liu
- Department of Cell Resource Center, Institute of Basic Medical Science, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Mengren Zhang
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Li R, Wang B, Wu C, Li D, Wu Y, Ye L, Ye L, Chen X, Li P, Yuan Y, Zhang H, Xie L, Li X, Xiao J, Wang J. Acidic fibroblast growth factor attenuates type 2 diabetes-induced demyelination via suppressing oxidative stress damage. Cell Death Dis 2021; 12:107. [PMID: 33479232 PMCID: PMC7819983 DOI: 10.1038/s41419-021-03407-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023]
Abstract
Prolonged type 2 diabetes mellitus (T2DM) produces a common complication, peripheral neuropathy, which is accompanied by nerve fiber disorder, axon atrophy, and demyelination. Growing evidence has characterized the beneficial effects of acidic fibroblast growth factor (aFGF) and shown that it relieves hyperglycemia, increases insulin sensitivity, and ameliorates neuropathic impairment. However, there is scarce evidence on the role of aFGF on remodeling of aberrant myelin under hyperglycemia condition. Presently, we observed that the expression of aFGF was rapidly decreased in a db/db T2DM mouse model. Administration of exogenous aFGF was sufficient to block acute demyelination and nerve fiber disorganization. Furthermore, this strong anti-demyelinating effect was most likely dominated by an aFGF-mediated increase of Schwann cell (SC) proliferation and migration as well as suppression of its apoptosis. Mechanistically, the beneficial biological effects of aFGF on SC behavior and abnormal myelin morphology were likely due to the inhibition of hyperglycemia-induced oxidative stress activation, which was most likely activated by kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived-like 2 (Nrf2) signaling. Thus, this evidence indicates that aFGF is a promising protective agent for relieving myelin pathology through countering oxidative stress signaling cascades under diabetic conditions.
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Affiliation(s)
- Rui Li
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China ,grid.268099.c0000 0001 0348 3990Research Center, Affiliated Xiangshang Hospital, Wenzhou Medical University, 315700 Ningbo, Zhejiang China ,grid.12981.330000 0001 2360 039XSchool of Chemistry, Sun Yat-sen University, 510275 Guangzhou, Guangdong China
| | - Beini Wang
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Chengbiao Wu
- grid.268099.c0000 0001 0348 3990Research Center, Affiliated Xiangshang Hospital, Wenzhou Medical University, 315700 Ningbo, Zhejiang China
| | - Duohui Li
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Yanqing Wu
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Libing Ye
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Luxia Ye
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Xiongjian Chen
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Peifeng Li
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Yuan Yuan
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Hongyu Zhang
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Ling Xie
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Xiaokun Li
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Jian Xiao
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
| | - Jian Wang
- grid.268099.c0000 0001 0348 3990Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, Zhejiang China
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Maiese K. Nicotinamide as a Foundation for Treating Neurodegenerative Disease and Metabolic Disorders. Curr Neurovasc Res 2021; 18:134-149. [PMID: 33397266 PMCID: PMC8254823 DOI: 10.2174/1567202617999210104220334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023]
Abstract
Neurodegenerative disorders impact more than one billion individuals worldwide and are intimately tied to metabolic disease that can affect another nine hundred individuals throughout the globe. Nicotinamide is a critical agent that may offer fruitful prospects for neurodegenerative diseases and metabolic disorders, such as diabetes mellitus. Nicotinamide protects against multiple toxic environments that include reactive oxygen species exposure, anoxia, excitotoxicity, ethanolinduced neuronal injury, amyloid (Aß) toxicity, age-related vascular disease, mitochondrial dysfunction, insulin resistance, excess lactate production, and loss of glucose homeostasis with pancreatic β-cell dysfunction. However, nicotinamide offers cellular protection in a specific concentration range, with dosing outside of this range leading to detrimental effects. The underlying biological pathways of nicotinamide that involve the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and mammalian forkhead transcription factors (FoxOs) may offer insight for the clinical translation of nicotinamide into a safe and efficacious therapy through the modulation of oxidative stress, apoptosis, and autophagy. Nicotinamide is a highly promising target for the development of innovative strategies for neurodegenerative disorders and metabolic disease, but the benefits of this foundation depend greatly on gaining a further understanding of nicotinamide's complex biology.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Suresh J, Khor IW, Kaur P, Heng HL, Torta F, Dawe GS, Tai ES, Tolwinski NS. Shared signaling pathways in Alzheimer’s and metabolic disease may point to new treatment approaches. FEBS J 2020; 288:3855-3873. [DOI: 10.1111/febs.15540] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/18/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022]
Affiliation(s)
| | - Ing Wei Khor
- Department of Medicine Yong Loo Lin School of MedicineNational University of Singapore
| | - Prameet Kaur
- Science Division Yale‐ NUS College Singapore Singapore
| | - Hui Li Heng
- Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore, and Neurobiology Programme
- Life Sciences Institute National University of Singapore Singapore
| | - Federico Torta
- Singapore Lipidomics Incubator Department of Biochemistry Yong Loo Lin School of MedicineNational University of Singapore Singapore
| | - Gavin S. Dawe
- Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore, and Neurobiology Programme
- Life Sciences Institute National University of Singapore Singapore
| | - E Shyong Tai
- Department of Medicine Yong Loo Lin School of MedicineNational University of Singapore
- Division of Endocrinology National University HospitalNational University Health System
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Maiese K. Dysregulation of metabolic flexibility: The impact of mTOR on autophagy in neurodegenerative disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 155:1-35. [PMID: 32854851 DOI: 10.1016/bs.irn.2020.01.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-communicable diseases (NCDs) that involve neurodegenerative disorders and metabolic disease impact over 400 million individuals globally. Interestingly, metabolic disorders, such as diabetes mellitus, are significant risk factors for the development of neurodegenerative diseases. Given that current therapies for these NCDs address symptomatic care, new avenues of discovery are required to offer treatments that affect disease progression. Innovative strategies that fill this void involve the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), AMP activated protein kinase (AMPK), trophic factors that include erythropoietin (EPO), and the programmed cell death pathways of autophagy and apoptosis. These pathways are intriguing in their potential to provide effective care for metabolic and neurodegenerative disorders. Yet, future work is necessary to fully comprehend the entire breadth of the mTOR pathways that can effectively and safely translate treatments to clinical medicine without the development of unexpected clinical disabilities.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY, United States.
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24
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Impact of Overweight in Mens with Family History of Hypertension: Early Heart Rate Variability and Oxidative Stress Disarrangements. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3049831. [PMID: 32802262 PMCID: PMC7415118 DOI: 10.1155/2020/3049831] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 05/26/2020] [Accepted: 07/03/2020] [Indexed: 11/17/2022]
Abstract
Aim To evaluate cardiovascular, autonomic, and oxidative stress markers in eutrophic and overweight offspring of hypertensive parents comparing them to eutrophic and overweight offspring of normotensive parents. Methods We conducted a cross-sectional study. We selected 71 male and sedentary subjects, divided into 4 groups: eutrophic group with a negative family history of hypertension (EH-, n = 18) or positive family history of hypertension (EH+, n = 17), overweight group with a negative family history of hypertension (OH-, n = 19) or a positive family history of hypertension (OH+, n = 17), and aged between 18 and 35 years. Results Blood glucose was higher in the OH+ group when compared to other groups. Diastolic blood pressure was increased in OH- and OH+ groups when compared to eutrophic groups. Regarding the HRV, the LF abs was higher in OH- and OH+ groups when compared to the EH- group. LF/HF values were higher in EH+ and OH+ groups when compared to the EH- and OH- groups. As to oxidative stress and the metabolism of nitric oxide, we observed an increase in hydrogen peroxide and nitrite levels in the OH+ group, and in the NADPH oxidase in OH- and OH+ groups when compared to the other groups. Conclusion Our findings demonstrate that the overweight group with a family history of hypertension presented all the dysfunctions observed in isolation from these risk factors. We observed an exacerbation of cardiac sympathetic modulation and early prooxidants increase, which may be associated with target organ damage and cardiovascular risk in this population.
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Abstract
Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic beta-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022,
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26
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Kordi M, Khoramshahi S, Eshghi S, Gaeeni A, Moosakhani A. The effect of high intensity interval training on some atrophic and anti-atrophic gene expression in rat skeletal muscle with diabetes. Sci Sports 2020. [DOI: 10.1016/j.scispo.2019.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Adelusi TI, Du L, Hao M, Zhou X, Xuan Q, Apu C, Sun Y, Lu Q, Yin X. Keap1/Nrf2/ARE signaling unfolds therapeutic targets for redox imbalanced-mediated diseases and diabetic nephropathy. Biomed Pharmacother 2020; 123:109732. [PMID: 31945695 DOI: 10.1016/j.biopha.2019.109732] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/27/2019] [Accepted: 12/05/2019] [Indexed: 12/22/2022] Open
Abstract
Hyperglycemia/oxidative stress has been implicated in the initiation and progression of diabetic complications while the components of Keap1/Nrf2/ARE signaling are being exploited as therapeutic targets for the treatment/management of these pathologies. Antioxidant agents like drugs, nutraceuticals and pure compounds that target the proteins of this pathway and their downstream genes hold the therapeutic strength to put the progression of this disease at bay. Here, we elucidate how the modulation of Keap1/Nrf2/ARE had been exploited for the treatment/management of end-stage diabetic kidney complication (diabetic nephropathy) by looking into (1) Nrf2 nuclear translocation and phosphorylation by some protein kinases at specific amino acid sequences and (2) Keap1 downregulation/Keap1-Nrf2 protein-protein inhibition (PPI) as potential therapeutic mechanisms exploited by Nrf2 activators for the modulation of diabetic nephropathy biomarkers (Collagen IV, Laminin, TGF-β1 and Fibronectin) that ultimately lead to the amelioration of this disease progression. Furthermore, we brought to limelight the relationship between diabetic nephropathy and Keap1/Nrf2/ARE and finally elucidate how the modulation of this signaling pathway could be further explored to create novel therapeutic milestones.
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Affiliation(s)
- Temitope Isaac Adelusi
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Lei Du
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Meng Hao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xueyan Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Qian Xuan
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Chowdhury Apu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Ying Sun
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
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Maiese K. Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes. Curr Neurovasc Res 2020; 17:765-783. [PMID: 33183203 PMCID: PMC7914159 DOI: 10.2174/1567202617999201111195232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020; 13:23-34. [PMID: 31794280 PMCID: PMC6959472 DOI: 10.1080/17512433.2020.1698288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Abstract
Introduction: Dementia is the 7th leading cause of death that imposes a significant financial and service burden on the global population. Presently, only symptomatic care exists for cognitive loss, such as Alzheimer's disease.Areas covered: Given the advancing age of the global population, it becomes imperative to develop innovative therapeutic strategies for cognitive loss. New studies provide insight to the association of cognitive loss with metabolic disorders, such as diabetes mellitus.Expert opinion: Diabetes mellitus is increasing in incidence throughout the world and affects 350 million individuals. Treatment strategies identifying novel pathways that oversee metabolic and neurodegenerative disorders offer exciting prospects to treat dementia. The mechanistic target of rapamycin (mTOR) and circadian clock gene pathways that include AMP activated protein kinase (AMPK), Wnt1 inducible signaling pathway protein 1 (WISP1), erythropoietin (EPO), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) provide novel strategies to treat cognitive loss that has its basis in metabolic cellular dysfunction. However, these pathways are complex and require precise regulation to maximize treatment efficacy and minimize any potential clinical disability. Further investigations hold great promise to treat both the onset and progression of cognitive loss that is associated with metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Jamali-Raeufy N, Baluchnejadmojarad T, Roghani M, keimasi S, goudarzi M. Isorhamnetin exerts neuroprotective effects in STZ-induced diabetic rats via attenuation of oxidative stress, inflammation and apoptosis. J Chem Neuroanat 2019; 102:101709. [DOI: 10.1016/j.jchemneu.2019.101709] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 11/01/2019] [Accepted: 11/01/2019] [Indexed: 12/13/2022]
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Wang Y, Yu H, Liu F, Song X. Analysis of key genes and their functions in placental tissue of patients with gestational diabetes mellitus. Reprod Biol Endocrinol 2019; 17:104. [PMID: 31783860 PMCID: PMC6884804 DOI: 10.1186/s12958-019-0546-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/20/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND This study was aimed at screening out the potential key genes and pathways associated with gestational diabetes mellitus (GDM). METHODS The GSE70493 dataset used for this study was obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in the placental tissue of women with GDM in relation to the control tissue samples were identified and submitted to protein-protein interaction (PPI) network analysis and subnetwork module mining. Functional enrichment analyses of the PPI network and subnetworks were subsequently carried out. Finally, the integrated miRNA-transcription factor (TF)-DEG regulatory network was analyzed. RESULTS In total, 238 DEGs were identified, of which 162 were upregulated and 76 were downregulated. Through PPI network construction, 108 nodes and 278 gene pairs were obtained, from which chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, protein tyrosine phosphatase, receptor type C (PTPRC), and human leukocyte antigen (HLA) were screened out as hub genes. Moreover, genes associated with the immune-related pathway and immune responses were found to be significantly enriched in the process of GDM. Finally, miRNAs and TFs that target the DEGs were predicted. CONCLUSIONS Four candidate genes (viz., CXCL9, CXCL10, PTPRC, and HLA) are closely related to GDM. miR-223-3p, miR-520, and thioredoxin-binding protein may play important roles in the pathogenesis of this disease.
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Affiliation(s)
- Yuxia Wang
- grid.452222.1Department of Gynecology, Jinan Central Hospital, Jinan City, 250013 Shandong Province China
| | - Haifeng Yu
- grid.452222.1Department of Obstetrics, Jinan Central Hospital, No. 105 Jiefang Road, Lixia District, Jinan City, 250013 Shandong Province China
| | - Fangmei Liu
- grid.452222.1Department of Obstetrics, Jinan Central Hospital, No. 105 Jiefang Road, Lixia District, Jinan City, 250013 Shandong Province China
| | - Xiue Song
- grid.452222.1Department of Obstetrics, Jinan Central Hospital, No. 105 Jiefang Road, Lixia District, Jinan City, 250013 Shandong Province China
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Schön M, Mousa A, Berk M, Chia WL, Ukropec J, Majid A, Ukropcová B, de Courten B. The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence. Nutrients 2019; 11:nu11061196. [PMID: 31141890 PMCID: PMC6627134 DOI: 10.3390/nu11061196] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/17/2019] [Accepted: 05/23/2019] [Indexed: 12/17/2022] Open
Abstract
Neurological, neurodegenerative, and psychiatric disorders represent a serious burden because of their increasing prevalence, risk of disability, and the lack of effective causal/disease-modifying treatments. There is a growing body of evidence indicating potentially favourable effects of carnosine, which is an over-the-counter food supplement, in peripheral tissues. Although most studies to date have focused on the role of carnosine in metabolic and cardiovascular disorders, the physiological presence of this di-peptide and its analogues in the brain together with their ability to cross the blood-brain barrier as well as evidence from in vitro, animal, and human studies suggest carnosine as a promising therapeutic target in brain disorders. In this review, we aim to provide a comprehensive overview of the role of carnosine in neurological, neurodevelopmental, neurodegenerative, and psychiatric disorders, summarizing current evidence from cell, animal, and human cross-sectional, longitudinal studies, and randomized controlled trials.
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Affiliation(s)
- Martin Schön
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 84215 Bratislava, Slovakia.
- Biomedical Research Center, Slovak Academy of Sciences, 81439 Bratislava, Slovakia.
| | - Aya Mousa
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Melbourne, Victoria 3168, Australia.
| | - Michael Berk
- School of Medicine, IMPACT Strategic Research Centre, Barwon Health, Deakin University, Geelong, Victoria 3220, Australia.
- Orygen, The Centre of Excellence in Youth Mental Health, the Department of Psychiatry and the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria 3052, Australia.
| | - Wern L Chia
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Melbourne, Victoria 3168, Australia.
| | - Jozef Ukropec
- Biomedical Research Center, Slovak Academy of Sciences, 81439 Bratislava, Slovakia.
| | - Arshad Majid
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
| | - Barbara Ukropcová
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 84215 Bratislava, Slovakia.
- Biomedical Research Center, Slovak Academy of Sciences, 81439 Bratislava, Slovakia.
- Faculty of Physical Education and Sports, Comenius University, 81469 Bratislava, Slovakia.
| | - Barbora de Courten
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Melbourne, Victoria 3168, Australia.
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Guzmán DC, Brizuela NO, Herrera MO, Peraza AV, Juárez-Olguín H, Mejía GB. Insulin plus zinc induces a favorable biochemical response effects on oxidative damage and dopamine levels in rat brain. Int J Biol Macromol 2019; 132:230-235. [PMID: 30928372 DOI: 10.1016/j.ijbiomac.2019.03.200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 01/27/2023]
Abstract
The aim was to determine the effect of zinc (Zn) and insulin on oxidative stress and levels of dopamine in brain of rats. Wistar rats were treated either with zinc alone or combined with insulin during 10 days. After the last dose blood glucose was measured. Their brains were extracted to measure H2O2, Ca+2, Mg+2 ATPase, glutathione (GSH), lipid peroxidation (Tbars) and Dopamine. Zn does not possess anti-glycemic effect like Insulin however, it is noticeable that the combination of Insulin plus Zn induces a major glucose reduction (p < 0.0001) than Insulin alone. In cerebellum/medulla oblongata, the groups treated with Insulin and Zn show a significantly increase in dopamine (p < 0.005). Insulin plus Zn reduced GSH level in cortex. Insulin plus Zn reduced level of H2O2 in Striatum and in cerebellum/medulla oblongata. Lipid peroxidation was significantly reduced by the administration of Insulin as in the combination of Insulin and Zn in all regions (p < 0.0001). In cerebellum medulla oblongata, ATPase activity showed an increase only in the group treated with Insulin + Zn. CONCLUSION: These results suggest that the use of insulin plus Zn produce favorable changes on oxidative stress and this as consequence on the levels of dopamine.
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Affiliation(s)
- David Calderón Guzmán
- Laboratory of Neurosciences, Instituto Nacional de Pediatría (INP), Mexico City, Mexico
| | - Norma Osnaya Brizuela
- Laboratory of Neurosciences, Instituto Nacional de Pediatría (INP), Mexico City, Mexico
| | | | | | - Hugo Juárez-Olguín
- Laboratory of Pharmacology, INP, Mexico City, Mexico; Department of Pharmacology, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico.
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Xu F, Xiao H, Liu R, Yang Y, Zhang M, Chen L, Chen Z, Liu P, Huang H. Paeonol Ameliorates Glucose and Lipid Metabolism in Experimental Diabetes by Activating Akt. Front Pharmacol 2019; 10:261. [PMID: 30941042 PMCID: PMC6433795 DOI: 10.3389/fphar.2019.00261] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/01/2019] [Indexed: 01/09/2023] Open
Abstract
Our previous study proved that paeonol (Pae) could lower blood glucose levels of diabetic mice. There are also a few reports of its potential use for diabetes treatment. However, the role of Pae in regulating glucose and lipid metabolism in diabetes remains largely unknown. Considering the critical role of serine/threonine kinase B (Akt) in glucose and lipid metabolism, we explored whether Pae could improve glucose and lipid metabolism disorders via Akt. Here, we found that Pae attenuated fasting blood glucose, glycosylated serum protein, serum cholesterol and triglyceride (TG), hepatic glycogen, cholesterol and TG in diabetic mice. Moreover, Pae enhanced glucokinase (GCK) and low-density lipoprotein receptor (LDLR) protein expressions, and increased the phosphorylation of Akt. In insulin-resistant HepG2 cells, Pae increased glucose uptake and decreased lipid accumulation. What’s more, Pae elevated LDLR and GCK expressions as well as Akt phosphorylation, which was consistent with the in vivo results. Knockdown and inhibition experiments of Akt revealed that Pae regulated LDLR and GCK expressions through activation of Akt. Finally, molecular docking assay indicated the steady hydrogen bond was formed between Pae and Akt2. Experiments above suggested that Pae ameliorated glucose and lipid metabolism disorders and the underlying mechanism was closely related to the activation of Akt.
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Affiliation(s)
- Futian Xu
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China.,Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Haiming Xiao
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China.,Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Renbin Liu
- Department of Traditional Chinese Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yan Yang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China
| | - Meng Zhang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China
| | - Lihao Chen
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China
| | - Zhiquan Chen
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China
| | - Peiqing Liu
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China
| | - Heqing Huang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, China.,Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
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Li W, Chang M, Qiu M, Chen Y, Zhang X, Li Q, Cui C. Exogenous obestatin decreases beta-cell apoptosis and alfa-cell proliferation in high fat diet and streptozotocin induced type 2 diabetic rats. Eur J Pharmacol 2019; 851:36-42. [PMID: 30776368 DOI: 10.1016/j.ejphar.2019.02.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/14/2019] [Accepted: 02/15/2019] [Indexed: 12/31/2022]
Abstract
Type 2 diabetes is a chronic metabolic disease characterized by progressive decrease of islet cell function. Delaying the process of islet failure remains a challenging goal in diabetes care. Previous studies have confirmed the role of obestatin, a gut peptide that belongs to ghrelin family, in the mediation of glucose metabolism. This study aimed to observe the long term effects of exogenous obestatin on glucose metabolism in type 2 diabetes rat model. Type 2 diabetic rat model was set up by high-fat diet (60%) followed by a low dose of streptozotocin intra-peritoneal injection. Exogenous obestatin was administered at a dose of 20 nmol/kg for 12 weeks by intraperitoneal injection. Compared to placebo group (saline intraperitoneal injection), obestatin treatment decreased the glucagon levels and increased the c-peptide levels. Furthermore, obestatin treatment led to a significant restoration of islet morphology, increasing insulin and reducing glucagon expressions. Apoptosis assay showed a reduction in the number of TUNEL positive-cells. The up-regulation of Akt and GSK3β in pancreas was confirmed by Real-Time PCR. These results demonstrated that obestatin might have a potential therapeutic relevance in improving islet cell function, including increasing insulin secretion through inhibiting beta cell apoptosis and decreasing glucagon secretion by inhibiting alfa cell proliferation in type 2 diabetes. In spite of its role in these phenomena, it is necessary to further discuss, especially regarding the role of obestatin on glucagon.
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Affiliation(s)
- Wensong Li
- Department of Infectious Disease, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Manli Chang
- Department of Laboratory Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Mingli Qiu
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Yangli Chen
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Xiaochen Zhang
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Qiang Li
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Can Cui
- Department of Endocrinology and Metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
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Yelumalai S, Giribabu N, Karim K, Omar SZ, Salleh NB. In vivo administration of quercetin ameliorates sperm oxidative stress, inflammation, preserves sperm morphology and functions in streptozotocin-nicotinamide induced adult male diabetic rats. Arch Med Sci 2019; 15:240-249. [PMID: 30697276 PMCID: PMC6348351 DOI: 10.5114/aoms.2018.81038] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 11/14/2016] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Diabetes mellitus (DM) has been associated with sperm damage. In view of the fact that quercetin possesses antioxidant and anti-inflammatory activities, this compound may help to protect sperm against damage in DM. In this study, in-vivo effects of quercetin on sperm parameters in DM were investigated. MATERIAL AND METHODS Quercetin (10, 25 and 50 mg/kg/b.w.) was given orally to streptozotocin-nicotinamide induced adult male diabetic rats for 28 days. Following treatment completion, rats were sacrificed and sperm were harvested from the cauda epididymis. Sperm count, motility, viability, hyperosmotic swelling (HOS) tail-coiled sperm and morphology were assessed. Levels of lipid peroxidation (LPO) and anti-oxidative enzymes (SOD, CAT and GPx) in sperm with and without H2O2 incubation were determined by biochemical assays. Expression levels of SOD, CAT and GPx mRNAs in sperm were evaluated by qPCR. Sperm DNA integrity was estimated by flow cytometry while expression levels of the inflammatory markers NF-κβ and TNF-α in sperm were determined by Western blotting. RESULTS In diabetic rats receiving quercetin, sperm count and motility, viability and HOS tail-coiled sperm increased (p < 0.05) while sperm with abnormal morphology decreased. Moreover, sperm SOD, CAT, GPx activities and their mRNA expression levels increased while sperm LPO, NF-κβ and TNF-α levels decreased. In normal and diabetic rat sperm incubated with H2O2, a further increase in MDA and further decreases in SOD, CAT and GPx were observed, and these were ameliorated by quercetin treatment. CONCLUSIONS In-vivo administration of quercetin to diabetic rats helps to ameliorate sperm damage and improves sperm morphology and functions in DM.
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Affiliation(s)
- Suseela Yelumalai
- Department of Obstetric and Gynaecology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Nelli Giribabu
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kamarulzaman Karim
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Siti Zawiah Omar
- Department of Obstetric and Gynaecology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Naguib Bin Salleh
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Maiese K. Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors. Curr Neurovasc Res 2018; 15:81-91. [PMID: 29557749 PMCID: PMC6021214 DOI: 10.2174/1567202615666180319151244] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 01/23/2018] [Accepted: 02/07/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND With the global increase in lifespan expectancy, neurodegenerative disorders continue to affect an ever-increasing number of individuals throughout the world. New treatment strategies for neurodegenerative diseases are desperately required given the lack of current treatment modalities. METHODS Here, we examine novel strategies for neurodegenerative disorders that include circadian clock genes, non-coding Ribonucleic Acids (RNAs), and the mammalian forkhead transcription factors of the O class (FoxOs). RESULTS Circadian clock genes, non-coding RNAs, and FoxOs offer exciting prospects to potentially limit or remove the significant disability and death associated with neurodegenerative disorders. Each of these pathways has an intimate relationship with the programmed death pathways of autophagy and apoptosis and share a common link to the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and the mechanistic target of rapamycin (mTOR). Circadian clock genes are necessary to modulate autophagy, limit cognitive loss, and prevent neuronal injury. Non-coding RNAs can control neuronal stem cell development and neuronal differentiation and offer protection against vascular disease such as atherosclerosis. FoxOs provide exciting prospects to block neuronal apoptotic death and to activate pathways of autophagy to remove toxic accumulations in neurons that can lead to neurodegenerative disorders. CONCLUSION Continued work with circadian clock genes, non-coding RNAs, and FoxOs can offer new prospects and hope for the development of vital strategies for the treatment of neurodegenerative diseases. These innovative investigative avenues have the potential to significantly limit disability and death from these devastating disorders.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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38
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Badr JM, Ibrahim SRM, Abou-Hussein DR. Plicosepalin A, a new antioxidant catechin-gallic acid derivative of inositol from the mistletoe Plicosepalus curviflorus. ACTA ACUST UNITED AC 2017; 71:375-380. [PMID: 27206319 DOI: 10.1515/znc-2015-0231] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 04/20/2016] [Indexed: 01/27/2023]
Abstract
Phytochemical investigation of the semi-parasitic plant, Plicosepalus curviflorus (Loranthaceae) growing in Saudi Arabia resulted in the isolation of a new catechin-gallic acid derivative of inositol, plicosepalin A (1) [(+) catechin-4'-O-(1″-O-galloyl-5″-O-methyl)-myo-inositol], along with seven known compounds: methyl gallate (2), catechin (3), quercetin (4), gallic acid (5), lupeol (6), β-sitosterol (7), and ursolic acid (8). Their structures were elucidated on the basis of spectroscopic analyses, including HRESIMS, ESIMS, 1H and 13C NMR, HSQC, and HMBC, as well as comparison with reported data. The antioxidant and antimicrobial activities of 1 were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the disc diffusion assay, respectively. Compound 1 exhibited potent free radical scavenging activity with an IC50 value of 9.0 ± 0.27 μM. Moreover, significant activities against Staphylococcus aureus and Bacillus subtilis were recorded.
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Ganjifrockwala FA, Joseph JT, George G. Decreased total antioxidant levels and increased oxidative stress in South African type 2 diabetes mellitus patients. JOURNAL OF ENDOCRINOLOGY METABOLISM AND DIABETES OF SOUTH AFRICA 2017. [DOI: 10.1080/16089677.2017.1324590] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- FA Ganjifrockwala
- Department of Human Biology, Walter Sisulu University, Mthatha, South Africa
| | - JT Joseph
- Department of Human Biology, Walter Sisulu University, Mthatha, South Africa
| | - G George
- Department of Human Biology, Walter Sisulu University, Mthatha, South Africa
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Refat MS, El-Megharbel SM, Hussien MA, Hamza RZ, Al-Omar MA, Naglah AM, Afifi WM, Kobeasy MI. Spectroscopic, structural characterizations and antioxidant capacity of the chromium (III) niacinamide compound as a diabetes mellitus drug model. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2017; 173:122-131. [PMID: 27619974 DOI: 10.1016/j.saa.2016.08.053] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 07/02/2016] [Accepted: 08/28/2016] [Indexed: 06/06/2023]
Abstract
New binuclear chromium (III) niacinamide compound with chemical formula [Cr2(Nic)(Cl)6(H2O)4]·H2O was obtained upon the reaction of chromium (III) chloride with niacinamide (Nic) in methanol solvent at 60°C. The proposed structure was discussed with the help of microanalytical analyses, conductivity, spectroscopic (FT-IR and UV-vis.), magnetic calculations, thermogravimetric analyses (TG/TGA), and morphological studies (X-ray of solid powder and scan electron microscopy. The infrared spectrum of free niacinamide in comparison with its chromium (III) compound indicated that the chelation mode occurs via both nitrogen atoms of pyridine ring and primary -NH2 group. The efficiency of chromium (III) niacinamide compound in decreasing of glucose level of blood and HbA1c in case of diabetic rats was checked. The ameliorating gluconeogenic enzymes, lipid profile and antioxidant defense capacities are considered as an indicator of the efficiency of new chromium (III) compound as antidiabetic drug model.
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Affiliation(s)
- Moamen S Refat
- Chemistry Department, Faculty of Science, Taif University, P.O. Box 888, Al-Hawiah, Taif 21974, Saudi Arabia; Department of Chemistry, Faculty of Science, Port Said, Port Said University, Egypt.
| | - Samy M El-Megharbel
- Chemistry Department, Faculty of Science, Taif University, P.O. Box 888, Al-Hawiah, Taif 21974, Saudi Arabia; Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - M A Hussien
- Department of Chemistry, Faculty of Science, Port Said, Port Said University, Egypt
| | - Reham Z Hamza
- Department of Zoology, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Mohamed A Al-Omar
- Department of Pharmaceutical Chemistry, Drug Exploration and Development Chair, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed M Naglah
- Department of Pharmaceutical Chemistry, Drug Exploration and Development Chair, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre, 12622-Dokki, Cairo, Egypt
| | - Walid M Afifi
- International Extended Care Center, Jeddah, Saudi Arabia; Nephrology Unit, Zagazig University Hospital, Egypt
| | - Mohamed I Kobeasy
- Chemistry Department, Faculty of Science, Taif University, P.O. Box 888, Al-Hawiah, Taif 21974, Saudi Arabia; Department of Biochemistry, Faculty of Agriculture, Cairo University, Giza, Egypt
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Tran YH, Groen H, Bergman JEH, Hak E, Wilffert B. Exposure to reactive intermediate-inducing drugs during pregnancy and the incident use of psychotropic medications among children. Pharmacoepidemiol Drug Saf 2017; 26:265-273. [PMID: 28097730 DOI: 10.1002/pds.4161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 12/07/2016] [Accepted: 12/11/2016] [Indexed: 11/11/2022]
Abstract
PURPOSE Our study aimed to investigate the association between prenatal exposure to reactive intermediate (RI)-inducing drugs and the initiation of psychotropic medications among children. METHODS We designed a cohort study using a pharmacy prescription database. Pregnant women were considered exposed when they received a prescription of RI-inducing drugs. These drugs could be either used alone (RI+/FAA-) or combined with drugs exhibiting folic acid antagonism (FAA, RI+/FAA+). The reference group included pregnant women who did not receive any RI-inducing drugs or FAA drugs. RESULTS We analyzed 4116 exposed and 30 422 reference pregnancies. The hazard ratio (HR) with 95% confidence interval (CI) was 1.27 (95%CI 1.15-1.41) for pregnancies exposed to RI-inducing drugs as a whole. Considering subgroups of RI-inducing drugs, prenatal exposure to both RI+/FAA+ and RI+/FAA- was associated with the children's initiation of psychotropic medications, HRs being 1.35 (95%CI 1.10-1.66) and 1.26 (1.13-1.41), respectively. The HRs were increased with prolonged exposure to RI-inducing drugs, especially in the first and second trimesters. In a detailed examination of the psychotropics, the incidences of receiving antimigraine preparations and psychostimulants were significantly increased for the exposed children, compared with the reference children. The incidences of receiving antipsychotics and hypnotics were also higher for the exposed children; however, the HRs did not reach significance after adjustment. CONCLUSIONS We found a significantly increased incident use of psychotropic medications among children prenatally exposed to RI-inducing drugs, especially during the first and second trimesters. This suggests a detrimental effect during critical periods of brain development. Copyright © 2017 John Wiley & Sons, Ltd.
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Affiliation(s)
- Yen-Hao Tran
- Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, Epidemiology and Economics, University of Groningen, Groningen, The Netherlands
| | - Henk Groen
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jorieke E H Bergman
- Eurocat Registration Northern Netherlands, Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Eelko Hak
- Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, Epidemiology and Economics, University of Groningen, Groningen, The Netherlands
| | - Bob Wilffert
- Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, Epidemiology and Economics, University of Groningen, Groningen, The Netherlands.,Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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42
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Wen L, Zhang Y, Sun-Waterhouse D, You L, Fu X. Advantages of the polysaccharides from Gracilaria lemaneiformis over metformin in antidiabetic effects on streptozotocin-induced diabetic mice. RSC Adv 2017. [DOI: 10.1039/c6ra26970b] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
In the present study, polysaccharides fromGracilaria lemaneiformis(GLP) were obtained by citric acid extraction, and had a low molecular weight (21.2 kDa) with a high amount of galactose.
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Affiliation(s)
- Lingrong Wen
- School of Food Science and Engineering
- South China University of Technology
- Guangzhou 510640
- China
- Center of Guangdong Food Green Processing and Nutrition Regulation Engineering Technology
| | - Yunlin Zhang
- School of Food Science and Engineering
- South China University of Technology
- Guangzhou 510640
- China
- Center of Guangdong Food Green Processing and Nutrition Regulation Engineering Technology
| | - Dongxiao Sun-Waterhouse
- School of Food Science and Engineering
- South China University of Technology
- Guangzhou 510640
- China
- Center of Guangdong Food Green Processing and Nutrition Regulation Engineering Technology
| | - Lijun You
- School of Food Science and Engineering
- South China University of Technology
- Guangzhou 510640
- China
- Center of Guangdong Food Green Processing and Nutrition Regulation Engineering Technology
| | - Xiong Fu
- School of Food Science and Engineering
- South China University of Technology
- Guangzhou 510640
- China
- Center of Guangdong Food Green Processing and Nutrition Regulation Engineering Technology
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43
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Ahshin-Majd S, Zamani S, Kiamari T, Kiasalari Z, Baluchnejadmojarad T, Roghani M. Carnosine ameliorates cognitive deficits in streptozotocin-induced diabetic rats: Possible involved mechanisms. Peptides 2016; 86:102-111. [PMID: 27777064 DOI: 10.1016/j.peptides.2016.10.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 10/12/2016] [Accepted: 10/21/2016] [Indexed: 12/23/2022]
Abstract
Diabetic patients are at increased risk to develop cognitive deficit and senile dementia. This study was planned to assess the benefits of chronic carnosine administration on prevention of learning and memory deterioration in streptozotocin (STZ)-diabetic rats and to explore some of the involved mechanisms. Rats were divided into 5 groups: i.e., control, carnosine100-treated control, diabetic, and carnosine-treated diabetics (50 and 100mg/kg). Carnosine was injected i.p. at doses of 50 or 100mg/kg for 7 weeks, started 1 week after induction of diabetes using streptozotocin. Treatment of diabetic rats with carnosine at a dose of 100mg/kg at the end of the study lowered serum glucose, improved spatial recognition memory in Y maze, improved retention and recall in elevated plus maze, and prevented reduction of step-through latency in passive avoidance task. Furthermore, carnosine at a dose of 100mg/kg reduced hippocampal acetylcholinesterase (AChE) activity, lowered lipid peroxidation, and improved superoxide dismutase (SOD) activity and non-enzymatic antioxidant defense element glutathione (GSH), but not activity of catalase. Meanwhile, hippocampal level of nuclear factor-kappaB (NF-κB), tumor necrosis factor α (TNF-α), and glial fibrillary acidic protein (GFAP) decreased and level of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) increased upon treatment of diabetic group with carnosine at a dose of 100mg/kg. Taken together, chronic carnosine treatment could ameliorate learning and memory disturbances in STZ-diabetic rats through intonation of NF-κB/Nrf2/HO-1 signaling cascade, attenuation of astrogliosis, possible improvement of cholinergic function, and amelioration of oxidative stress and neuroinflammation.
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Affiliation(s)
| | | | | | - Zahra Kiasalari
- Neurophysiology Research Center, Shahed University, Tehran, Iran.
| | | | - Mehrdad Roghani
- Neurophysiology Research Center, Shahed University, Tehran, Iran.
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44
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Baluchnejadmojarad T, Kiasalari Z, Afshin-Majd S, Ghasemi Z, Roghani M. S-allyl cysteine ameliorates cognitive deficits in streptozotocin-diabetic rats via suppression of oxidative stress, inflammation, and acetylcholinesterase. Eur J Pharmacol 2016; 794:69-76. [PMID: 27887948 DOI: 10.1016/j.ejphar.2016.11.033] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 11/19/2016] [Accepted: 11/21/2016] [Indexed: 01/09/2023]
Abstract
Diabetes mellitus (DM) is associated with learning, memory, and cognitive deficits. S-allyl cysteine (SAC) is the main organosulfur bioactive molecule in aged garlic extract with anti-diabetic, antioxidant, anti-inflammatory and nootropic property. This research was conducted to evaluate the efficacy of SAC on alleviation of learning and memory deficits in streptozotocin (STZ)-diabetic rats and to explore involvement of toll-like receptor 4 (TLR4), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-kappa B (NF-κB), and heme oxygenase 1 (HO-1) signaling cascade. Male Wistar rats were divided into control, diabetic, SAC-treated diabetic, and glibenclamide-treated diabetic (positive control) groups. SAC was administered at a dose of 150mg/kg for seven weeks. Treatment of diabetic rats with SAC lowered serum glucose, improved spatial recognition memory in Y maze, discrimination ratio in novel object recognition task, and restored step-through latency (STL) in passive avoidance paradigm. In addition, SAC reduced acetylcholinesterase activity, lipid peroxidation marker malondialdehyde (MDA) and augmented antioxidant defensive system including superoxide dismutase (SOD), catalase and reduced glutathione (GSH) in hippocampal lysate. Meanwhile, SAC lowered hippocampal NF-kB, TLR4, and TNFα and prevented reduction of Nrf2 and heme oxygenase-1 (HO-1) in diabetic rats. Taken together, chronic SAC treatment could ameliorate cognitive deficits in STZ-diabetic rats through modulation of Nrf2/NF-κB/TLR4/HO-1, and acetylcholinesterase and attenuation of associated oxidative stress and neuroinflammation.
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Affiliation(s)
| | - Zahra Kiasalari
- Neurophysiology Research Center, Shahed University, Tehran, Iran.
| | | | - Zahra Ghasemi
- Department of Physiology, School of Medicine, Shahed University, Tehran, Iran
| | - Mehrdad Roghani
- Neurophysiology Research Center, Shahed University, Tehran, Iran.
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45
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Maiese K. Forkhead transcription factors: new considerations for alzheimer's disease and dementia. JOURNAL OF TRANSLATIONAL SCIENCE 2016; 2:241-247. [PMID: 27390624 PMCID: PMC4932907 DOI: 10.15761/jts.1000146] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Life expectancy of individuals in both developed and undeveloped nations continues to rise at an unprecedented rate. Coupled to this increase in longevity for individuals is the rise in the incidence of chronic neurodegenerative disorders that includes Alzheimer's disease (AD). Currently, almost ten percent of the population over the age of 65 suffers from AD, a disorder that is presently without definitive therapy to prevent the onset or progression of cognitive loss. Yet, it is estimated that AD will continue to significantly increase throughout the world to impact millions of individuals and foster the escalation of healthcare costs. One potential target for the development of novel strategies against AD and other cognitive disorders involves the mammalian forkhead transcription factors of the O class (FoxOs). FoxOs are present in "cognitive centers" of the brain to include the hippocampus, the amygdala, and the nucleus accumbens and may be required for memory formation and consolidation. FoxOs play a critical role in determining survival of multiple cell types in the nervous system, drive pathways of apoptosis and autophagy, and control stem cell proliferation and differentiation. FoxOs also interface with multiple cellular pathways that include growth factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1 (WISP1), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that ultimately may control FoxOs and determine the fate and function of cells in the nervous system that control memory and cognition. Future work that can further elucidate the complex relationship FoxOs hold over cell fate and cognitive function could yield exciting prospects for the treatment of a number of neurodegenerative disorders including AD.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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46
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Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res 2016; 11:372-85. [PMID: 27127460 PMCID: PMC4828986 DOI: 10.4103/1673-5374.179032] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
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47
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El-Sabagh M, Taniguchi D, Sugino T, Obitsu T. Metabolomic profiling reveals differential effects of glucagon-like peptide-1 and insulin on nutrient partitioning in ovine liver. Anim Sci J 2016; 87:1480-1489. [PMID: 26991154 DOI: 10.1111/asj.12614] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 12/25/2015] [Accepted: 01/14/2016] [Indexed: 12/25/2022]
Abstract
This study was conducted to identify the insulin-independent actions of glucagon-like peptide-1 (GLP-1 (7-36 amide)) in partitioning nutrient metabolism in ovine liver. Four Suffolk wethers (60.0 ± 6.7 kg body weight (BW)) were used in a repeated-measure design under euglycemic--hyperinsulinemic and hyper -GLP-1 clamps for 150 min with intravenous infusion of insulin (0.5 mU/kg BW/min; from 0 to 90 min), GLP-1 (0.5 µg/kg BW/min; from 60 to 150 min) and both hormones co-administered from 60 to 90 min. Liver biopsies were collected at 0, 60, 90 and 150 min to represent the metabolomic profiling of baseline, insulin, insulin plus GLP-1, and GLP-1, respectively, and were analyzed for metabolites using Capillary Electrophoresis Time-of-Flight Mass Spectrometer. Metabolomics analysis reveals 51 metabolites as being significantly altered (P < 0.05) by insulin and GLP-1 infusion compared to baseline values. Insulin infusion enhanced glycolysis, lipogenesis, oxidative stress defense and cell proliferation pathways, but reduced protein breakdown, gluconeogenesis and ketogenesis pathways. Conversely, GLP-1 infusion promoted lipolytic and ketogenic pathways accompanied by a lowered lipid clearance from the liver as well as elevated oxidative stress defense and nucleotide degradation. Despite further research still being warranted, our data suggest that GLP-1 may exert insulin-antagonistic effects on hepatic lipid and nucleotide metabolism in ruminants.
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Affiliation(s)
- Mabrouk El-Sabagh
- The Research Center for Animal Science, Graduate School of Biosphere Science, Hiroshima University, Higashi Hiroshima, Japan.,Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | - Dai Taniguchi
- The Research Center for Animal Science, Graduate School of Biosphere Science, Hiroshima University, Higashi Hiroshima, Japan
| | - Toshihisa Sugino
- The Research Center for Animal Science, Graduate School of Biosphere Science, Hiroshima University, Higashi Hiroshima, Japan
| | - Taketo Obitsu
- The Research Center for Animal Science, Graduate School of Biosphere Science, Hiroshima University, Higashi Hiroshima, Japan
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48
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Wang P, Xing Y, Chen C, Chen Z, Qian Z. Advanced glycation end-product (AGE) induces apoptosis in human retinal ARPE-19 cells via promoting mitochondrial dysfunction and activating the Fas-FasL signaling. Biosci Biotechnol Biochem 2016; 80:250-6. [PMID: 26479732 DOI: 10.1080/09168451.2015.1095065] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Abstract
Advanced glycation end-products (AGEs) are extremely accumulated in the retinal vascular and epithelial cells of diabetes mellitus (DM) patients, particularly with diabetic retinopathy (DR). To elucidate the pathogenesis of the AGE-induced toxicity to retinal epithelial cells, we investigated the role of Fas–Fas ligand (FasL) signaling and mitochondrial dysfunction in the AGE-induced apoptosis. Results demonstrated that the AGE-BSA- induced apoptosis of retinal ARPE-19 cells. And the AGE-BSA treatment caused mitochondrial dysfunction, via deregulating the B-cell lymphoma 2 (Bcl-2) signaling. Moreover, the Fas/FasL and its downstreamer Caspase 8 were promoted by the AGE-BSA treatment, and the exogenous α-Fas exacerbated the activation of Caspase 3/8. On the other side, the siRNA-mediated knockdown of Fas/FasL inhibited the AGE-BSA-induced apoptosis. Taken together, we confirmed the activation of Fas–FasL signaling and of mitochondrial dysfunction in the AGE-BSA-promoted apoptosis in retinal ARPE-19 cells, implying the important role of Fas–FasL signaling in the DR in DM.
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Affiliation(s)
- Pu Wang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
- Department of Ophthalmology, Inner Mongolia People’s Hospital, Hohhot, People’s Republic of China
| | - Yiqiao Xing
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Changzheng Chen
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Zhen Chen
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Zhimin Qian
- Department of Ophthalmology, Inner Mongolia People’s Hospital, Hohhot, People’s Republic of China
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Pektaş MB, Sadi G, Koca HB, Yuksel Y, Vurmaz A, Koca T, Tosun M. Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin-Induced Diabetes. Drug Dev Res 2016; 77:12-9. [DOI: 10.1002/ddr.21287] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 12/09/2015] [Indexed: 12/16/2022]
Affiliation(s)
- Mehmet Bilgehan Pektaş
- Department of Medical Pharmacology, Faculty of Medicine; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Gökhan Sadi
- Department of Biology, K.Ö. Science Faculty; Karamanoglu Mehmetbey University; Karaman Turkey
| | - Halit Bugra Koca
- Department of Medical Biochemistry, Faculty of Medicine; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Yasemin Yuksel
- Department of Histology, Faculty of Medicine; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Ayhan Vurmaz
- Department of Medical Biochemistry, Faculty of Medicine; Afyon Kocatepe University; Afyonkarahisar Turkey
| | - Tulay Koca
- Department of Medical Laboratory, Ataturk Vocational School of Health Services; Afyon Kocatepe University; Afyonkarahisar and Karaman Turkey
| | - Murat Tosun
- Department of Histology, Faculty of Medicine; Afyon Kocatepe University; Afyonkarahisar Turkey
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50
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Petersen KE, Rakipovski G, Raun K, Lykkesfeldt J. Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies. Curr Diabetes Rev 2016; 12:331-358. [PMID: 26381142 PMCID: PMC5101636 DOI: 10.2174/1573399812666150918150608] [Citation(s) in RCA: 27] [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: 02/06/2015] [Revised: 09/15/2015] [Accepted: 09/18/2015] [Indexed: 02/07/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) has shown to influence the oxidative stress status in a number of in vitro, in vivo and clinical studies. Well-known effects of GLP-1 including better glycemic control, decreased food intake, increased insulin release and increased insulin sensitivity may indirectly contribute to this phenomenon, but glucose-independent effects on ROS level, production and antioxidant capacity have been suggested to also play a role. The potential 'antioxidant' activity of GLP-1 along with other proposed glucose-independent modes of action related to ameliorating redox imbalance remains a controversial topic but could hold a therapeutic potential against micro- and macrovascular diabetic complications. This review discusses the presently available knowledge from experimental and clinical studies on the effects of GLP-1 on oxidative stress in diabetes and diabetes-related complications.
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Affiliation(s)
| | | | | | - Jens Lykkesfeldt
- Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870, Frederiksberg C, Denmark.
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