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Al-Ashram MM, Nader MA, El-Sheakh AR. Role of sacubitril/valsartan in modulating diabetes mediated cognitive and neuronal impairment. Int Immunopharmacol 2025; 154:114431. [PMID: 40157081 DOI: 10.1016/j.intimp.2025.114431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 02/19/2025] [Accepted: 03/03/2025] [Indexed: 04/01/2025]
Abstract
Earlier investigations had established that Diabetes mellitus (DM) caused significant damage in the central nervous system, bringing about diabetic encephalopathy and increasing the risk of cognitive-related problems. Nonetheless, the inherent pathophysiology of cognitive dysfunctions in DM is not well understood. The current study aimed to examine the possible influences of sacubitril/valsartan (SAC/VAL), an angiotensin receptor blocker/neprilysin inhibitor (ARNI), on cognitive dysfunction associated with streptozotocin (STZ)-induced diabetic rats. SAC/VAL and VAL treatments were initiated three days after the diabetic condition was established and continued daily for eight weeks. Normal, non-diabetic rats were reserved as a control group. Both SAC/VAL and VAL treatment in diabetic rats ameliorated diabetes induced oxidative stress as indicated by reduced malondialdehyde (MDA), increased total antioxidant capacity (TAO) in hippocampal tissue and decreased serum advanced glycation end products (AGEs), also inflammatory and apoptotic changes were observed and proved by the reduction of tumor necrosis factor alpha (TNF-α) and caspase -3 in rat hippocampus. SAC/VAL administration to diabetic rats also improved neuronal damages as reflected by restored cAMP response element-binding protein (CREB), brain derived neurotrophic factor (BDNF) and pre-synaptic phosphoproteins, synapsin I and growth associated protein-43 (GAP-43) in the hippocampus of diabetic rats. Additionally, SAC/VAL treated diabetic rats markedly reduced signs of cognitive deterioration during the Morris water maze test. Collectively, these findings suggested that SAC/VAL might play a vital role in improvement of the cognitive impairment observed in diabetic rats through antioxidant, anti-inflammatory and anti-apoptotic actions.
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Affiliation(s)
- Mai M Al-Ashram
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansura University, Mansura, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansura National University, Gamasa, Egypt.
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansura University, Mansura, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansura National University, Gamasa, Egypt
| | - Ahmed R El-Sheakh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansura University, Mansura, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansura National University, Gamasa, Egypt; Future studies and Risks management, National Committee of Drugs, Academy of Scientific Research, Ministry of Higher Education, Elsayeda Zeinab, Egypt
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Wang Y, Ortiz R, Chang A, Nasseef T, Rubalcaba N, Munson C, Ghaw A, Balaji S, Kwon Y, Athreya D, Kedharnath S, Kulkarni PP, Ferris CF. Following changes in brain structure and function with multimodal MRI in a year-long prospective study on the development of Type 2 diabetes. FRONTIERS IN RADIOLOGY 2025; 5:1510850. [PMID: 40018732 PMCID: PMC11865244 DOI: 10.3389/fradi.2025.1510850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 01/27/2025] [Indexed: 03/01/2025]
Abstract
Aims To follow disease progression in a rat model of Type 2 diabetes using multimodal MRI to assess changes in brain structure and function. Material and methods Female rats (n = 20) were fed a high fat/high fructose diet or lab chow starting at 90 days of age. Diet fed rats were given streptozotocin to compromise pancreatic beta cells, while chow fed controls received vehicle. At intervals of 3, 6, 9, and 12 months, rats were tested for changes in behavior and sensitivity to pain. Brain structure and function were assessed using voxel based morphometry, diffusion weighted imaging and functional connectivity. Results Diet fed rats presented with elevated plasma glucose levels as early as 3 months and a significant gain in weight by 6 months as compared to controls. There were no significant changes in cognitive or motor behavior over the yearlong study but there was a significant increase in sensitivity to peripheral pain in diet fed rats. There were region specific decreases in brain volume e.g., basal ganglia, thalamus and brainstem in diet fed rats. These same regions showed elevated measures of water diffusivity evidence of putative vasogenic edema. By 6 months, widespread hyperconnectivity was observed across multiple brain regions. By 12 months, only the cerebellum and hippocampus showed increased connectivity, while the hypothalamus showed decreased connectivity in diet fed rats. Conclusions Noninvasive multimodal MRI identified site specific changes in brain structure and function in a yearlong longitudinal study of Type 2 diabetes in rats. The identified diabetic-induced neuropathological sites may serve as biomarkers for evaluating the efficacy of novel therapeutics.
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Affiliation(s)
- Yingjie Wang
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Richard Ortiz
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, United States
| | - Arnold Chang
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Taufiq Nasseef
- Department of Mathematics, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, Riyadh, Saudi
| | - Natalia Rubalcaba
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Chandler Munson
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Ashley Ghaw
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Shreyas Balaji
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Yeani Kwon
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Deepti Athreya
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Shruti Kedharnath
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Praveen P. Kulkarni
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Craig F. Ferris
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
- Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA, United States
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Yang Y, Lu SR, Xu Q, Yu J, Wang Z, Zhang BS, Hong K. Predictive value of nutritional status and serological indicators in elderly patients with mild cognitive impairment. World J Psychiatry 2024; 14:1925-1935. [PMID: 39704370 PMCID: PMC11622028 DOI: 10.5498/wjp.v14.i12.1925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/09/2024] [Accepted: 11/08/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND Mild cognitive impairment (MCI) in elderly individuals is a transitional stage between normal cognition and dementia. Understanding the risk factors for MCI and identifying those at high risk are extremely important for the elderly population. AIM To analyze the risk factors for MCI in the elderly population and construct a clinical prediction model. METHODS Total 295 elderly individuals presenting with memory loss diagnosed at Wuxi People's Hospital between March 2021 and March 2024 were included. Comprehensive demographic, clinical, and serological data were collected for analysis. Participants were categorized into either an MCI group or a normal group based on their performance on the Montreal Cognitive Assessment Scale. An elaborate clinical predictive model was developed to predict the likelihood of MCI in stroke patients; its accuracy was evaluated using area under curve values and calibration curves. RESULTS The results of the study showed that old age, hypertension, diabetes, hyperlipidemia, smoking, high-salt diet, high-cholesterol diet, decreased red blood count, increased neutrophil lymphocyte ratio and increased low-density lipoprotein cholesterol were risk factors for the onset of MCI, with A high vitamin diet and elevated high-density lipoprotein cholesterol being protective factors. In addition, the prediction model constructed in this study exhibits good degrees of differentiation and calibration. CONCLUSION The risk factors for MCI are diverse. Early identification of individuals at high risk of MCI can better intervene and improve their quality of life of MCI patients.
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Affiliation(s)
- Ying Yang
- Department of Geriatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, China
| | - Shou-Rong Lu
- Department of Geriatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, China
| | - Qiao Xu
- Department of Geriatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, China
| | - Jie Yu
- Department of Geriatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, China
| | - Zhuo Wang
- Department of Geriatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, China
| | - Bing-Shan Zhang
- Department of Geriatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, China
| | - Kan Hong
- Department of Geriatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi 214023, Jiangsu Province, China
- Wuxi Medical Center, Nanjing Medical University, Wuxi People's Hospital, Wuxi 214023, Jiangsu Province, China
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Tarhan M, Hartl T, Shchyglo O, Colitti-Klausnitzer J, Kuhla A, Breuer TM, Manahan-Vaughan D. Changes in hippocampal volume, synaptic plasticity and amylin sensitivity in an animal model of type 2 diabetes are associated with increased vulnerability to amyloid-beta in advancing age. Front Aging Neurosci 2024; 16:1373477. [PMID: 38974903 PMCID: PMC11224464 DOI: 10.3389/fnagi.2024.1373477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 05/28/2024] [Indexed: 07/09/2024] Open
Abstract
Type-2 diabetes (T2D) is a metabolic disorder that is considered a risk factor for Alzheimer's disease (AD). Cognitive impairment can arise due to hypoglycemia associated with T2D, and hyperamylinemia associated with insulin resistance can enhance AD pathology. We explored whether changes occur in the hippocampus in aging (6-12 months old) female V-Lep○b-/- transgenic (tg) mice, comprising an animal model of T2D. We also investigated whether an increase in vulnerability to Aβ (1-42), a known pathological hallmark of AD, is evident. Using magnetic resonance imaging we detected significant decreases in hippocampal brain volume in female tg-mice compared to wild-type (wt) littermates. Long-term potentiation (LTP) was impaired in tg compared to wt mice. Treatment of the hippocampus with Aβ (1-42) elicited a stronger debilitation of LTP in tg compared to wt mice. Treatment with an amylin antagonist (AC187) significantly enhanced LTP in wt and tg mice, and rescued LTP in Aβ (1-42)-treated tg mice. Taken together our data indicate that a T2D-like state results in an increased vulnerability of the hippocampus to the debilitating effects of Aβ (1-42) and that effects are mediated in part by changes in amylin receptor signaling.
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Affiliation(s)
- Melih Tarhan
- Department of Neurophysiology, Institute of Physiology, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Bochum, Germany
| | - Tim Hartl
- Department of Neurophysiology, Institute of Physiology, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Bochum, Germany
| | - Olena Shchyglo
- Department of Neurophysiology, Institute of Physiology, Ruhr University Bochum, Bochum, Germany
| | | | - Angela Kuhla
- Rudolf Zenker Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | | | - Denise Manahan-Vaughan
- Department of Neurophysiology, Institute of Physiology, Ruhr University Bochum, Bochum, Germany
- International Graduate School of Neuroscience, Bochum, Germany
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Stanisławska-Kubiak M, Majewska KA, Krasińska A, Wais P, Majewski D, Mojs E, Kȩdzia A. Brain functional and structural changes in diabetic children. How can intellectual development be optimized in type 1 diabetes? Ther Adv Chronic Dis 2024; 15:20406223241229855. [PMID: 38560719 PMCID: PMC10981223 DOI: 10.1177/20406223241229855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 01/11/2024] [Indexed: 04/04/2024] Open
Abstract
The neuropsychological functioning of people with type 1 diabetes (T1D) is of key importance to the effectiveness of the therapy, which, in its complexity, requires a great deal of knowledge, attention, and commitment. Intellectual limitations make it difficult to achieve the optimal metabolic balance, and a lack of this alignment can contribute to the further deterioration of cognitive functions. The aim of this study was to provide a narrative review of the current state of knowledge regarding the influence of diabetes on brain structure and functions during childhood and also to present possible actions to optimize intellectual development in children with T1D. Scopus, PubMed, and Web of Science databases were searched for relevant literature using selected keywords. The results were summarized using a narrative synthesis. Disturbances in glucose metabolism during childhood may have a lasting negative effect on the development of the brain and related cognitive functions. To optimize intellectual development in children with diabetes, it is essential to prevent disorders of the central nervous system by maintaining peri-normal glycemic levels. Based on the performed literature review, it seems necessary to take additional actions, including repeated neuropsychological evaluation with early detection of any cognitive dysfunctions, followed by the development of individual management strategies and the training of appropriate skills, together with complex, multidirectional environmental support.
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Affiliation(s)
- Maia Stanisławska-Kubiak
- Department of Clinical Psychology, Poznan University of Medical Sciences, ul. Bukowska 70, Poznan 60-812, Poland
| | - Katarzyna Anna Majewska
- Department of Pediatric Diabetes, Auxology and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | - Agata Krasińska
- Department of Pediatric Diabetes, Auxology and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | - Paulina Wais
- Department of Pediatric Diabetes, Auxology and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | - Dominik Majewski
- Department of Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Ewa Mojs
- Department of Clinical Psychology, Poznan University of Medical Sciences, Poznan, Poland
| | - Andrzej Kȩdzia
- Department of Pediatric Diabetes, Auxology and Obesity, Poznan University of Medical Sciences, Poznan, Poland
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Hristov M, Nankova A, Andreeva-Gateva P. Alterations of the glutamatergic system in diabetes mellitus. Metab Brain Dis 2024; 39:321-333. [PMID: 37747631 DOI: 10.1007/s11011-023-01299-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 09/17/2023] [Indexed: 09/26/2023]
Abstract
Diabetes mellitus (DM) is a chronic disease characterized by elevated blood glucose levels caused by a lack of insulin production (type 1 diabetes) or insulin resistance (type 2 diabetes). It is well known that DM is associated with cognitive deficits and metabolic and neurophysiological changes in the brain. Glutamate is the main excitatory neurotransmitter in the central nervous system that plays a key role in synaptic plasticity, learning, and memory processes. An increasing number of studies have suggested that abnormal activity of the glutamatergic system is implicated in the pathophysiology of DM. Dysfunction of glutamatergic neurotransmission in the central nervous system can provide an important neurobiological substrate for many disorders. Magnetic resonance spectroscopy (MRS) is a non-invasive technique that allows a better understanding of the central nervous system factors by measuring in vivo the concentrations of brain metabolites within the area of interest. Here, we briefly review the MRS studies that have examined glutamate levels in the brain of patients with DM. The present article also summarizes the available data on abnormalities in glutamatergic neurotransmission observed in different animal models of DM. In addition, the role of gut microbiota in the development of glutamatergic alterations in DM is addressed. We speculate that therapeutic strategies targeting the glutamatergic system may be beneficial in the treatment of central nervous system-related changes in diabetic patients.
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Affiliation(s)
- Milen Hristov
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, 2 "Zdrave" St, Sofia, 1431, Bulgaria.
| | - Anelia Nankova
- Department of Endocrinology, Faculty of Medicine, Medical University of Sofia, Sofia, 1431, Bulgaria
| | - Pavlina Andreeva-Gateva
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, 2 "Zdrave" St, Sofia, 1431, Bulgaria
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Palazzo E, Marabese I, Boccella S, Belardo C, Pierretti G, Maione S. Affective and Cognitive Impairments in Rodent Models of Diabetes. Curr Neuropharmacol 2024; 22:1327-1343. [PMID: 38279738 PMCID: PMC11092917 DOI: 10.2174/1570159x22666240124164804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 01/28/2024] Open
Abstract
Diabetes and related acute and long-term complications have a profound impact on cognitive, emotional, and social behavior, suggesting that the central nervous system (CNS) is a crucial substrate for diabetic complications. When anxiety, depression, and cognitive deficits occur in diabetic patients, the symptoms and complications related to the disease worsen, contributing to lower quality of life while increasing health care costs and mortality. Experimental models of diabetes in rodents are a fundamental and valuable tool for improving our understanding of the mechanisms underlying the close and reciprocal link between diabetes and CNS alterations, including the development of affective and cognitive disorders. Such models must reproduce the different components of this pathological condition in humans and, therefore, must be associated with affective and cognitive behavioral alterations. Beyond tight glycemic control, there are currently no specific therapies for neuropsychiatric comorbidities associated with diabetes; animal models are, therefore, essential for the development of adequate therapies. To our knowledge, there is currently no review article that summarizes changes in affective and cognitive behavior in the most common models of diabetes in rodents. Therefore, in this review, we have reported the main evidence on the alterations of affective and cognitive behavior in the different models of diabetes in rodents, the main mechanisms underlying these comorbidities, and the applicable therapeutic strategy.
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Affiliation(s)
- Enza Palazzo
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Ida Marabese
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Serena Boccella
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Carmela Belardo
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Gorizio Pierretti
- Department of Plastic Surgery, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Sabatino Maione
- Department of Experimental Medicine, Pharamacology Division, University of Campania “L. Vanvitelli”, Naples, Italy
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Li R, Geng T, Li L, Lu Q, Li R, Chen X, Ou Y, Liu S, Lin X, Tian Q, Qiu Z, Zhu K, Tang Z, Yang K, Pan A, Liu G. Associations of Glucose Metabolism Status with Brain Macrostructure and Microstructure: Findings from the UK Biobank. J Clin Endocrinol Metab 2023; 109:e234-e242. [PMID: 37497611 DOI: 10.1210/clinem/dgad442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/11/2023] [Accepted: 07/26/2023] [Indexed: 07/28/2023]
Abstract
CONTEXT Evidence linking glucose metabolism status with brain macro- and microstructure is limited and inconsistent. OBJECTIVE We aim to investigate the associations of glucose metabolism status with brain macrostructure and microstructure, including brain volumes, subcortical gray matter volumes, and white matter microstructural metrics. METHODS This study enrolled 29 251 participants from the UK Biobank. Glucose metabolism status was classified into normal glucose metabolism (NGM), prediabetes, type 2 diabetes (T2D) with HbA1c <7%, and T2D with HbA1c ≥7%. Brain macrostructural metrics included volumes of total and subcortical gray matter, white matter, white matter hyperintensity (WMH), cerebrospinal fluid, and brain stem. Brain microstructural metrics included fractional anisotropy (FA) and mean diffusivity in white matter tracts. Multivariable linear regression models were used to estimate β values and 95% CI. RESULTS After multivariable adjustment including demographic and lifestyle factors, medical history, and total intracranial volume, those with prediabetes had smaller total and subcortical gray matter volumes than participants with NGM, while atrophy of total and subcortical gray matter was more pronounced in those with T2D (all P trend < .05). Moreover, participants with T2D had larger volumes of white matter and WMH (both P trend < .05). For brain microstructure, participants with prediabetes had lower FA values in commissural fibers (β -0.04; 95% CI -0.08, -0.003). Global and tract-specific microstructural abnormalities of white matter were observed in participants with T2D, especially for T2D with HbA1c ≥ 7% (all P trend < .05), except for FA values in projection fibers. CONCLUSION These findings suggest that interventions for hyperglycemia at an earlier stage may help protect brain health.
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Affiliation(s)
- Ruyi Li
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Geng
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition and Food Hygiene, School of Public Health, Institute of Nutrition, Fudan University, Shanghai, China
| | - Lin Li
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Lu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Li
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunjing Ou
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sen Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Lin
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingying Tian
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zixin Qiu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziyue Tang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Yang
- Department of Endocrinology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - An Pan
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhang L, Zhi K, Su Y, Peng W, Meng X. Effect of eIF2α in Neuronal Injury Induced by High Glucose and the Protective Mechanism of Resveratrol. Mol Neurobiol 2023; 60:6043-6059. [PMID: 37410333 DOI: 10.1007/s12035-023-03457-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/21/2023] [Indexed: 07/07/2023]
Abstract
Diabetes mellitus (DM) is a type of metabolic disease characterized by chronic hyperglycemia, which can lead to different degrees of cognitive decline. Therefore, it is crucial to explore the molecular biological mechanisms of neuronal injury. In this study, we investigated the effect of high glucose on eIF2α expression and the mechanism of neuronal injury, and on this basis, the protective mechanism of resveratrol is explored. Treatment with 50 mM high glucose in cortical neurons increased the levels of eIF2α phosphorylation; the expressions of ATF4 and CHOP increased. ISRIB alleviated high glucose-induced neuronal injury by reducing eIF2α phosphorylation when neurons were pretreated with ISRIB before high glucose treatment. Compared with the high glucose-treated group, resveratrol pretreatment reduced eIF2α phosphorylation, the levels of its downstream molecules ATF4 and CHOP, and LDH release. Resveratrol reduced the level of cortical eIF2α phosphorylation and the expression of its downstream molecules in DM mice and improved the ability of spatial memory and learning in DM mice without affecting anxiety and motor performance. Meanwhile, resveratrol modulated the expression of Bcl-2 protein and also effectively decreased the DM-induced up-regulation of Bax, caspase-3, p53, p21, and p16. Taken together, these results suggested that high glucose caused neuronal injury through the eIF2α/ATF4/CHOP pathway which was inhibited by ISRIB and resveratrol. The present study indicates that eIF2α is the new target for the treatment of high glucose-induced neuronal injury, and resveratrol is a potential new medicine to treat diabetes encephalopathy.
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Affiliation(s)
- Lijing Zhang
- Department of Neurobiology, Institute of Brain Research, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Kaining Zhi
- Department of Neurobiology, Institute of Brain Research, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yanfang Su
- Department of Neurobiology, Institute of Brain Research, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wenpeng Peng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xianfang Meng
- Department of Neurobiology, Institute of Brain Research, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Elzinga SE, Eid SA, McGregor BA, Jang DG, Hinder LM, Dauch JR, Hayes JM, Zhang H, Guo K, Pennathur S, Kretzler M, Brosius FC, Koubek EJ, Feldman EL, Hur J. Transcriptomic analysis of diabetic kidney disease and neuropathy in mouse models of type 1 and type 2 diabetes. Dis Model Mech 2023; 16:dmm050080. [PMID: 37791586 PMCID: PMC10565109 DOI: 10.1242/dmm.050080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/26/2023] [Indexed: 10/05/2023] Open
Abstract
Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying pathogenesis of these complications are unclear. In this study, we optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background. Glomeruli and sciatic nerve transcriptomic data from T1D and T2D mice were analyzed by self-organizing map and differential gene expression analysis. Consistent with prior literature, pathways related to immune function and inflammation were dysregulated in both complications in T1D and T2D mice. Gene-level analysis identified a high degree of concordance in shared differentially expressed genes (DEGs) in both complications and across diabetes type when using mice from the same cohort and genetic background. As we have previously shown a low concordance of shared DEGs in DPN when using mice from different cohorts and genetic backgrounds, this suggests that genetic background may influence diabetic complications. Collectively, these findings support the role of inflammation and indicate that genetic background is important in complications of both T1D and T2D.
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Affiliation(s)
- Sarah E. Elzinga
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stephanie A. Eid
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Brett A. McGregor
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, USA
| | - Dae-Gyu Jang
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lucy M. Hinder
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - John M. Hayes
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hongyu Zhang
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kai Guo
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Subramaniam Pennathur
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Matthias Kretzler
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Frank C. Brosius
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Medicine, University of Arizona, Tucson, AZ 85721, USA
| | - Emily J. Koubek
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Junguk Hur
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, USA
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11
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Oyeniran OH, Ademiluyi AO, Oboh G. Host-parasite relationship modulates the effect of African mistletoe leaves on the cholinergic, monoaminergic and carbohydrate hydrolyzing enzymes in fruit fly. J Basic Clin Physiol Pharmacol 2023; 34:591-601. [PMID: 34463440 DOI: 10.1515/jbcpp-2020-0298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 04/15/2021] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Mistletoe infests common plant trees of great medicinal values such as Moringa and Almond. According to folklore, mistletoe leaves have been found to have application as food and medicine in the alleviation of various degenerative diseases. Host-parasite relationship may possibly influence the phytochemical and biological activities of mistletoe leaves. Hence, we examined the polyphenol contents, antioxidant properties, α-amylase, α-glucosidase, acetylcholinesterase (AChE) and monoamine oxidase (MAO) inhibitory activities of African mistletoe leaves obtained from Moringa and Almond host plants in fruit fly in vitro. METHODS The phenolic constituents of the leaves were evaluated using HPLC system. The antioxidant activities were determined through the ABTS, DPPH and OH free radicals scavenging properties, ferric (Fe3+) and malondialdehyde (MDA) reducing abilities and Fe2+ chelation. The inhibitory effects of the leaves aqueous extracts on α-amylase, α-glucosidase, AChE and MAO activities were also assessed. RESULTS The HPLC characterization of the leaves revealed that host plants caused marked variation in their phenolic composition, however, Almond mistletoe leaves had significantly (p<0.05) greater amounts of phenolic constituents. Both Moringa and Almond mistletoe leaves reduced Fe3+ and MDA levels, scavenged free radicals, chelated Fe2+ and inhibited α-amylase, α-glucosidase, AChE and MAO activities with the Almond mistletoe leaves having significantly (p<0.05) higher antioxidant properties and enzyme inhibitory activities. CONCLUSIONS This present study indicated that host plants could positively modulate the phenolic profile of mistletoe leaves and this probably brought about the vivid noticeable changes in their antioxidant abilities, cholinergic, monoaminergic and carbohydrate hydrolyzing enzymes inhibitory activities.
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Affiliation(s)
- Olubukola H Oyeniran
- Department of Biochemistry, Functional Foods, Nutraceuticals and Phytomedicine Unit, Federal University of Technology, Akure, Nigeria
- Department of Biochemistry, Federal University, Oye-Ekiti, Ekiti State, Nigeria
| | - Adedayo O Ademiluyi
- Department of Biochemistry, Functional Foods, Nutraceuticals and Phytomedicine Unit, Federal University of Technology, Akure, Nigeria
| | - Ganiyu Oboh
- Department of Biochemistry, Functional Foods, Nutraceuticals and Phytomedicine Unit, Federal University of Technology, Akure, Nigeria
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12
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Pelle MC, Zaffina I, Giofrè F, Pujia R, Arturi F. Potential Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Cognitive Decline and Dementia in Diabetes Mellitus. Int J Mol Sci 2023; 24:11301. [PMID: 37511061 PMCID: PMC10379573 DOI: 10.3390/ijms241411301] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Dementia is a permanent illness characterized by mental instability, memory loss, and cognitive decline. Many studies have demonstrated an association between diabetes and cognitive dysfunction that proceeds in three steps, namely, diabetes-associated cognitive decrements, mild cognitive impairment (MCI; both non-amnesic MCI and amnesic MCI), and dementia [both vascular dementia and Alzheimer's disease (AD)]. Based on this association, this disease has been designated as type 3 diabetes mellitus. The underlying mechanisms comprise insulin resistance, inflammation, lipid abnormalities, oxidative stress, mitochondrial dysfunction, glycated end-products and autophagy. Moreover, insulin and insulin-like growth factor-1 (IGF-1) have been demonstrated to be involved. Insulin in the brain has a neuroprotective role that alters cognitive skills and alteration of insulin signaling determines beta-amyloid (Aβ) accumulation, in turn promoting brain insulin resistance. In this complex mechanism, other triggers include hyperglycemia-induced overproduction of reactive oxygen species (ROS) and inflammatory cytokines, which result in neuroinflammation, suggesting that antidiabetic drugs may be potential treatments to protect against AD. Among these, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are the most attractive antidiabetic drugs due to their actions on synaptic plasticity, cognition and cell survival. The present review summarizes the significant data concerning the underlying pathophysiological and pharmacological mechanisms between diabetes and dementia.
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Affiliation(s)
- Maria Chiara Pelle
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Isabella Zaffina
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Federica Giofrè
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Roberta Pujia
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
| | - Franco Arturi
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
- Research Center for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy
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13
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Gupta M, Pandey S, Rumman M, Singh B, Mahdi AA. Molecular mechanisms underlying hyperglycemia associated cognitive decline. IBRO Neurosci Rep 2023; 14:57-63. [PMID: 36590246 PMCID: PMC9800261 DOI: 10.1016/j.ibneur.2022.12.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 12/10/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia. DM can lead to a number of secondary complications affecting multiple organs in the body including the eyes, kidney, heart, and brain. The most common effect of hyperglycemia on the brain is cognitive decline. It has been estimated that 20-70% of people with DM have cognitive deficits. High blood sugar affects key brain areas involved in learning, memory, and spatial navigation, and the structural complexity of the brain has made it prone to a variety of pathological disorders, including T2DM. Studies have reported that cognitive decline can occur in people with diabetes, which could go undetected for several years. Moreover, studies on brain imaging suggest extensive effects on different brain regions in patients with T2D. It remains unclear whether diabetes-associated cognitive decline is a consequence of hyperglycemia or a complication that co-occurs with T2D. The exact mechanism underlying cognitive impairment in diabetes is complex; however, impaired glucose metabolism and abnormal insulin function are thought to play important roles. In this review, we have tried to summarize the effect of hyperglycemia on the brain structure and functions, along with the potential mechanisms underlying T2DM-associated cognitive decline.
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Affiliation(s)
- Mrinal Gupta
- Department of Biochemistry, King George’s Medical University, Lucknow, Uttar Pradesh, India
| | - Shivani Pandey
- Department of Biochemistry, King George’s Medical University, Lucknow, Uttar Pradesh, India
| | - Mohammad Rumman
- Department of Biochemistry, King George’s Medical University, Lucknow, Uttar Pradesh, India
| | - Babita Singh
- Department of Biochemistry, King George’s Medical University, Lucknow, Uttar Pradesh, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George’s Medical University, Lucknow, Uttar Pradesh, India
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14
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Martin S, Taylor SB, Shideler BL, Ogrin R, Begg R. Effects of diabetes mellitus on step length and minimum toe clearance adaptation. Biomed Eng Online 2023; 22:43. [PMID: 37165365 PMCID: PMC10170732 DOI: 10.1186/s12938-023-01082-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/15/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Adaptive gait involves the ability to adjust the leading foot in response to the requirement of dynamic environments during walking. Accurate adjustments of the minimum toe clearance (MTC) height and step length can prevent older people from falling when walking and responding to hazards. Although older people with diabetes fall more frequently than healthy older adults, no previous studies have quantified their adaptive gait abilities. This study aimed to investigate the effects of diabetes mellitus on step length and MTC height adjustments using a non-immersive virtual-reality system. METHODS Sixteen young adults (26 ± 5 years, 7 females), 16 healthy older adults (68 ± 5 years, 6 females), and 16 older adults with diabetes (70 ± 5 years, 6 females) completed adaptability tests while walking on a treadmill. A computer system visualised a continuous real-time signal of absolute step length and MTC on a monitor. Each person responded to four discrete participant-specific step length and MTC visual targets that were presented on the same signal. Tasks were to match the peaks of interest on each signal to presented targets. Targets were 10% longer or shorter than the mean baseline step length, and 2.5 cm, and 3.5 cm higher than the mean baseline MTC. When a target was displayed, it remained unchanged for 10 consecutive foot displacement adaptation attempts. Then, the target was removed and a new target or the same target was present after 10 consecutive steps and remained for 10 steps. Each target was randomly presented three times (3 × 10). Step length and MTC height adjustments in response to targets were measured and compared among groups. RESULTS Mean preferred walking speeds were not different among groups significantly when no targets were presented on the monitor in baseline walking. However, when participants walked on a treadmill while attempting to match step lengths or MTC heights to displayed targets on the monitor, the group with diabetes had reduced step length and MTC adjustments compared with other groups significantly. They showed greater errors (differences between their step lengths/MTC heights and presented targets) on the monitor. CONCLUSIONS This study quantified reduced abilities for older individuals with diabetes to adjust both step length and MTC in response to stimuli compared to healthy older counterparts. Reduced step length and MTC height adjustments can increase falls in at risk populations. The presented virtual-reality system has merits for assessing and training step and MTC adaptation.
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Affiliation(s)
- Suzanne Martin
- Institute for Health and Sport, Victoria University, Melbourne, VIC, 3011, Australia.
| | - Simon B Taylor
- Institute for Health and Sport, Victoria University, Melbourne, VIC, 3011, Australia
| | | | - Rajna Ogrin
- Bolton Clarke Research Institute, Melbourne, VIC, Australia
| | - Rezaul Begg
- Institute for Health and Sport, Victoria University, Melbourne, VIC, 3011, Australia
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15
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Kinattingal N, Mehdi S, Undela K, Wani SUD, Almuqbil M, Alshehri S, Shakeel F, Imam MT, Manjula SN. Prevalence of Cognitive Decline in Type 2 Diabetes Mellitus Patients: A Real-World Cross-Sectional Study in Mysuru, India. J Pers Med 2023; 13:jpm13030524. [PMID: 36983706 PMCID: PMC10052732 DOI: 10.3390/jpm13030524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023] Open
Abstract
The goal of this research is to study the prevalence of cognitive impairment in diabetes mellitus (DM) patients and establish the necessity of detecting and treating it early in these patients. A cross-sectional study was conducted at a tertiary care hospital in Mysuru for 4 months examined diabetic patients (test) and nondiabetic subjects (control) for cognitive decline using the Montreal Cognitive Assessment (MoCA) tool. Cognitive functions such as visuospatial/executive function, naming, attention, language, abstraction, delayed recall, and orientation were assessed in both groups. The diabetic group showed a significantly lower total MoCA score than the non-diabetic group (18.99 ± 0.48 and 26.21 ± 0.46, respectively; p < 0.001). Assessment of scores in diabetic patients demonstrated the significant influence of age demographics on cognitive impairment (p-value < 0.001). Furthermore, a higher proportion of diabetic patients displayed cognitive impairment despite a higher score in a single subdomain, making it evident that diabetes is diverse and multifactorial in origin, where oxidative stress and inflammatory responses play a predominant role. This study suggested that the local T2DM population residing in Mysuru (India) has a high prevalence of cognitive impairment, evident from poor performance in almost all cognitive domains assessed by MoCA. Future studies could examine the generalizability of cognitive function findings in diabetic patients across diverse geographic regions and ethnic groups, as well as investigate interventions such as lifestyle modifications and medication to prevent or delay cognitive decline in those with diabetes.
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Affiliation(s)
- Nabeel Kinattingal
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, India
| | - Seema Mehdi
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, India
| | - Krishna Undela
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781101, India
| | - Shahid Ud Din Wani
- Department of Pharmaceutical Sciences, School of Applied Science and Technology, University of Kashmir, Srinagar 190006, India
| | - Mansour Almuqbil
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sultan Alshehri
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia
| | - Faiyaz Shakeel
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad T. Imam
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Santhepete N. Manjula
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, India
- Correspondence:
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16
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Zhou H, Rao Z, Zhang Z, Zhou J. Function of the GABAergic System in Diabetic Encephalopathy. Cell Mol Neurobiol 2023; 43:605-619. [PMID: 35460435 PMCID: PMC11415196 DOI: 10.1007/s10571-022-01214-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 03/17/2022] [Indexed: 11/03/2022]
Abstract
Diabetes is a common metabolic disease characterized by loss of blood sugar control and a high rate of complications. γ-Aminobutyric acid (GABA) functions as the primary inhibitory neurotransmitter in the adult mammalian brain. The normal function of the GABAergic system is affected in diabetes. Herein, we summarize the role of the GABAergic system in diabetic cognitive dysfunction, diabetic blood sugar control disorders, diabetes-induced peripheral neuropathy, diabetic central nervous system damage, maintaining diabetic brain energy homeostasis, helping central control of blood sugar and attenuating neuronal oxidative stress damage. We show the key regulatory role of the GABAergic system in multiple comorbidities in patients with diabetes and hope that further studies elucidating the role of the GABAergic system will yield benefits for the treatment and prevention of comorbidities in patients with diabetes.
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Affiliation(s)
- Hongli Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China
| | - Zhili Rao
- Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, People's Republic of China
| | - Zuo Zhang
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China
| | - Jiyin Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China.
- Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, People's Republic of China.
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17
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Omer AB, Afzal O, Altamimi ASA, Patil S, AlGhamdi SA, Alghamdi AM, Alzarea SI, Almalki WH, Kazmi I. Neuroprotective Effect of Barbaloin on Streptozotocin-Induced Cognitive Dysfunction in Rats via Inhibiting Cholinergic and Neuroinflammatory Cytokines Pathway-TNF-α/IL-1β/IL-6/NF-κB. ACS OMEGA 2023; 8:8110-8118. [PMID: 36872976 PMCID: PMC9979232 DOI: 10.1021/acsomega.2c08277] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/07/2023] [Indexed: 06/18/2023]
Abstract
Streptozotocin (STZ) impairs memory in rats through altering the central nervous systems (CNS) as a result of impaired cholinergic dysfunction, oxidative stress, persistent hyperglycemia, and alterations in the glucagon-like peptide (GLP). In this model cholinergic agonist, antioxidant and antihyperglycemic treatment has been shown to have positive effects. Barbaloin has a variety of pharmacological effects. However, there is no evidence on how barbaloin improves memory dysfunction caused by STZ. Thus, we examined its effectiveness against cognitive damage caused by STZ at a dose of 60 mg/kg i.p. in Wistar rats. Blood glucose levels (BGL) and body weight (BW) were assessed. To assess learning and memory skills, the Y-maze test and Morris water maze (MWM) test were utilized. Superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), and glutathione (GSH) as oxidative stress markers were regulated to reverse the cognitive deterioration, and choline-acetyltransferase (ChAT) and acetyl-cholinesterase (AChE) as indicators of cholinergic dysfunction, nuclear factor kappa-B (NF-κB), IL-1β (interleukin-1β), IL-6, and tumor necrosis factor-α (TNF-α) contents were used. Barbaloin treatment thereby significantly decreased the BW and learning and memory capacities, resulting in substantial behavioral improvement in the Y-maze and MWM test. BGL, SOD, CAT, MDA, GSH, AChE, ChAT, NF-κB, IL-6, TNF-α, and IL-1β levels were also altered. In conclusion, the findings revealed that barbaloin had a protective impact against cognitive dysfunction caused by STZ.
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Affiliation(s)
- Asma B. Omer
- Department
of Basic Health Sciences, Foundation Year for the Health Colleges, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Obaid Afzal
- Department
of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Abdulmalik S. A. Altamimi
- Department
of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Shaktipal Patil
- Department
of Pharmacology, H. R. Patel Institute of
Pharmaceutical Education and Research, Karwand naka, Shirpur- 425405, Maharashtra, India
| | - Shareefa A. AlGhamdi
- Department
of Biochemistry, Faculty of Sciences, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
- Experimental
Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Amira M. Alghamdi
- Department
of Biochemistry, Faculty of Sciences, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sami I. Alzarea
- Department
of Pharmacology, College of Pharmacy, Jouf
University, Aljouf, Sakaka 72341, Saudi Arabia
| | - Waleed Hassan Almalki
- Department
of Pharmacology, College of Pharmacy, Umm
Al-Qura University, Makkah 21955, Saudi Arabia
| | - Imran Kazmi
- Department
of Biochemistry, Faculty of Sciences, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
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18
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Diabetic Encephalopathy in a Preclinical Experimental Model of Type 1 Diabetes Mellitus: Observations in Adult Female Rat. Int J Mol Sci 2023; 24:ijms24021196. [PMID: 36674713 PMCID: PMC9860834 DOI: 10.3390/ijms24021196] [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: 11/29/2022] [Revised: 12/30/2022] [Accepted: 01/01/2023] [Indexed: 01/11/2023] Open
Abstract
Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer's disease, but the mechanisms are not fully explored. In the male animal models of DM, the development of cognitive impairment seems to be the result of the concomitance of different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrant synaptogenesis. However, even if diabetic encephalopathy shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, in an experimental model of type 1 DM (T1DM), we explored the impact of one month of pathology on memory abilities by the novel object recognition test and on neuroinflammation, synaptogenesis and mitochondrial functionality. Moreover, given that steroids are involved in memory and learning, we also analysed their levels and receptors. We reported that memory dysfunction can be associated with different features in the female hippocampus and cerebral cortex. Indeed, in the hippocampus, we observed aberrant synaptogenesis and neuroinflammation but not mitochondrial dysfunction and oxidative stress, possibly due to the results of locally increased levels of progesterone metabolites (i.e., dihydroprogesterone and allopregnanolone). These observations suggest specific brain-area effects of T1DM since different alterations are observed in the cerebral cortex.
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19
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Jin Y, Arroo R. The protective effects of flavonoids and carotenoids against diabetic complications-A review of in vivo evidence. Front Nutr 2023; 10:1020950. [PMID: 37032781 PMCID: PMC10080163 DOI: 10.3389/fnut.2023.1020950] [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: 08/16/2022] [Accepted: 02/24/2023] [Indexed: 04/11/2023] Open
Abstract
Diabetes mellitus is a chronic metabolic disorder caused either by inadequate insulin secretion, impaired insulin function, or both. Uncontrolled diabetes is characterized by hyperglycemia which over time leads to fatal damage to both macro-and microvascular systems, causing complications such as cardiovascular diseases, retinopathy and nephropathy. Diabetes management is conventionally delivered through modifications of diet and lifestyle and pharmacological treatment, using antidiabetic drugs, and ultimately insulin injections. However, the side effects and financial cost of medications often reduce patient compliance to treatment, negatively affecting their health outcomes. Natural phytochemicals from edible plants such as fruits and vegetables (F&V) and medicinal herbs have drawn a growing interest as potential therapeutic agents for treating diabetes and preventing the onset and progression of diabetic complications. Flavonoids, the most abundant polyphenols in the human diet, have shown antidiabetic effects in numerous in vitro and preclinical studies. The underlying mechanisms have been linked to their antioxidant, anti-inflammatory and immunomodulatory activities. Carotenoids, another major group of dietary phytochemicals, have also shown antidiabetic potential in recent in vitro and in vivo experimental models, possibly through a mechanism of action similar to that of flavonoids. However, scientific evidence on the efficacy of these phytochemicals in treating diabetes or preventing the onset and progression of its complications in clinical settings is scarce, which delays the translation of animal study evidence to human applications and also limits the knowledge on their modes of actions in diabetes management. This review is aimed to highlight the potential roles of flavonoids and carotenoids in preventing or ameliorating diabetes-related complications based on in vivo study evidence, i.e., an array of preclinical animal studies and human intervention trials. The current general consensus of the underlying mechanisms of action exerted by both groups of phytochemicals is that their anti-inflammatory action is key. However, other potential mechanisms of action are considered. In total, 50 in vivo studies were selected for a review after a comprehensive database search via PubMed and ScienceDirect from January 2002 to August 2022. The key words used for analysis are type-2 diabetes (T2DM), diabetic complications, flavonoids, carotenoids, antioxidant, anti-inflammatory, mechanisms of prevention and amelioration, animal studies and human interventions.
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Affiliation(s)
- Yannan Jin
- Leicester School of Allied Health Sciences, Faculty of Health & Life Sciences, De Montfort University, Leicester, United Kingdom
- *Correspondence: Yannan Jin,
| | - Randolph Arroo
- Leicester School of Pharmacy, Faculty of Health & Life Sciences, De Montfort University, Leicester, United Kingdom
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20
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Zein-Elabedein A, Abo El-Fotoh WMM, Al Shourah WM, Moaty AS. Assessment of cognitive function in young children with type 1 diabetes mellitus using electrophysiological tests. Pediatr Diabetes 2022; 23:1080-1087. [PMID: 35700327 DOI: 10.1111/pedi.13383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 05/28/2022] [Accepted: 06/05/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/OBJECTIVES Diabetes mellitus is a chronic disease that affects many body systems, including the nervous and auditory systems. It is noted that there is a scarcity of research on the effect of diabetes on cognitive functions in particular and auditory functions in general in children with type 1 diabetes. Therefore, this study was designed to assess cognitive and auditory functions in children with type 1 diabetes mellitus and to correlate the reflection of diabetes control on cognitive functions. METHODS This study is a case-control study that included 100 children divided into two groups, the patient group, which includes 50 children with type 1 diabetes, and the control group, which consists of 50 healthy children. Subjects in the current study were submitted to pure tone audiometry, speech recognition threshold test, immittancemetry study, and measurement of cortical auditory evoked and P300 potentials (CAEPs and P300). These audiometric measures were statistically analyzed and correlated with the clinical characteristics of the study group. RESULTS The latency of P300 and CAEPs was significantly increased while the amplitude of P300 and CAEPs was significantly decreased in the patient group compared to the control group (p < 0.001). P300 and CAEPs latency has a positive correlation with HbA1c levels (r = 0.460). In addition, there was significant differences between the two groups regarding the hearing threshold at 8000 Hz, and 28% of patients had bilateral sensorineural hearing loss (SNHL) at 8 kHz. CONCLUSION The prolonged P300 and CAEPs latency and decreased amplitude in patients indicate a cognitive decline in individuals with type 1 diabetes compared to healthy individuals. HbA1c levels may increase the risk of cognitive impairment in children. In addition, the risk of bilateral SNHL increased at 8 kHz in children with type 1 diabetes mellitus.
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Affiliation(s)
| | | | | | - Asmaa Salah Moaty
- Department of ENT (Audiology Unit), Menoufia University, Shebin Elkom, Egypt
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21
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Čater M, Hölter SM. A Pathophysiological Intersection of Diabetes and Alzheimer's Disease. Int J Mol Sci 2022; 23:11562. [PMID: 36232867 PMCID: PMC9569835 DOI: 10.3390/ijms231911562] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 12/06/2022] Open
Abstract
Diabetes is among the most prevalent diseases of the modern world and is strongly linked to an increased risk of numerous neurodegenerative disorders, although the exact pathophysiological mechanisms are not clear yet. Insulin resistance is a serious pathological condition, connecting type 2 diabetes, metabolic syndrome, and obesity. Recently, insulin resistance has been proven to be connected also to cognitive decline and dementias, including the most prevalent form, Alzheimer's disease. The relationship between diabetes and Alzheimer's disease regarding pathophysiology is so significant that it has been proposed that some presentations of the condition could be termed type 3 diabetes.
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Affiliation(s)
- Maša Čater
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, 1230 Domžale, Slovenia
| | - Sabine M. Hölter
- Institute of Developmental Genetics, Helmholtz Munich, 85764 Neuherberg, Germany
- School of Life Sciences, Technical University Munich, 85354 Freising, Germany
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22
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Marissal-Arvy N, Moisan MP. Diabetes and associated cognitive disorders: Role of the Hypothalamic-Pituitary Adrenal axis. Metabol Open 2022; 15:100202. [PMID: 35958117 PMCID: PMC9357829 DOI: 10.1016/j.metop.2022.100202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 11/12/2022] Open
Abstract
Both diabetes types, types 1 and 2, are associated with cognitive impairments. Each period of life is concerned, and this is an increasing public health problem. Animal models have been developed to investigate the biological actors involved in such impairments. Many levels of the brain function (structure, volume, neurogenesis, neurotransmission, behavior) are involved. In this review, we detailed the part potentially played by the Hypothalamic-Pituitary Adrenal axis in these dysfunctions. Notably, regulating glucocorticoid levels, their receptors and their bioavailability appear to be relevant for future research studies, and treatment development.
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Affiliation(s)
- Nathalie Marissal-Arvy
- INRAE, Laboratoire de Nutrition et Neurobiologie Intégrée, UMR 1286, UFR de Pharmacie, 146 Rue Léo Saignat, 33076, Bordeaux Cedex, France
| | - Marie-Pierre Moisan
- University of Bordeaux, Nutrition et Neurobiologie Intégrée, UMR 1286, 33000, Bordeaux, France
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23
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Patel VN, Chorawala MR, Shah MB, Shah KC, Dave BP, Shah MP, Patel TM. Emerging Pathophysiological Mechanisms Linking Diabetes Mellitus and Alzheimer’s Disease: An Old Wine in a New Bottle. J Alzheimers Dis Rep 2022; 6:349-357. [PMID: 35891636 PMCID: PMC9277673 DOI: 10.3233/adr-220021] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/30/2022] [Indexed: 01/15/2023] Open
Abstract
Type-2 diabetes mellitus (T2DM) is a chronic immuno-inflammatory and metabolic disease characterized by hyperglycemia and insulin resistance with corresponding hyperinsulinemia. On the other hand, Alzheimer’s disease (AD) is a neurodegenerative disease involving cognitive impairment, neuronal dysfunction, and memory loss. Several recently published literatures suggest a causal relationship between T2DM and AD. In this review, we have discussed several potential mechanisms underlying diabetes-induced cognitive impairment which include, abnormal insulin signaling, amyloid-β accumulation, oxidative stress, immuno-inflammation, mitochondrial dysfunction, advanced glycation end products, acetylcholinesterase and butyrylcholinesterase, advanced lipid peroxidation products, and apolipoprotein E. All these interconnected mechanisms may act either individually or synergistically which eventually leads to neurodegeneration and AD.
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Affiliation(s)
- Vishvas N. Patel
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Mehul R. Chorawala
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Maitri B. Shah
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Kashvi C. Shah
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Bhavarth P. Dave
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Manal P. Shah
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India
| | - Tanvi M. Patel
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India
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24
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Cai M, Wang H, Song H, Yang R, Wang L, Xue X, Sun W, Hu J. Lactate Is Answerable for Brain Function and Treating Brain Diseases: Energy Substrates and Signal Molecule. Front Nutr 2022; 9:800901. [PMID: 35571940 PMCID: PMC9099001 DOI: 10.3389/fnut.2022.800901] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
Research to date has provided novel insights into lactate's positive role in multiple brain functions and several brain diseases. Although notable controversies and discrepancies remain, the neurobiological role and the metabolic mechanisms of brain lactate have now been described. A theoretical framework on the relevance between lactate and brain function and brain diseases is presented. This review begins with the source and route of lactate formation in the brain and food; goes on to uncover the regulatory effect of lactate on brain function; and progresses to gathering the application and concentration variation of lactate in several brain diseases (diabetic encephalopathy, Alzheimer's disease, stroke, traumatic brain injury, and epilepsy) treatment. Finally, the dual role of lactate in the brain is discussed. This review highlights the biological effect of lactate, especially L-lactate, in brain function and disease studies and amplifies our understanding of past research.
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Affiliation(s)
- Ming Cai
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
- Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Hongbiao Wang
- Department of Physical Education, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Haihan Song
- Central Lab, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Ruoyu Yang
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Liyan Wang
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Xiangli Xue
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Wanju Sun
- Central Lab, Shanghai Pudong New Area People's Hospital, Shanghai, China
- *Correspondence: Wanju Sun
| | - Jingyun Hu
- Central Lab, Shanghai Pudong New Area People's Hospital, Shanghai, China
- Jingyun Hu
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25
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Mehan S, Bhalla S, Siddiqui EM, Sharma N, Shandilya A, Khan A. Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration. Degener Neurol Neuromuscul Dis 2022; 12:31-59. [PMID: 35300067 PMCID: PMC8921673 DOI: 10.2147/dnnd.s247153] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington’s. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-β deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-β and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.
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Affiliation(s)
- Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
- Correspondence: Sidharth Mehan, Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India, Tel +91 8059889909; +91 9461322911, Email ;
| | - Sonalika Bhalla
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ehraz Mehmood Siddiqui
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Nidhi Sharma
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ambika Shandilya
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Andleeb Khan
- Department of Pharmacology & Toxicology, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia
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26
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Ryan MC, Hong LE, Hatch KS, Gao S, Chen S, Haerian K, Wang J, Goldwaser EL, Du X, Adhikari BM, Bruce H, Hare S, Kvarta MD, Jahanshad N, Nichols TE, Thompson PM, Kochunov P. The additive impact of cardio-metabolic disorders and psychiatric illnesses on accelerated brain aging. Hum Brain Mapp 2022; 43:1997-2010. [PMID: 35112422 PMCID: PMC8933252 DOI: 10.1002/hbm.25769] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 11/28/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022] Open
Abstract
Severe mental illnesses (SMI) including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD) elevate accelerated brain aging risks. Cardio‐metabolic disorders (CMD) are common comorbidities in SMI and negatively impact brain health. We validated a linear quantile regression index (QRI) approach against the machine learning “BrainAge” index in an independent SSD cohort (N = 206). We tested the direct and additive effects of SMI and CMD effects on accelerated brain aging in the N = 1,618 (604 M/1,014 F, average age = 63.53 ± 7.38) subjects with SMI and N = 11,849 (5,719 M/6,130 F; 64.42 ± 7.38) controls from the UK Biobank. Subjects were subdivided based on diagnostic status: SMI+/CMD+ (N = 665), SMI+/CMD− (N = 964), SMI−/CMD+ (N = 3,765), SMI−/CMD− (N = 8,083). SMI (F = 40.47, p = 2.06 × 10−10) and CMD (F = 24.69, p = 6.82 × 10−7) significantly, independently impacted whole‐brain QRI in SMI+. SSD had the largest effect (Cohen’s d = 1.42) then BD (d = 0.55), and MDD (d = 0.15). Hypertension had a significant effect on SMI+ (d = 0.19) and SMI− (d = 0.14). SMI effects were direct, independent of MD, and remained significant after correcting for effects of antipsychotic medications. Whole‐brain QRI was significantly (p < 10−16) associated with the volume of white matter hyperintensities (WMH). However, WMH did not show significant association with SMI and was driven by CMD, chiefly hypertension (p < 10−16). We used a simple and robust index, QRI, the demonstrate additive effect of SMI and CMD on accelerated brain aging. We showed a greater effect of psychiatric illnesses on QRI compared to cardio‐metabolic illness. Our findings suggest that subjects with SMI should be among the targets for interventions to protect against age‐related cognitive decline.
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Affiliation(s)
- Meghann C Ryan
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - L Elliot Hong
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Kathryn S Hatch
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Si Gao
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Shuo Chen
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Division of Biostatistics and Bioinformatics, Department of Public Health and Epidemiology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Krystl Haerian
- Department of Clinical Research and Leadership, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia, USA
| | - Jingtao Wang
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Eric L Goldwaser
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Xiaoming Du
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Bhim M Adhikari
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Heather Bruce
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Stephanie Hare
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Mark D Kvarta
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Neda Jahanshad
- Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Thomas E Nichols
- Nuffield Department of Population Health of the University of Oxford, Oxford, UK
| | - Paul M Thompson
- Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Peter Kochunov
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
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27
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Mankovsky B. Editorial commentary to manuscript "Neural correlates of slower gait in middle-aged persons with childhood-onset type 1 diabetes mellitus: The impact of accelerated brain aging" by Royse et al. J Diabetes Complications 2022; 36:108109. [PMID: 35063342 DOI: 10.1016/j.jdiacomp.2021.108109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 11/25/2022]
Affiliation(s)
- Boris Mankovsky
- Shupyk National Healthcare University of Ukraine, Kiev, Ukraine.
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28
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Erichsen JM, Fadel JR, Reagan LP. Peripheral versus central insulin and leptin resistance: Role in metabolic disorders, cognition, and neuropsychiatric diseases. Neuropharmacology 2022; 203:108877. [PMID: 34762922 PMCID: PMC8642294 DOI: 10.1016/j.neuropharm.2021.108877] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/14/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
Insulin and leptin are classically regarded as peptide hormones that play key roles in metabolism. In actuality, they serve several functions in both the periphery and central nervous system (CNS). Likewise, insulin and leptin resistance can occur both peripherally and centrally. Metabolic disorders such as diabetes and obesity share several key features including insulin and leptin resistance. While the peripheral effects of these disorders are well-known (i.e. cardiovascular disease, hypertension, stroke, dyslipidemia, etc.), the CNS complications of leptin and insulin resistance have come into sharper focus. Both preclinical and clinical findings have indicated that insulin and leptin resistance are associated with cognitive deficits and neuropsychiatric diseases such as depression. Importantly, these studies also suggest that these deficits in neuroplasticity can be reversed by restoration of insulin and leptin sensitivity. In view of these observations, this review will describe, in detail, the peripheral and central functions of insulin and leptin and explain the role of insulin and leptin resistance in various metabolic disorders, cognition, and neuropsychiatric diseases.
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Affiliation(s)
- Jennifer M Erichsen
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA.
| | - Jim R Fadel
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA
| | - Lawrence P Reagan
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA; Columbia VA Health Care System, Columbia, SC, 29208, USA
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29
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Liu L, Zhang J, Han Y, Liu D. The mechanism of Girdin in degenerative brain disease caused by high glucose stimulation. Front Endocrinol (Lausanne) 2022; 13:892897. [PMID: 36329890 PMCID: PMC9623676 DOI: 10.3389/fendo.2022.892897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
UNLABELLED Girdin, as an actin-binding protein, plays a major role in maintaining the stability of the actin skeleton structure and affects the growth, development, and migration of neurons. This study discusses the mechanism of Girdin in brain degeneration caused by high glucose stimulation. We examined the expression of Girdin in diabetic patients. The positive expression rate of Girdin in the diabetic group was 17.2% (5/29), which was obviously lower than the positive expression rate of 83.3% (20/24) in the non-diabetic group. We examined the expression of Girdin and its signaling pathway-related proteins Akt and STAT3 in hippocampal neurons induced by high glucose. The results showed that, in contrast to the control group (glucose concentration = 25 mmol/L), the expression of Girdin in the high-glucose group (glucose concentration = 225 mmol/L) was reduced (P < 0.05); the phosphorylation levels of Akt and STAT3 related to Girdin signaling pathway were also reduced (P < 0.05). Under high-glucose stimulation, the structure of neurons is abnormal, such as the reduction or disappearance of dendritic spines, and the number of neurons is reduced. In addition, Girdin and Akt were less expressed in neurons and synapses, especially the most obvious reduction in synaptic terminals. The activity of Girdin and its signaling pathway-related proteins Akt and STAT3 decreased in neurons under high glucose stimulation, indicating that the mechanism of Girdin in brain degeneration caused by high glucose stimulation was closely related to the Akt and STAT3 pathways. GRAPHIC ABSTRACT The mechanism of Girdin in degenerative brain disease caused by high glucose stimulation. This article discusses the mechanism of Girdin in brain degeneration induced by high glucose stimulation. The expression of Girdin in the diabetic group was significantly lower than that in the non-diabetic group. The expression of Girdin and its signaling pathway-related proteins Akt and STAT3 in hippocampal neurons was significantly reduced under high glucose stimulation. Under high glucose stimulation, the structure of neurons is abnormal and the number decreases; synapses become shorter. It indicates that the mechanism of brain degeneration caused by high glucose stimulation by Girdin is closely related to the Akt and STAT3 pathways.
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Affiliation(s)
- Longteng Liu
- Department of Pathology, Beijing Hospital; National Center of Gerontology; Institute of Geriatric Medicine; Chinese Academy of Medical Sciences, Beijing, China
| | - Jinsong Zhang
- Department of Pathology, Beijing Hospital; National Center of Gerontology; Institute of Geriatric Medicine; Chinese Academy of Medical Sciences, Beijing, China
| | - Yanxi Han
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, P.R. China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Dongge Liu
- Department of Pathology, Beijing Hospital; National Center of Gerontology; Institute of Geriatric Medicine; Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Dongge Liu,
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30
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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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Afzal M, Al-Abbasi FA, Kazmi I, Imam SS, Alshehri S, Ghoneim MM, Almalki WH, Nadeem MS, Sayyed N. Fustin Inhibits Oxidative Free Radicals and Inflammatory Cytokines in Cerebral Cortex and Hippocampus and Protects Cognitive Impairment in Streptozotocin-Induced Diabetic Rats. ACS Chem Neurosci 2021; 12:4587-4597. [PMID: 34860003 DOI: 10.1021/acschemneuro.1c00712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The phytogenic flavanol component of the plant Rhus verniciflua Stokes is fustin which is implicated in various disease aliments and has promising therapeutic efficacy and a long history of its uses in the Indian medicinal system. The present study investigated the ameliorative effect of fustin in streptozotocin (STZ) induced cognitive impairments in the diabetic animal paradigm. A total of five different animal groups were used for the present study.The preclinical efficacy of fustin at 50 mg/kg and 100 mg/kg was studied in diabetic male rats by employing a 35-day study design. In the present investigation the Morris water maze test (MWM) and elevated plus maze (EPM) test were employed as behavioral paradigms for the assessment of memory impairments. The study design also carried out certain biochemical parameters which include glutathione (GSH), superoxide dismutase (SOD), catalase activity (CAT), malondialdehyde (MDA), nitric oxide (NO), relative interleukin-6 (IL-6), and IL-1B in samples obtained from cerebral cortex and hippocampus. The behavioral parameters with MWM and EPM were significant restored in fustin treatment groups as compared to elevated levels in the diabetic control group. Furthermore, fustin significantly improved the altered levels of several biochemical parameters for cognitive dysfunction such as GSH, SOD, CAT, MDA, NO, and relative IL-6 and IL-1B compared to a diabetic control group. The present investigation highlights certain preclinical pieces of evidence that strongly indicate that fustin might restore the normal cognitive function in the experimental animal paradigm.
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Affiliation(s)
- Muhammad Afzal
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf-72341, Saudi Arabia
| | - Fahad A. Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Syed Sarim Imam
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Muhammad Shahid Nadeem
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Nadeem Sayyed
- Clinical Research Department, Meril Life Sciences Pvt. Ltd., Vapi, Gujurat 396191, India
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32
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Damphousse CC, Medeiros J, Marrone DF. Functional Integration of Adult-Generated Neurons in Diabetic Goto-Kakizaki Rats. Front Behav Neurosci 2021; 15:734359. [PMID: 34675787 PMCID: PMC8523851 DOI: 10.3389/fnbeh.2021.734359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/31/2021] [Indexed: 11/30/2022] Open
Abstract
Adult-born neurons in the dentate gyrus (DG) make important contributions to learning as they integrate into neuronal networks. Neurogenesis is dramatically reduced by a number of conditions associated with cognitive impairment, including type 2 diabetes mellitus (T2DM). Increasing neurogenesis may thus provide a therapeutic target for ameliorating diabetes-associated cognitive impairments, but only if new neurons remain capable of normal function. To address the capacity for adult-generated neurons to incorporate into functional circuits in the hyperglycemic DG, we measured Egr1 expression in granule cells (GCs), BrdU labeled four weeks prior, in Goto-Kakizaki (GK) rats, an established model of T2DM, and age-matched Wistars. The results indicate that while fewer GCs are generated in the DG of GK rats, GCs that survive readily express Egr1 in response to spatial information. These data demonstrate that adult-generated GCs in the hyperglycemic DG remain functionally competent and support neurogenesis as a viable therapeutic target.
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Affiliation(s)
| | - Jaclyn Medeiros
- Department of Psychology, Wilfrid Laurier University, Waterloo, ON, Canada
| | - Diano F Marrone
- Department of Psychology, Wilfrid Laurier University, Waterloo, ON, Canada
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Tanashyan MM, Surkova EV, Antonova KV, Lagoda OV, Naminov AV, Berdnikovich ES, Fedin PA, Titkova II. Type 2 diabetes and cognitive functions in patients with chronic cerebrovascular diseases. TERAPEVT ARKH 2021; 93:1179-1185. [DOI: 10.26442/00403660.2021.10.201108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 11/04/2021] [Indexed: 11/22/2022]
Abstract
Background. Type 2 diabetes (Т2DM) both directly and indirectly impacts the development of morphological and functional changes of the central nervous system.
Aim. The study was to determine clinical and neurophysiological patterns of cognitive impairment (CI) in patients with chronic cerebrovascular diseases (CCD) and Т2DM.
Materials and methods. We examined 132 patients with CCD. First group included 58 patients without Т2DM aged 64.5 [58; 72], second group 74 patients with CCD and Т2DM 63 [57; 70]. Clinical, neurological, neuropsychological, neurophysiological (cognitive evoked potentials (EP) and neurovisualisation (brain MRI) examination was carried out to all patients.
Results. Somatic and neurological characteristics of the patients were similar in both groups with the exception of more distinct metabolic changes in Т2DM patients. Neurovisualisation study of the brain MRI in Т2DM patients revealed more distinct changes in the form of white matter hyperintensity and subarachnoidal spaces enlargement. Neuropsychological examination in patients revealed the reduction of intellectual flexibility, constructive praxis disruption, optical spatial dysfunction and deteoration of delayed word recall. Significant disorders in the way of overall cognitive impairment, lobar dysfunction and impaired verbal associative productivity, proved by statistically lower amplitude and higher latency of P300 EP peak were noted in Т2DM patients. Correlation links were detected: for P300 amplitude and direct and inverse number listing test (r=0.366 and r=0.520; p=0.006 and p0.001 respectively); P300 latency and HbA1c (r=0.32; р0.05) in group 2 and glucose levels in both groups (r=0.30; p0.05); inverse relationship of latency with control functions evaluation (r=-0.34; p=0.008).
Conclusion. CCD especially with Т2DM manifests with neurocognitive imbalance, including control functions disruption and are accompanied by neurophysiological and neurovisualistion changes.
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Luna R, Talanki Manjunatha R, Bollu B, Jhaveri S, Avanthika C, Reddy N, Saha T, Gandhi F. A Comprehensive Review of Neuronal Changes in Diabetics. Cureus 2021; 13:e19142. [PMID: 34868777 PMCID: PMC8628358 DOI: 10.7759/cureus.19142] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2021] [Indexed: 12/11/2022] Open
Abstract
There has been an exponential rise in diabetes mellitus (DM) cases on a global scale. Diabetes affects almost every system of the body, and the nervous system is no exception. Although the brain is dependent on glucose, providing it with the energy required for optimal functionality, glucose also plays a key role in the regulation of oxidative stress, cell death, among others, which furthermore contribute to the pathophysiology of neurological disorders. The variety of biochemical processes engaged in this process is only matched by the multitude of clinical consequences resulting from it. The wide-ranging effects on the central and peripheral nervous system include, but are not limited to axonopathies, neurodegenerative diseases, neurovascular diseases, and general cognitive impairment. All language search was conducted on MEDLINE, COCHRANE, EMBASE, and GOOGLE SCHOLAR till September 2021. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "CNS," "Diabetic Neuropathy," and "Insulin." We explored the literature on diabetic neuropathy, covering its epidemiology, pathophysiology with the respective molecular pathways, clinical consequences with a special focus on the central nervous system and finally, measures to prevent and treat neuronal changes. Diabetes is slowly becoming an epidemic, rapidly increasing the clinical burden on account of its wide-ranging complications. This review focuses on the neuronal changes occurring in diabetes such as the impact of hyperglycemia on brain function and structure, its association with various neurological disorders, and a few diabetes-induced peripheral neuropathic changes. It is an attempt to summarize the relevant literature about neuronal consequences of DM as treatment options available today are mostly focused on achieving better glycemic control; further research on novel treatment options to prevent or delay the progression of neuronal changes is still needed.
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Affiliation(s)
- Rudy Luna
- Neurofisiología, Instituto Nacional de Neurologia y Neurocirugia, CDMX, MEX
| | | | | | | | - Chaithanya Avanthika
- Medicine and Surgery; Pediatrics, Karnataka Institute of Medical Sciences, Hubli, IND
| | - Nikhil Reddy
- Internal Medicine, Kamineni Academy of Medical Science and Research Centre, Hyderabad, IND
| | - Tias Saha
- Internal Medicine, Diabetic Association Medical College, Faridpur, BGD
| | - Fenil Gandhi
- Medicine, Shree Krishna Hospital, Anand, IND
- Research Project Associate, Memorial Sloan Kettering Cancer Center, New York, USA
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35
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Eid SA, Hinder LM, Zhang H, Eksi R, Nair V, Eddy S, Eichinger F, Park M, Saha J, Berthier CC, Jagadish HV, Guan Y, Pennathur S, Hur J, Kretzler M, Feldman EL, Brosius FC. Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: Predictors of pathology and RAS blockade effects. FASEB J 2021; 35:e21467. [PMID: 33788970 DOI: 10.1096/fj.202002387r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/31/2022]
Abstract
Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two common diabetic complications. However, their pathogenesis remains elusive and current therapies are only modestly effective. We evaluated genome-wide expression to identify pathways involved in DKD and DPN progression in db/db eNOS-/- mice receiving renin-angiotensin-aldosterone system (RAS)-blocking drugs to mimic the current standard of care for DKD patients. Diabetes and eNOS deletion worsened DKD, which improved with RAS treatment. Diabetes also induced DPN, which was not affected by eNOS deletion or RAS blockade. Given the multiple factors affecting DKD and the graded differences in disease severity across mouse groups, an automatic data analysis method, SOM, or self-organizing map was used to elucidate glomerular transcriptional changes associated with DKD, whereas pairwise bioinformatic analysis was used for DPN. These analyses revealed that enhanced gene expression in several pro-inflammatory networks and reduced expression of development genes correlated with worsening DKD. Although RAS treatment ameliorated the nephropathy phenotype, it did not alter the more abnormal gene expression changes in kidney. Moreover, RAS exacerbated expression of genes related to inflammation and oxidant generation in peripheral nerves. The graded increase in inflammatory gene expression and decrease in development gene expression with DKD progression underline the potentially important role of these pathways in DKD pathogenesis. Since RAS blockers worsened this gene expression pattern in both DKD and DPN, it may partly explain the inadequate therapeutic efficacy of such blockers.
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Affiliation(s)
- Stephanie A Eid
- Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Lucy M Hinder
- Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Hongyu Zhang
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ridvan Eksi
- Department of Computational Medicine and Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Viji Nair
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Sean Eddy
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Felix Eichinger
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Meeyoung Park
- Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jharna Saha
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Celine C Berthier
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Hosagrahar V Jagadish
- Department of Computational Medicine and Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yuanfang Guan
- Department of Computational Medicine and Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Subramaniam Pennathur
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Junguk Hur
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, USA
| | - Matthias Kretzler
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Computational Medicine and Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Eva L Feldman
- Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Frank C Brosius
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Medicine, University of Arizona, Tucson, AZ, USA
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36
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Muniroh M, Nindita Y, Karlowee V, Purwoko Y, Rahmah ND, Widyowati R, Suryono S. Effect of Garcinia mangostana pericarp extract on glial NF-κB levels and expression of serum inflammation markers in an obese-type 2 diabetes mellitus animal model. Biomed Rep 2021; 15:63. [PMID: 34113445 PMCID: PMC8188163 DOI: 10.3892/br.2021.1439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 05/17/2021] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is an age-related disease associated with cerebral inflammation and Alzheimer's disease. Garcinia mangostana pericarp (GMP) possesses antihyperglycemic, antidiabetic and anti-inflammatory effects. The aim of the present study was to evaluate the effect of GMP extract on cerebral inflammation in Wistar rats with T2DM by examining the expression levels of glial nuclear factor-κB (NF-κB), interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and superoxide dismutase (SOD). A total of 36 8-10-week-old male Wistar rats were randomly divided into six groups and provided a standard diet (normal control; C1), high-fat diet (HFD) with 200 g/kg GMP extract BW/day (GMP control; C2), HFD with streptozotocin-nicotinamide (diabetic control; C3), and HFD with 100 (M1), 200 (M2) or 400 g/kg body weight (BW)/day (M3) GMP extract for Wistar rats with diabetes. GMP extract was administered for 8 weeks after induction of T2DM was confirmed. Glial NF-κB activity was assessed by immunohistochemical staining, and by measuring IL-6 levels, TNF-α levels and SOD activity in the serum using ELISA. BW significantly increased following HFD treatment. After 7 weeks, the BW remained significantly higher compared with the normal control and GMP extract-treated groups, but decreased continuously in the T2DM groups. Glial NF-κB immunoreaction in the hippocampal region was significantly higher in the diabetic Wistar rats compared with the normal control Wistar rats, and 200 g/kg BW/day GMP significantly reduced its activity. The T2DM Wistar rats showed significantly higher expression levels of serum IL-6 and TNF-α and lower activity of SOD compared with the normal control Wistar rats. Meanwhile, rats in GMP groups M1, M2 and M3 exhibited significant reductions in the levels of IL-6 and TNF-α expression, and increases in SOD activity. GMP extract treatment effectively reduced hippocampal NF-κB, IL-6 and TNF-α levels and increased antioxidant SOD activity. These results suggest that GMP extract prevents cerebral inflammation in T2DM Wistar rats.
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Affiliation(s)
- Muflihatul Muniroh
- Department of Physiology, Faculty of Medicine Diponegoro University, Semarang, Java 50275, Indonesia
| | - Yora Nindita
- Department of Pharmacology and Therapeutics, Faculty of Medicine Diponegoro University, Semarang, Java 50275, Indonesia
| | - Vega Karlowee
- Department of Anatomical Pathology, Faculty of Medicine Diponegoro University, Semarang, Java 50275, Indonesia
| | - Yosef Purwoko
- Department of Physiology, Faculty of Medicine Diponegoro University, Semarang, Java 50275, Indonesia.,Department of Internal Medicine, Faculty of Medicine Diponegoro University, Semarang, Java 50275, Indonesia
| | - Nadya Diena Rahmah
- Department of Nutrition Science, Faculty of Medicine Diponegoro University, Semarang, Java 50275, Indonesia
| | - Retno Widyowati
- Department of Pharmaceutical Science, Faculty of Pharmacy Airlangga University, Surabaya, East Java 60115, Indonesia
| | - Suryono Suryono
- Department of Physics, Faculty of Science and Mathematics Diponegoro University, Semarang, Java 50275, Indonesia
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Zhao J, Imai R, Ukon N, Shimoyama S, Tan C, Maejima Y, Omiya Y, Takahashi K, Nan G, Zhao S, Ito H, Shimomura K. Evaluation of Effect of Ninjin'yoeito on Regional Brain Glucose Metabolism by 18F-FDG Autoradiography With Insulin Loading in Aged Mice. Front Nutr 2021; 8:657663. [PMID: 34055854 PMCID: PMC8152663 DOI: 10.3389/fnut.2021.657663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/16/2021] [Indexed: 12/02/2022] Open
Abstract
Introduction: A recent clinical study revealed that Ninjin'yoeito (NYT) may potentially improve cognitive outcome. However, the mechanism by which NYT exerts its effect on elderly patients remains unclear. The aim of this study is to evaluate the effect of Ninjin'yoeito on regional brain glucose metabolism by 18F-FDG autoradiography with insulin loading in aged wild-type mice. Materials and Methods: After 12 weeks of feeding NYT, mice were assigned to the control and insulin-loaded groups and received an intraperitoneal injection of human insulin (2 U/kg body weight) 30 min prior to 18F-FDG injection. Ninety minutes after the injection, brain autoradiography was performed. Results: After insulin loading, the 18F-FDG accumulation showed negative changes in the cortex, striatum, thalamus, and hippocampus in the control group, whereas positive changes were observed in the NYT-treated group. Conclusions: Ninjin'yoeito may potentially reduce insulin resistance in the brain regions in aged mice, thereby preventing age-related brain diseases.
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Affiliation(s)
- Jingmin Zhao
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.,Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, Japan
| | - Ryota Imai
- Tsumura Kampo Research Laboratories, Kampo Research and Development Division, Tsumura & Co., Ibaraki, Japan.,Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
| | - Naoyuki Ukon
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Saki Shimoyama
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Chengbo Tan
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan.,Department of Neurosurgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuko Maejima
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yuji Omiya
- Tsumura Kampo Research Laboratories, Kampo Research and Development Division, Tsumura & Co., Ibaraki, Japan
| | - Kazuhiro Takahashi
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Guangxian Nan
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Songji Zhao
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan.,Department of Pathophysiology, Basic Medical College of Jilin University, Changchun, China
| | - Hiroshi Ito
- Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, Japan.,Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Kenju Shimomura
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
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38
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Wang M, Yoon G, Song J, Jo J. Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition. Sci Rep 2021; 11:8326. [PMID: 33859286 PMCID: PMC8050263 DOI: 10.1038/s41598-021-87809-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/30/2021] [Indexed: 12/13/2022] Open
Abstract
Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.
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Affiliation(s)
- Ming Wang
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea
| | - Gwangho Yoon
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea
- Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do, 58128, Republic of Korea
| | - Juhyun Song
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea.
- Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-do, 58128, Republic of Korea.
| | - Jihoon Jo
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 seoyangro, Hwasun, 58128, Republic of Korea.
- NeuroMedical Convergence Lab, Biomedical Research Institute, Chonnam National University Hospital, Jebong-ro, Gwangju, 501-757, Republic of Korea.
- Department of Neurology, Chonnam National University Medical School, Gwangju, 501-757, Republic of Korea.
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39
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Zhao J, Tan C, Imai R, Ukon N, Shimoyama S, Maejima Y, Omiya Y, Takahashi K, Ito H, Nan G, Zhao S, Shimomura K. Evaluation of organ glucose metabolism by 18F-FDG accumulation with insulin loading in aged mice compared with young normal mice. Sci Rep 2021; 11:7421. [PMID: 33795778 PMCID: PMC8016832 DOI: 10.1038/s41598-021-86825-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 03/17/2021] [Indexed: 12/20/2022] Open
Abstract
It is important to determine the functional changes of organs that occur as a result of aging, the understanding of which may lead to the maintenance of a healthy life. Glucose metabolism in healthy bodies is one of the potential markers used to evaluate the changes of organ function. Thus, information about normal organ glucose metabolism may help to understand the functional changes of organs. [18F]-Fluoro-2-deoxy-2-d-glucose (18F-FDG), a glucose analog, has been used to measure glucose metabolism in various fields, such as basic medical research and drug discovery. However, glucose metabolism changes in aged animals have not yet been fully clarified. The aim of this study is to evaluate changes in glucose metabolism in organs and brain regions by measuring 18F-FDG accumulation and 18F-FDG autoradiography with insulin loading in aged and young wild-type mice. In the untreated groups, the levels of 18F-FDG accumulation in the blood, plasma, muscle, lungs, spleen, pancreas, testes, stomach, small intestine, kidneys, liver, brain, and brain regions, namely, the cortex, striatum, thalamus, and hippocampus, were all significantly higher in the aged mice. The treated group showed lower 18F-FDG accumulation levels in the pancreas and kidneys, as well as in the cortex, striatum, thalamus, and hippocampus in the aged mice than the untreated groups, whereas higher 18F-FDG accumulation levels were observed in those in the young mice. These results demonstrate that insulin loading decreases effect on 18F-FDG accumulation levels in some organs of the aged mice. Therefore, aging can increase insulin resistance and lead to systemic glucose metabolism dysfunction.
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Affiliation(s)
- Jingmin Zhao
- Department of Neurology, China-Japan Union Hospital of Jilin University, 126 XianTai Street, Changchun, 130031, Jilin, China.,Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, Japan
| | - Chengbo Tan
- Department of Neurosurgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Ryota Imai
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan.,Tsumura Kampo Research Laboratories, Kampo Research & Development Division, Tsumura & Co., Ibaraki, Japan
| | - Naoyuki Ukon
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Saki Shimoyama
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Yuko Maejima
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yuji Omiya
- Tsumura Kampo Research Laboratories, Kampo Research & Development Division, Tsumura & Co., Ibaraki, Japan
| | - Kazuhiro Takahashi
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Hiroshi Ito
- Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, Japan.,Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Guangxian Nan
- Department of Neurology, China-Japan Union Hospital of Jilin University, 126 XianTai Street, Changchun, 130031, Jilin, China.
| | - Songji Zhao
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, 960-1295, Japan. .,Basic Medical College of Jilin University, Changchun, China.
| | - Kenju Shimomura
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
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40
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Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions. Life (Basel) 2021; 11:life11030262. [PMID: 33810179 PMCID: PMC8005009 DOI: 10.3390/life11030262] [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: 02/11/2021] [Revised: 03/12/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023] Open
Abstract
Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.
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41
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Hao L, Mi J, Song L, Guo Y, Li Y, Yin Y, Zhang C. SLC40A1 Mediates Ferroptosis and Cognitive Dysfunction in Type 1 Diabetes. Neuroscience 2021; 463:216-226. [PMID: 33727075 DOI: 10.1016/j.neuroscience.2021.03.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023]
Abstract
Cognitive dysfunction often accompanies diabetes. Both hypoglycemia and hyperglycemia cause cognitive dysfunctions. However, the underlying pathophysiology remains unclear. Recent evidence show that ferroptosis primarily triggers nerve cell death, Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). The present study aimed to investigate whether ferroptosis is a vital pathogenic pathway in diabetes-induced cognitive dysfunction. Type 1 diabetic rat model was created by intraperitoneal injection of streptozotocin (STZ). Significant cognitive dysfunction was observed in the diabetic rats as evidenced by increase in latency period to find a hidden platform and decreased cumulative time spent in the target quadrant (TQ) in the Morris water maze test. We detected the amplitude of low-frequency fluctuation (ALFF) of the BOLD (Blood Oxygenation Level-Dependent) signal using resting-state functional magnetic resonance imaging (rs-fMRI). Consequently, we found that the ALFF values, as well as the T2 relaxation time of the bilateral hippocampus, were reduced in Type 1 diabetic rats. We detected Fe2+ level and lipid peroxidation products (malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE)) in the hippocampus. Mitochondria and neuron injury in the STZ-induced diabetic rats were determined using a Transmission Electron Microscope and Nissl body staining. Iron overload and ferroptosis were detected in the hippocampus. Furthermore, mRNA microarray analysis revealed 201 dysregulated mRNAs in STZ-induced type 1 diabetes (T1D). Pathway enrichment analyses indicated that differentially expressed mRNAs associated-coding genes were associated with ferroptosis. Among ferroptosis signaling pathway genes, Slc40a1 gene (ferroportin) was downregulated. We show that ferroptosis is associated with diabetic cognitive dysfunction and Slc40a1 mediates ferroptosis in T1D.
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Affiliation(s)
- Lijun Hao
- Department of Pain, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, PR China
| | - Jun Mi
- Department of Pain, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, PR China
| | - Liping Song
- Department of Pain, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, PR China
| | - Yinnan Guo
- Department of Pain, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, PR China
| | - Yanli Li
- Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - Yiru Yin
- Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China.
| | - Ce Zhang
- Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China.
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42
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Carvalho C, Cardoso S. Diabetes-Alzheimer's Disease Link: Targeting Mitochondrial Dysfunction and Redox Imbalance. Antioxid Redox Signal 2021; 34:631-649. [PMID: 32098477 DOI: 10.1089/ars.2020.8056] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Significance: It is of common sense that the world population is aging and life expectancy is increasing. However, as the population ages, there is also an exponential risk to live into the ages where the brain-related frailties and neurodegenerative diseases develop. Hand in hand with those events, the world is witnessing a major upsurge in diabetes diagnostics. Remarkably, all of this seems to be narrowly related, and clinical and research communities highlight for the upcoming threat that it will represent for the present and future generations. Recent Advances: It is of utmost importance to clarify the influence of diabetes-related metabolic features on brain health and the mechanisms underlying the increased likelihood of developing neurodegenerative diseases, in particular Alzheimer's disease. Thereupon, a wealth of evidence suggests that mitochondria and associated oxidative stress are at the root of the link between diabetes and co-occurring disorders in the brain. Critical Issues: The scientific community has been challenged with constant failures of clinical trials raising major issues in the advance of the therapeutic field to fight chronic diseases epidemics. Thus, a change of paradigms is urgently needed. Future Directions: It has become urgent to identify new and solid candidates able to clinically reproduce the positive outcomes obtained in preclinical studies. On this basis, strategies settled to counteract diabetes-induced neurodegeneration encompassing mitochondrial dysfunction, redox status imbalance, and/or insulin dysregulation seem worth to follow. Hopefully, ongoing innovative research based on reliable experimental tools will soon bring the desired answers allowing pharmaceutical industry to apply such knowledge to human medicine.
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Affiliation(s)
- Cristina Carvalho
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,IIIUC-Interdisciplinarie Institute of Investigation, University of Coimbra, Coimbra, Portugal
| | - Susana Cardoso
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,IIIUC-Interdisciplinarie Institute of Investigation, University of Coimbra, Coimbra, Portugal
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Ravi R, Balasubramaniam V, Kuppusamy G, Ponnusankar S. Current concepts and clinical importance of glycemic variability. Diabetes Metab Syndr 2021; 15:627-636. [PMID: 33743360 DOI: 10.1016/j.dsx.2021.03.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Evolving evidence indicate that variations in blood glucose levels are likely to be an important factor in developing diabetic complications. Monitoring glucose fluctuations in patients remains as a therapeutic challenge and more evidence needs to be created in order to bring GV into limelight. This review encapsulates the most important findings conducted and discusses on them to provide readers a better understanding on this emerging subject. METHODS Keyword-based comprehensive desktop search was conducted to gather the relevant literature. Triple-stage cascade type content analysis of the literature was conducted to draw relevant themes of discussions. RESULTS High glycemic variability is associated with an increased risk of development of diabetic complications especially in cardiac conditions. The widely used and accepted metrics to determine the variations in blood glucose are Standard deviation (SD), MAGE (Mean amplitude of glycemic excursions) and MODD (Mean of daily differences). Occurrence of blood glucose variations affects at a molecular level thereby causing more harm than the occurrence of hyperglycemia alone. CONCLUSION Available data suggest that Glycemic Variability should be used as an additional marker of glycemia. Additional research globally, and in India are required.
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Affiliation(s)
- Ramya Ravi
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Udhagamandalam, The Nilgiris, Tamil Nadu, India
| | - V Balasubramaniam
- Department of Surgery, Govt. Medical College Hospital, Udhagamandalam, The Nilgiris, Tamil Nadu, India
| | - Gowthamarajan Kuppusamy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Udhagamandalam, The Nilgiris, Tamil Nadu, India
| | - Sivasankaran Ponnusankar
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Udhagamandalam, The Nilgiris, Tamil Nadu, India.
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Reddy VS, Pandarinath S, Archana M, Reddy GB. Impact of chronic hyperglycemia on Small Heat Shock Proteins in diabetic rat brain. Arch Biochem Biophys 2021; 701:108816. [PMID: 33631184 DOI: 10.1016/j.abb.2021.108816] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/21/2022]
Abstract
Small heat shock proteins (sHsps) are a family of proteins. Some are induced in response to multiple stimuli and others are constitutively expressed. They are involved in fundamental cellular processes, including protein folding, apoptosis, and maintenance of cytoskeletal integrity. Hyperglycemia created during diabetes leads to neuronal derangements in the brain. In this study, we investigated the impact of chronic hyperglycemia on the expression of sHsps and heat shock transcription factors (HSFs), solubility and aggregation of sHsps and amyloidogenic proteins, and their role in neuronal apoptosis in a diabetic rat model. Diabetes was induced in Sprague-Dawley rats with streptozotocin and hyperglycemia was maintained for 16 weeks. Expressions of sHsps and HSFs were analyzed by qRT-PCR and immunoblotting in the cerebral cortex. Solubility of sHsps and amyloidogenic proteins, including α-synuclein and Tau, was analyzed by the detergent soluble assay. Neuronal cell death was analyzed by TUNEL staining and apoptotic markers. The interaction of sHsps with amyloidogenic proteins and Bax was assessed using co-immunoprecipitation. Hyperglycemia decreased Hsp27 and HSF1, and increased αBC, Hsp22, and HSF4 levels at transcript and protein levels. Diabetes induced the aggregation of αBC, Hsp22, α-synuclein, and pTau, as their levels were higher in the insoluble fraction. Additionally, diabetes impaired the interaction of αBC with α-synuclein and pTau. Furthermore, diabetes reduced the interaction of αBC with Bax, which may possibly contribute to neuronal apoptosis. Together, these results indicate that chronic hyperglycemia induces differential responses of sHsps by altering their expression, solubility, interaction, and roles in apoptosis.
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Affiliation(s)
- V Sudhakar Reddy
- Biochemistry Division, ICMR-National Institute of Nutrition, Hyderabad, India.
| | - S Pandarinath
- Biochemistry Division, ICMR-National Institute of Nutrition, Hyderabad, India
| | - M Archana
- Biochemistry Division, ICMR-National Institute of Nutrition, Hyderabad, India
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Kshirsagar V, Thingore C, Juvekar A. Insulin resistance: a connecting link between Alzheimer's disease and metabolic disorder. Metab Brain Dis 2021; 36:67-83. [PMID: 32986168 DOI: 10.1007/s11011-020-00622-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/22/2020] [Indexed: 12/11/2022]
Abstract
Recent evidence suggests that Alzheimer's disease (AD) is closely linked with insulin resistance, as seen in type 2 diabetes mellitus (T2DM). Insulin signaling is impaired in AD brains due to insulin resistance, ultimately resulting in the formation of neurofibrillary tangles (NFTs). AD and T2DM are connected at molecular, clinical, and epidemiological levels making it imperative to understand the contribution of T2DM, and other metabolic disorders, to AD pathogenesis. In this review, we have discussed various modalities involved in the pathogenesis of these two diseases and explained the contributing parameters. Insulin is vital for maintaining glucose homeostasis and it plays an important role in regulating inflammation. Here, we have discussed the roles of various contributing factors like miRNA, leptin hormone, neuroinflammation, metabolic dysfunction, and gangliosides in insulin impairment both in AD and T2DM. Understanding these mechanisms will be a big step forward for making molecular therapies that may help maintain or prevent both AD and T2DM, thus reducing the burden of both these diseases.
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Affiliation(s)
- Viplav Kshirsagar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Near Khalsa college, Matunga, Mumbai, Maharashtra, 400019, India
| | - Chetan Thingore
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Near Khalsa college, Matunga, Mumbai, Maharashtra, 400019, India
| | - Archana Juvekar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Near Khalsa college, Matunga, Mumbai, Maharashtra, 400019, India.
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Momeni Z, Neapetung J, Pacholko A, Kiir TAB, Yamamoto Y, Bekar LK, Campanucci VA. Hyperglycemia induces RAGE-dependent hippocampal spatial memory impairments. Physiol Behav 2020; 229:113287. [PMID: 33316294 DOI: 10.1016/j.physbeh.2020.113287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022]
Abstract
Diabetes is a prevalent metabolic disorder that has long been associated with changes in different regions of the brain, including the hippocampus. Changes in hippocampal synaptic plasticity and subsequent impairment in cognitive functions such as learning and memory, are well documented in animal models of type 1 and type 2 diabetes. It is known that RAGE contributes to peripheral micro- and macro-vascular complications of diabetes. However, it is still unknown if RAGE plays a similar role in the development of CNS complications of diabetes. Therefore, we hypothesize that RAGE contributes to cognitive dysfunction, such as learning and memory impairments, in a mouse model of STZ-induced hyperglycemia. Control and STZ-induced hyperglycemic mice from WT and RAGE-KO groups were used for the behavioral experiments. While STZ-induced hyperglycemia decreased locomotor activity in the open field (OF) test, it did not affect the recognition memory in the novel object recognition (NOR) test in either genotype. Spatial memory, however, was impaired in STZ-induced hyperglycemic mice in WT but not in RAGE-KO group in both the Barnes maze (BM) and the Morris water maze (MWM) tests. Consistently, the RAGE antagonist FPS-ZM1 protected WT STZ-induced hyperglycemic mice from spatial memory impairment in the BM test. Our findings indicate that the parameters associated with locomotor activity and recognition memory were independent of RAGE in STZ-induced hyperglycemic mice. In contrast, the parameters associated with hippocampal-dependent spatial memory were dependent on RAGE expression.
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Affiliation(s)
- Zeinab Momeni
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Joseph Neapetung
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Anthony Pacholko
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Tabitha Achan Bol Kiir
- College of Arts and Science, 9 Campus Drive, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Lane K Bekar
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Verónica A Campanucci
- Department of Anatomy, Physiology and Pharmacology, 107 Wiggins Road, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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Lawson CM, Rentrup KFG, Cai X, Kulkarni PP, Ferris CF. Using multimodal MRI to investigate alterations in brain structure and function in the BBZDR/Wor rat model of type 2 diabetes. Animal Model Exp Med 2020; 3:285-294. [PMID: 33532703 PMCID: PMC7824967 DOI: 10.1002/ame2.12140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 09/13/2020] [Accepted: 09/21/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND This is an exploratory study using multimodal magnetic resonance imaging (MRI) to interrogate the brain of rats with type 2 diabetes (T2DM) as compared to controls. It was hypothesized there would be changes in brain structure and function that reflected the human disorder, thus providing a model system by which to follow disease progression with noninvasive MRI. METHODS The transgenic BBZDR/Wor rat, an animal model of T2MD, and age-matched controls were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting-state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. RESULTS There was an overall reduction in brain volume focused primarily on the somatosensory cortex, cerebellum, and white matter tracts. The putative changes in white and gray matter microarchitecture were pervasive affecting much of the brain and not localized to any region. There was a general increase in connectivity in T2DM rats as compared to controls. The cerebellum presented with strong functional coupling to pons and brainstem in T2DM rats but negative connectivity to hippocampus. CONCLUSION The neuroradiological measures collected in BBBKZ/Wor rats using multimodal imaging methods did not reflect those reported for T2DB patients in the clinic. The data would suggest the BBBKZ/Wor rat is not an appropriate imaging model for T2DM.
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Affiliation(s)
| | | | - Xuezhu Cai
- Center for Translational NeuroImagingNortheastern UniversityBostonMAUSA
| | | | - Craig F. Ferris
- Center for Translational NeuroImagingNortheastern UniversityBostonMAUSA
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Seppan P, Muhammed I, Mohammad ZIK, Sathyanathan SB. Pathobiology of ischiocavernosus and bulbospongiosus muscles in long-term diabetic male rats and its implication on erectile dysfunction. Aging Male 2020; 23:979-990. [PMID: 31368398 DOI: 10.1080/13685538.2019.1647160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE To analyze pathobiology of ischiocavernosus (IC) and bulbospongiosus (BS) muscles in long-term diabetic male rats and its implication on erectile dysfunction (ED). METHODS Male rats were grouped into control and diabetic rats (received single injection of 60 mg/kg bw. of streptozotocin [STZ]). At 120th day, the animals were subjected to various analyses like serum hormone, penile reflex, electromyography of IC and BS muscles, after euthanasia IC and BS muscles were processed for morphological, histology, histometric analysis, immunostaining and immunoblotting synaptophysin, nNOS and NADPH diaphorase histochemistry. RESULTS Significant reduction in serum hormone level, penile reflex, reduced action potential or activity in both these muscles and wide range of histological alterations were observed in STZ rats. Muscles showed significant reduction in the diameter, volume and numerical density of the fiber in both muscles of STZ rats. Synaptophysin, nNOS and NADPH diaphorase were significantly reduced in diabetic animal IC and BS. CONCLUSION Severe neuromuscular circuitry alteration in IC and BS. Study concludes that degenerative changes in IC and BS may play a major role in ED in diabetic condition. Indicating diabetic-induced postsynaptic neuronal degeneration along with impaired motor action of the muscle and severe muscle degeneration affecting ED.
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Affiliation(s)
- Prakash Seppan
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, Tamil Nadu, India
| | - Ibrahim Muhammed
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, Tamil Nadu, India
| | - Zafar Iqbal Khan Mohammad
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, Tamil Nadu, India
| | - Sathya Bharathy Sathyanathan
- Department of Electrical and Electronics Engineering, Loyola-ICAM College of Engineering and Technology, Chennai, Tamil Nadu, India
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Demir CF, Balduz M, Taşcı İ, Kuloğlu T. Protective effect of pregabalin on the brain tissue of diabetic rats. Diabetol Int 2020; 12:207-216. [PMID: 33786275 DOI: 10.1007/s13340-020-00476-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 10/28/2020] [Indexed: 01/24/2023]
Abstract
Purpose Diabetes mellitus (DM) is a metabolic disorder characterized by insulin deficiency or insulin resistance. Pregabalin (PGB) is an antiepileptic drug with proven efficacy in the treatment of epilepsy, generalized anxiety disorder, and neuropathic pain. In this study, we aimed to investigate the protective effects of PGB in brain tissue of rats with streptozotocin (STZ)-induced experimental diabetes. Materials and methods Twenty-eight Wistar albino male rats were randomly divided into four groups with seven rats each: (I) Control group, (II) PGB (50 mg/kg PBG), (III) DM, and (IV) DM + PGB (50 mg/kg/day PGB per orally for 8 weeks). Diabetes was induced with an intraperitoneal (i.p.) STZ injection (Sigma Chemical Co Louis Missour, USA) at a dose of 180 mg/kg. STZ was dissolved in 0.1 M phosphate-citrate tampon (pH 4.5). Paraffin sections were examined using histological and immunohistochemical analyses. To detect oxidative damage biochemically, malondialdehyde (MDA), the end product of lipid peroxidation; superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) which are antioxidant enzymes, levels were studied. In addition, bax, caspase-3 enzyme activities and TUNEL assay were studied to evaluate the apoptosis status. Results In the DM group, MDA concentrations were significantly higher and GPx and SOD activities were significantly lower compared to the control group. MDA concentrations were significantly lower and SOD activity was significantly higher in the DM + PGB group than in the DM group. The GPx activity in the DM group decreased significantly compared to the control group. In immunohistochemical examinations (Bax, Caspase-3 and TUNEL), the apoptosis rate was significantly lower in the in DM + PGB group than in the DM group. Conclusion Pregabalin may prevent harmful effects of oxidative damage by decreasing the MDA levels and increasing the SOD levels. In addition, it was thought that PGB may have antiapoptotic properties due to decreased bax and caspase-3 immunoreactivity and TUNEL positivity in PGB groups. Based on these findings, we think that PGB may be effective in reducing the risk of brain damage associated with DM.
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Affiliation(s)
- Caner F Demir
- Department of Neurology, Firat University School of Medicine, Elazig, Turkey
| | - Metin Balduz
- Department of Neurology, Çukurova State Hospital, Adana, Turkey
| | - İrem Taşcı
- Department of Neurology, Malatya Training Research Hospital, Malatya, Turkey
| | - Tuncay Kuloğlu
- Department of Histology, Firat University School of Medicine, Elazig, Turkey
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Rababa'h AM, Alzoubi KH, Baydoun S, Khabour OF. Levosimendan Prevents Memory Impairment Induced by Diabetes in Rats: Role of Oxidative Stress. Curr Alzheimer Res 2020; 16:1300-1308. [PMID: 31894746 DOI: 10.2174/1567205017666200102153239] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/24/2019] [Accepted: 12/29/2019] [Indexed: 01/23/2023]
Abstract
BACKGROUND Levosimendan is a calcium sensitizer and phosphodiesterase inhibitor that has potent antioxidant and anti-inflammatory activities. OBJECTIVES The aim of the current study is to investigate the potential protective effect of levosimendan on learning and memory impairment induced by diabetes. METHODS Adult Wister rats were randomly divided into four groups (n=15 rats/group): control, levosimendan, streptozotocin (STZ) induced diabetes, and levosimendan-STZ diabetes. Upon confirmation of the success of the STZ diabetic model, intraperitoneal levosimendan (100µg/kg/week) was administrated to the assigned groups for 4 weeks. Then, the radial arm water maze was used to evaluate spatial learning and memory. Oxidative stress biomarkers and brain-derived neurotrophic factor were evaluated in hippocampal tissues. RESULTS The results showed that Diabetes Mellitus (DM) impaired both short- and long- term memory (P<0.01), while levosimendan protected the animals from memory impairment. In addition, levosimendan prevented DM-induced reduction in the hippocampal levels of superoxide dismutase and glutathione peroxidase (P<0.05). Moreover, the administration of levosimendan prevented DM-induced increases in hippocampal thiobarbituric acid reactive substances level (P<0.05). Furthermore, levosimendan restored the ratio of reduced/oxidized glutathione (GSH/GSSG) in DM rats to that observed in the control group (P<0.05). CONCLUSIONS In summary, DM induced learning and memory impairment, and treatment with levosimendan impeded this impairment probably through preventing alterations in the antioxidant system in the hippocampus.
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Affiliation(s)
- Abeer M Rababa'h
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Karem H Alzoubi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Sandy Baydoun
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Omar F Khabour
- Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan
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