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Kaur M, Kumar D, Kaur N, Muthuraman AM, Devi S, Gupta S. Therapeutic Potential of 3-(4-Chlorophenyl)-4-(2-Hydroxyphenyl) 1,3-Oxazetidin-2-One in STZ-Induced Diabetic Neuropathic Pain in Rats. Fundam Clin Pharmacol 2025; 39:e70026. [PMID: 40421777 DOI: 10.1111/fcp.70026] [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: 05/12/2024] [Revised: 05/03/2025] [Accepted: 05/05/2025] [Indexed: 05/28/2025]
Abstract
The present study was designed to investigate the therapeutic potential of oxazetidin-2-one derivatives in a rat model of streptozotocin (STZ)-induced diabetic neuropathic pain. A single dose of STZ (i.e., 75 mg/kg; i.p.) was administered to induce diabetes-associated neuropathic pain in rats. The serum glucose level was estimated on days 0, 3, 42, and 45. A battery of behavioral tests, i.e., hot plate, plantar, tail immersion, and tail flick tests, were performed to assess the degree of thermal hyperalgesia in the paw and tail regions at different time intervals, i.e., 42nd and 44th day. Total protein, thiobarbituric acid reactive substances (TBARS), nitrite, reduced glutathione (GSH), and total calcium levels in sciatic nerve tissue were also estimated on the 45th day of the experiment. The test compound (CHO; 5, 10, or 15 mg/kg; p.o.) and pregabalin (10 mg/kg; p.o.) were administered for three consecutive days beginning on the 42nd day after STZ administration. STZ significantly induced diabetic neuropathic pain, as indicated by thermal hyperalgesia in the paw and tail along with increases in the TBARS, nitrite, and total calcium levels and a decrease in the GSH level. Administration of CHO attenuated STZ-induced behavioral and biochemical changes in a dose-dependent manner compared to those in the pregabalin-treated group. The attenuating effect of CHO (15 mg/kg) on STZ-induced diabetic neuropathic pain may be attributed to its neuroprotective potential via multiple pharmacological actions, including anti-lipid peroxidation, free radical scavenging, and inhibition of intracellular calcium accumulation.
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Affiliation(s)
- Manpreet Kaur
- Department of Chemistry, Mata Gujri College, Fatehgarh Sahib, Punjab, India
| | - Dhruva Kumar
- Department of Chemistry, Guru Nanak College, Budhlada, Punjab, India
| | - Navjeet Kaur
- Department of Physics, Mata Gujri College, Fatehgarh Sahib, Punjab, India
| | - A M Muthuraman
- Department of Pharmacology, Akal Toxicology Research Centre, Akal College of Pharmacy & Technical Education, Sangrur, Punjab, India
- Toxicology and Basic Health Sciences Unit, Faculty of Pharmacy, AIMST University, Bedong, Kedah, Malaysia
| | - Sushma Devi
- Chitkara College of Pharmacy, Chitkara University, Rajpura
| | - Saurabh Gupta
- Department of Microbiology, Mata Gujri College, Fatehgarh Sahib, Punjab, India
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Sikorska E, Kasarełło K, Dziedziak J, Wołosz D, Koperski Ł, Cudnoch-Jędrzejewska A. Neurotrophins of the retina and their involvement in early-stage diabetic retinopathy in an animal model of type 1 diabetes mellitus. Eur J Ophthalmol 2025:11206721251341596. [PMID: 40368327 DOI: 10.1177/11206721251341596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
IntroductionDiabetic retinopathy (DR) is a blindness-causing disease which belongs to the group of neurodegenerative diseases. Neurodegeneration of the retina is a process, in which retinal neurons suffer irreversible damage. This study aimed to assess the involvement of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) in the pathogenesis of DR.MethodsThe study was performed using male Lewis rats with type 1 diabetes mellitus induced by streptozotocin, and the control group included rats without drug administration. In vivo examinations performed over four weeks included eye fundus imaging, measurement of intraocular pressure, and glycemia. After sacrifice, serum and eyeballs were harvested. Post-mortem analyses included a histopathological analysis of the retina and the measurement of BDNF and NGF levels in the serum and eyeball homogenate.ResultsIn the experimental group, early-stage DR was confirmed, and changes in the retina were observed: diabetic rats had relatively thicker outer nuclear layers and relatively thinner inner plexiform layers. A lower level of BDNF was observed in the serum of rats with DR, while the level of NGF in the eyeball homogenate positively correlated with vascular changes.ConclusionsThe observed changes in the levels of neurotrophins in early-stage DR may indicate their involvement in the disease pathogenesis.
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Affiliation(s)
- Ewa Sikorska
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Kaja Kasarełło
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Dziedziak
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Dominika Wołosz
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | - Łukasz Koperski
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Cudnoch-Jędrzejewska
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
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Loyola-Leyva A, Hernandez-Vidales K, Ruiz-Garcia J, Loyola-Rodriguez JP. Characterization of Green Synthesized Nanoparticles with Anti-diabetic Properties. A Systematic Review. Curr Diabetes Rev 2025; 21:67-85. [PMID: 38778591 DOI: 10.2174/0115733998306451240425135229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Plants are used in medicine because they are low-cost, widely available, and have few side effects (compared to pharmacological treatment). Plants have phytocompounds with antidiabetic properties that can be delivered using nanoparticles (NPs). OBJECTIVE To describe the antidiabetic properties of green synthesized NPs (GSNPs) and their characterization methods. METHODS Three databases were consulted using the terms "type 2 diabetes mellitus," "antidiabetic effects," "phytochemicals," "plants," and "nanoparticles." Studies describing the antidiabetic effects (in vitro or animal models) of NPs synthesized by plant extracts and characterizing them through UV-Vis spectroscopy, FTIR, XRD, SEM, TEM, and DLS were included. RESULTS 16 studies were included. In vitro studies reported enzyme inhibition values between 11% (H. polyrhizus) and 100% (A. concinna) for alfa-amylase and between 41.1% (M. zapota) and 100% (A. concinna) for alfa-glucosidase. Animal studies with Wistar Albino rats having diabetes (induced by alloxan or streptozotocin) reported improved blood glucose, triglycerides, total cholesterol, LDL, and HDL after treatment with GSNPs. Regarding characterization, NP sizes were measured with DLS (25-181.5 nm), SEM (52.1-91 nm), and TEM (8.7-40.6 nm). The surface charge was analyzed with zeta potential (-30.7 to -2.9 mV). UV-Vis spectroscopy was employed to confirm the formations of AgNPs (360-460 nm), AuNPs (524-540 nm), and ZnONPs (300-400 nm), and FTIR was used to identify plant extract functional groups. CONCLUSION GSNP characterization (shape, size, zeta potential, and others) is essential to know the viability and stability, which are important to achieve health benefits for biomedical applications. Studies reported good enzyme inhibition percentages in in vitro studies, decreasing blood glucose levels and improving lipid profiles in animal models with diabetes. However, these studies had limitations in the methodology and potential risk of bias, so results need careful interpretation.
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Affiliation(s)
- Alejandra Loyola-Leyva
- Biological Physics Laboratory, Physics Institute. Autonomous University of San Luis Potosí, (Universidad Autónoma de San Luis Potosí), Av. Manuel Nava #6, Zona Universitaria, C.P. 78290, San Luis Potosí, S.L.P., México
| | - Karen Hernandez-Vidales
- Institute of Applied Science and Technology, National Autonomous University of Mexico, Cto. Exterior S/N, C.U., Coyoacán, C.P. 04510, Ciudad de México, México
| | - Jaime Ruiz-Garcia
- Biological Physics Laboratory, Physics Institute. Autonomous University of San Luis Potosí, (Universidad Autónoma de San Luis Potosí), Av. Manuel Nava #6, Zona Universitaria, C.P. 78290, San Luis Potosí, S.L.P., México
| | - Juan Pablo Loyola-Rodriguez
- Biological Physics Laboratory, Physics Institute. Autonomous University of San Luis Potosí, (Universidad Autónoma de San Luis Potosí), Av. Manuel Nava #6, Zona Universitaria, C.P. 78290, San Luis Potosí, S.L.P., México
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Hormay E, László B, Szabó I, Mintál K, Berta B, Ollmann T, Péczely L, Nagy B, Tóth A, László K, Lénárd L, Karádi Z. Dopamine-Sensitive Anterior Cingulate Cortical Glucose-Monitoring Neurons as Potential Therapeutic Targets for Gustatory and Other Behavior Alterations. Biomedicines 2024; 12:2803. [PMID: 39767710 PMCID: PMC11672934 DOI: 10.3390/biomedicines12122803] [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: 10/25/2024] [Revised: 11/29/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Background: The anterior cingulate cortex (ACC) is known for its involvement in various regulatory functions, including in the central control of feeding. Activation of local elements of the central glucose-monitoring (GM) neuronal network appears to be indispensable in these regulatory processes. Destruction of these type 2 glucose transporter protein (GLUT2)-equipped chemosensory cells results in multiple feeding-associated functional alterations. Methods: In order to examine this complex symptomatology, (1) dopamine sensitivity was studied in laboratory rats by means of the single-neuron-recording multibarreled microelectrophoretic technique, and (2) after local bilateral microinjection of the selective type 2 glucose transporter proteindemolishing streptozotocin (STZ), open-field, elevated plus maze, two-bottle and taste reactivity tests were performed. Results: A high proportion of the anterior cingulate cortical neurons changed their firing rate in response to microelectrophoretic administration of D-glucose, thus verifying them as local elements of the central glucose-monitoring network. Approximately 20% of the recorded cells displayed activity changes in response to microelectrophoretic application of dopamine, and almost 50% of the glucose-monitoring units here proved to be dopamine-sensitive. Moreover, taste stimulation experiments revealed even higher (80%) gustatory sensitivity dominance of these chemosensory cells. The anterior cingulate cortical STZ microinjections resulted in extensive behavioral and taste-associated functional deficits. Conclusions: The present findings provided evidence for the selective loss of glucose-monitoring neurons in the anterior cingulate cortex leading to motivated behavioral and gustatory alterations. This complex dataset also underlines the varied significance of the type 2 glucose transporter protein-equipped, dopamine-sensitive glucose-monitoring neurons as potential therapeutic targets. These units appear to be indispensable in adaptive control mechanisms of the homeostatic-motivational-emotional-cognitive balance for the overall well-being of the organism.
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Affiliation(s)
- Edina Hormay
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
| | - Bettina László
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - István Szabó
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - Kitti Mintál
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
| | - Beáta Berta
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - Tamás Ollmann
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - László Péczely
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - Bernadett Nagy
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - Attila Tóth
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
| | - Kristóf László
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - László Lénárd
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
| | - Zoltán Karádi
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary; (B.L.); (B.B.); (T.O.); (Z.K.)
- Medical and Engineering Multidisciplinary Cellular Bioimpedance Research Group, Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
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Sun H, Gao X, Niu J, Chen P, He S, Xu S, Ge J. AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal Injection of Streptozotocin. eNeuro 2024; 11:ENEURO.0310-24.2024. [PMID: 39626951 DOI: 10.1523/eneuro.0310-24.2024] [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: 07/14/2024] [Revised: 11/01/2024] [Accepted: 11/04/2024] [Indexed: 12/16/2024] Open
Abstract
Increasing data suggest a crucial relationship between glycolipid metabolic disorder and neuropsychiatric injury. The aim of this study is to investigate the behavioral performance changes and neuropathological injuries in mice challenged with high-fat diet (HFD) and streptozotocin (STZ). The glucose metabolism indicators and behavioral performance were detected. The mRNA expression of IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds and protein expression of APP, p-Tau, p-IRS1, p-AKT, p-ERK, and TREM1/2 were measured. The fluorescence intensities of MAP-2, NeuN, APP, p-Tau, GFAP, and IBA-1 were observed. The results showed that combination of HFD and STZ/I.P. could induce glucose metabolic turmoil and Alzheimer's disease (AD)-like neuropsychiatric dysfunction in mice, as indicated by the increased concentrations of fasting blood glucose and impaired learning and memory ability. Moreover, the model mice presented increased levels of APP, p-Tau, p-IRS1, TREM2, IL-1β, IL-6, TNF-α, ocln, zo-1, and clnds; decreased levels of p-AKT, p-ERK, and TREM1; and neuron damage and the hyperactivation of astrocytes and microglia in the hippocampus as compared with control mice. Only male mice were used in this study. Although AD and type 2 diabetes mellitus (T2DM) are distinct pathologies, our results suggested that combination of HFD and STZ/I.P., a widely used T2DM modeling method, could successfully induce AD-like behavioral impairments and neuropathological injuries in mice; the mechanism might be involved with neuroinflammation and its associated dysfunction of IRS1/AKT/ERK signaling pathway. Our findings further support the potential overlap between T2DM and AD pathophysiology, providing insight into the mechanisms underlying the comorbidity of these diseases.
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Affiliation(s)
- Huaizhi Sun
- School of Pharmacy, Anhui Medical University, Hefei 230032, PR China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, PR China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei 230032, PR China
| | - Xinran Gao
- School of Pharmacy, Anhui Medical University, Hefei 230032, PR China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, PR China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei 230032, PR China
| | - Jiachun Niu
- School of Pharmacy, Anhui Medical University, Hefei 230032, PR China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, PR China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei 230032, PR China
| | - Pengquan Chen
- School of Pharmacy, Anhui Medical University, Hefei 230032, PR China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, PR China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei 230032, PR China
| | - Shuai He
- School of Pharmacy, Anhui Medical University, Hefei 230032, PR China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, PR China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei 230032, PR China
| | - Songlin Xu
- School of Pharmacy, Anhui Medical University, Hefei 230032, PR China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, PR China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei 230032, PR China
| | - Jinfang Ge
- School of Pharmacy, Anhui Medical University, Hefei 230032, PR China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, PR China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei 230032, PR China
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Canet G, Gratuze M, Zussy C, Bouali ML, Diaz SD, Rocaboy E, Laliberté F, El Khoury NB, Tremblay C, Morin F, Calon F, Hébert SS, Julien C, Planel E. Age-dependent impact of streptozotocin on metabolic endpoints and Alzheimer's disease pathologies in 3xTg-AD mice. Neurobiol Dis 2024; 198:106526. [PMID: 38734152 DOI: 10.1016/j.nbd.2024.106526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/13/2024] Open
Abstract
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease with a complex origin, thought to involve a combination of genetic, biological and environmental factors. Insulin dysfunction has emerged as a potential factor contributing to AD pathogenesis, particularly in individuals with diabetes, and among those with insulin deficiency or undergoing insulin therapy. The intraperitoneal administration of streptozotocin (STZ) is widely used in rodent models to explore the impact of insulin deficiency on AD pathology, although prior research predominantly focused on young animals, with no comparative analysis across different age groups. Our study aimed to fill this gap by analyzing the impact of insulin dysfunction in 7 and 23 months 3xTg-AD mice, that exhibit both amyloid and tau pathologies. Our objective was to elucidate the age-specific consequences of insulin deficiency on AD pathology. STZ administration led to insulin deficiency in the younger mice, resulting in an increase in cortical amyloid-β (Aβ) and tau aggregation, while tau phosphorylation was not significantly affected. Conversely, older mice displayed an unexpected resilience to the peripheral metabolic impact of STZ, while exhibiting an increase in both tau phosphorylation and aggregation without significantly affecting amyloid pathology. These changes were paralleled with alterations in signaling pathways involving tau kinases and phosphatases. Several markers of blood-brain barrier (BBB) integrity declined with age in 3xTg-AD mice, which might have facilitated a direct neurotoxic effect of STZ in older mice. Overall, our research confirms the influence of insulin signaling dysfunction on AD pathology, but also advises careful interpretation of data related to STZ-induced effects in older animals.
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Affiliation(s)
- Geoffrey Canet
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada; Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada.
| | - Maud Gratuze
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada; Institute of Neurophysiopathology (INP), University of Aix-Marseille, CNRS UMR 7051, 13385 Marseille, France.
| | - Charleine Zussy
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada; Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada.
| | - Mohamed Lala Bouali
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada.
| | - Sofia Diego Diaz
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada.
| | - Emma Rocaboy
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada.
| | - Francis Laliberté
- Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada
| | - Noura B El Khoury
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada; University of Balamand, Faculty of Arts and Sciences, Departement of Psychology, Tueini Building Kalhat, Al-Kurah, P.O. Box 100, Tripoli, Lebanon.
| | - Cyntia Tremblay
- Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada.
| | - Françoise Morin
- Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada.
| | - Frédéric Calon
- Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; Laval University, Faculty of Pharmacy, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada.
| | - Sébastien S Hébert
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada; Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada.
| | - Carl Julien
- Research Center in Animal Sciences of Deschambault, Québec, QC G0A 1S0, Canada; Laval University, Faculty of Agricultural and Food Sciences, Québec, QC G1V 0A6, Canada.
| | - Emmanuel Planel
- Laval University, Faculty of Medicine, Neurosciences and Psychiatry department, Québec, QC G1V 0A6, Canada; Neurosciences axis, CHU de Québec Research Center, Québec, QC G1V 4G2, Canada.
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da Silva EMG, Fischer JSG, Souza IDLS, Andrade ACC, Souza LDCE, Andrade MKD, Carvalho PC, Souza RLR, Vital MABF, Passetti F. Proteomic Analysis of a Rat Streptozotocin Model Shows Dysregulated Biological Pathways Implicated in Alzheimer's Disease. Int J Mol Sci 2024; 25:2772. [PMID: 38474019 DOI: 10.3390/ijms25052772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/12/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive impairment, affecting 35 million individuals worldwide. Intracerebroventricular (ICV) injection of low to moderate doses of streptozotocin (STZ) in adult male Wistar rats can reproduce classical physiopathological hallmarks of AD. This biological model is known as ICV-STZ. Most studies are focused on the description of behavioral and morphological aspects of the ICV-STZ model. However, knowledge regarding the molecular aspects of the ICV-STZ model is still incipient. Therefore, this work is a first attempt to provide a wide proteome description of the ICV-STZ model based on mass spectrometry (MS). To achieve that, samples from the pre-frontal cortex (PFC) and hippocampus (HPC) of the ICV-STZ model and control (wild-type) were used. Differential protein abundance, pathway, and network analysis were performed based on the protein identification and quantification of the samples. Our analysis revealed dysregulated biological pathways implicated in the early stages of late-onset Alzheimer's disease (LOAD), based on differentially abundant proteins (DAPs). Some of these DAPs had their mRNA expression further investigated through qRT-PCR. Our results shed light on the AD onset and demonstrate the ICV-STZ as a valid model for LOAD proteome description.
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Affiliation(s)
- Esdras Matheus Gomes da Silva
- Instituto Carlos Chagas, FIOCRUZ, Curitiba 81310-020, PR, Brazil
- Laboratory of Toxinology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro 21040-361, RJ, Brazil
| | | | | | | | | | | | - Paulo C Carvalho
- Instituto Carlos Chagas, FIOCRUZ, Curitiba 81310-020, PR, Brazil
| | | | | | - Fabio Passetti
- Instituto Carlos Chagas, FIOCRUZ, Curitiba 81310-020, PR, Brazil
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Jbrael YJ, Hamad BK. Ameliorating impact of coenzyme Q10 on the profile of adipokines, cardiomyopathy, and hematological markers correlated with the glucotoxicity sequelae in diabetic rats. PLoS One 2024; 19:e0296775. [PMID: 38227584 PMCID: PMC10790996 DOI: 10.1371/journal.pone.0296775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/18/2023] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND In diabetes, high blood glucose induces glucotoxicity, resulting in the further damage of pancreatic beta-cells and then precipitating diabetic complications. This study was aimed to investigate the relationship between glucotoxicity with the level of adipokines, diabetic cardiomyopathy, and hematological markers. Moreover, the study examined the potential modulatory effect of coenzyme Q10 (CoQ10) on the aforementioned markers associated with the sequelae of diabetes mellitus. MATERIAL AND METHODS Twenty-four male rats were randomly assigned to receive an injection of STZ to induce diabetes (n = 16) or to remain uninduced (n = 8). The hyperglycemic status was induced in fasting rats by single intraperitoneal injection of STZ (45 mg /kg b.w.) dissolved in citrate buffer (pH 4.5). Three days after STZ injection, rats were divided into three groups; Normal control group (A), Diabetic control group (B), and CoQ10- treated diabetic group (C). The group (C) was fed with the basal diet supplemented with 5 g of CoQ10 per kilogram of diet for three weeks after the diabetes induction. After 21 days, the blood and serum samples were taken to conduct biochemical analyses. Blood glucose was determined by Blood Glucose Monitoring System. Adipokines or cytokines were evaluated by ELISA from a serum sample. Cardiac myopathy biomarkers were estimated by UP-Converting Phosphor Immunoassay Analyzer, and hematological parameters were measured by automatic hematology analyzer. RESULTS In hyperglycemic rats, the level of fasting blood glucose, and serum level of resistin, omentin, TNF-α, and cardiomyopathy biomarkers significantly increased (P < 0.05). The treatment with CoQ10 significantly decreased the profile of adipokines and cardiomyopathy markers (cardiac enzymes and LPPLA2) in diabetic rats and also reduced glucose levels (P < 0.05). Lymphocyte percentages significantly decreased while significant increases were observed in granulocytes and MID percentages in hyperglycemic rats. CONCLUSION Diabetic rats had higher serum levels of adipokines and cardiomyopathy markers. Among the hematological markers, GRA% and MID% increased while LYM% decreased. The profile of adipokines and cardiomyopathy markers improved when CoQ10 was supplemented. The study suggests that CoQ10 may have a beneficial effect on improving diabetic complications.
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Affiliation(s)
- Yousif Jameel Jbrael
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Badraldin Kareem Hamad
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- University of Kurdistan Hawler (UKH), School of Medicine, Erbil, Iraq
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9
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Bilateral intracerebroventricular injection of streptozotocin induces AD-like behavioral impairments and neuropathological features in mice: Involved with the fundamental role of neuroinflammation. Biomed Pharmacother 2022; 153:113375. [PMID: 35834993 DOI: 10.1016/j.biopha.2022.113375] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/17/2022] [Accepted: 07/06/2022] [Indexed: 01/31/2023] Open
Abstract
OBJECTIVE To establish an Alzheimer's disease (AD) mouse model, investigate the behavioral performance changes and intracerebral molecular changes induced by bilateral intracerebroventricular injection of streptozotocin (STZ/I.C.V), and explore the potential pathogenesis of AD. METHODS An AD mouse model was established by STZ/I.C.V. The behavioral performance was observed via the open field test (OFT), novel object recognition test (NOR), and tail suspension test (TST). The mRNA and protein expressions of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) in the hippocampus were measured via qPCR and Western blot. The expression of β-amyloid 1-42 (Aβ1-42), phosphorylated Tau protein (p-Tau (Ser396)), Tau5, β-site amyloid precursor protein (APP) cleaving enzyme (BACE), insulin receptor substrate 1 (IRS1), brain-derived neurotrophic factor (BDNF), Copine6, synaptotagmin-1 (Syt-1), synapsin-1, phosphoinositol 3 kinase (PI3K), serine/threonine kinase (Akt), phosphorylated serine/threonine kinase (p-Akt (Ser473)), triggering receptor expressed on myeloid cells-1/2 (TREM1/2) were detected using Western blot, and the expression of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (IBA1), Aβ1-42, p-Tau(Ser396), Syt-1, BDNF were measured via immunofluorescence staining. RESULTS STZ/I.C.V induced AD-like neuropsychiatric behaviors in mice, as indicated by the impairment of learning and memory, together with the reduced spontaneous movement and exploratory behavior. The expression of BACE, Aβ1-42, p-Tau(Ser396), and TREM2 were significantly increased in the hippocampus of model mice, while the expression of IRS1, BDNF, Copine6, Syt-1, synapsin-1, PI3K, p-Akt(Ser473), and TREM1 were decreased as compared with that of the controls. Furthermore, the model mice presented a hyperactivation of astrocytes and microglia in the hippocampus, accompanied by the increased mRNA and protein expressions of IL-1β, IL-6 and TNF-α. CONCLUSION STZ/I.C.V is an effective way to induce AD mice model, with not only AD-like neuropsychiatric behaviors, but also typic AD-like neuropathological features including neurofibrillary tangles, deposit of β-amyloid (Aβ), neuroinflammation, and imbalanced synaptic plasticity.
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Comparatively analyzing the liver-specific transcriptomic profiles in Kunming mice afflicted with streptozotocin- and natural food-induced type 2 diabetes mellitus. Mol Biol Rep 2021; 49:1369-1377. [PMID: 34846649 DOI: 10.1007/s11033-021-06970-1] [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: 07/02/2021] [Accepted: 11/17/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Streptozotocin is a classic drug used to induce diabetes in animal models. OBJECTIVE The aim of this study is to investigate the liver transcriptome of Kunming mice with diabetes induced by either streptozotocin (STZ) or Non-STZ. METHODS Forty male mice were randomly assigned into four groups: Control (Ctr, standard diet), mHH (high fat and high carbohydrate diet), mHS (high fat and high carbohydrate diet for 4 weeks followed by 60 mg/kg STZ for 3 consecutive days) and mSH (60 mg/kg STZ for 3 consecutive days followed by a high fat and high carbohydrate diet for 12 weeks). All mice injected with STZ were identified as diabetic despite the sequential feeding of high fat and high carbohydrate diets. RESULTS Only 7 of 13 mice in the mHH group met the diagnostic criteria for diabetes. The asting blood glucose (FBG) of the mHH, mHS, mSH and Ctrl groups was 13.27 ± 1.14, 15.01 ± 2.59, 15.95 ± 4.38 and 6.28 ± 0.33 mmol/L at the 12th week, respectively. Compared with the mHH group, transcription was elevated in 85 genes in the livers of mHS mice, while 21 genes were downregulated and 97 genes were upregulated in the mSH group while 35 genes were decreased. A total of 43 co-expressed genes were identified in the mHS vs mHH and mSH vs mHH groups. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses showed that two corporate GO terms and two KEGG pathways were significantly annotated in the STZ-treated groups. Both the GO term and pathway were related to the metabolism mediated by p53. CONCLUSION A high fat and high carbohydrate diet combined with a low dose of STZ can effectively induce diabetes in Kunming mice despite the abnormal expressions of genes in the liver. The differentially expressed genes were related to metabolism mediated by p53.
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Esquivel-Gutiérrez ER, Manzo-Avalos S, Peña-Montes DJ, Saavedra-Molina A, Morreeuw ZP, Reyes AG. Hypolipidemic and Antioxidant Effects of Guishe Extract from Agave lechuguilla, a Mexican Plant with Biotechnological Potential, on Streptozotocin-Induced Diabetic Male Rats. PLANTS (BASEL, SWITZERLAND) 2021; 10:2492. [PMID: 34834855 PMCID: PMC8620599 DOI: 10.3390/plants10112492] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 05/07/2023]
Abstract
In the present study, we used a by-product from Agave lechuguilla (guishe) to test its antidiabetic effect, hypolipidemic activity, and capacity to mitigate the oxidative stress in kidney mitochondria from streptozotocin-induced diabetic rats. Orally, a crude aqueous extract from lyophilized guishe was administered over 5 weeks at different doses. Blood glucose and body weight were monitored. Also, blood chemistry, bilirubin, and alanine aminotransferase were assayed. Furthermore, the activity of catalase, thiobarbituric acid reactive species, mitochondrial superoxide dismutase, glutathione and glutathione peroxidase were determined in isolated kidney mitochondria. Our results show that guishe extracts have no antidiabetic properties at any dose. Nevertheless, it was able to diminish serum triglyceride levels and regulate the oxidative stress observed in isolated kidney mitochondria. These observations indicate that the aqueous extract from guishe can be used to treat abnormalities in serum lipids, as a hypolipidemic, and mitigate the oxidative stress, as an antioxidant, occurring during diabetes.
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Affiliation(s)
- Edgar R. Esquivel-Gutiérrez
- Centro de Investigaciones Biológicas del Noroeste S.C., Av. Instituto Politécnico Nacional 195, Col. Playa Palo de Santa Rita Sur, La Paz C.P. 23096, Baja California Sur, Mexico; (E.R.E.-G.); (Z.P.M.)
| | - Salvador Manzo-Avalos
- Instituto de Investigaciones, Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia C.P. 58030, Michoacan, Mexico; (S.M.-A.); (D.J.P.-M.); (A.S.-M.)
| | - Donovan J. Peña-Montes
- Instituto de Investigaciones, Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia C.P. 58030, Michoacan, Mexico; (S.M.-A.); (D.J.P.-M.); (A.S.-M.)
| | - Alfredo Saavedra-Molina
- Instituto de Investigaciones, Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia C.P. 58030, Michoacan, Mexico; (S.M.-A.); (D.J.P.-M.); (A.S.-M.)
| | - Zoé P. Morreeuw
- Centro de Investigaciones Biológicas del Noroeste S.C., Av. Instituto Politécnico Nacional 195, Col. Playa Palo de Santa Rita Sur, La Paz C.P. 23096, Baja California Sur, Mexico; (E.R.E.-G.); (Z.P.M.)
| | - Ana G. Reyes
- CONACYT—Centro de Investigaciones Biológicas del Noroeste S.C., Av. Instituto Politécnico Nacional 195, Col. Playa Palo de Santa Rita Sur, La Paz C.P. 23096, Baja California Sur, Mexico
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Homolak J, Babic Perhoc A, Knezovic A, Osmanovic Barilar J, Salkovic-Petrisic M. Failure of the Brain Glucagon-Like Peptide-1-Mediated Control of Intestinal Redox Homeostasis in a Rat Model of Sporadic Alzheimer's Disease. Antioxidants (Basel) 2021; 10:1118. [PMID: 34356351 PMCID: PMC8301063 DOI: 10.3390/antiox10071118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer's disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore (i) gastrointestinal homeostasis in the STZ-icv model (ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and (iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and low molecular weight thiols (LMWT), protein sulfhydryls (SH), and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that (i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, (ii) brain GLP-1R signaling is involved in systemic redox regulation, (iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.
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Affiliation(s)
- Jan Homolak
- Department of Pharmacology, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia; (A.B.P.); (A.K.); (J.O.B.); (M.S.-P.)
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia
| | - Ana Babic Perhoc
- Department of Pharmacology, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia; (A.B.P.); (A.K.); (J.O.B.); (M.S.-P.)
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia
| | - Ana Knezovic
- Department of Pharmacology, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia; (A.B.P.); (A.K.); (J.O.B.); (M.S.-P.)
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia
| | - Jelena Osmanovic Barilar
- Department of Pharmacology, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia; (A.B.P.); (A.K.); (J.O.B.); (M.S.-P.)
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia
| | - Melita Salkovic-Petrisic
- Department of Pharmacology, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia; (A.B.P.); (A.K.); (J.O.B.); (M.S.-P.)
- Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia
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Abstract
Streptozotocin (STZ) is an antibiotic that causes pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this article are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition. © 2021 The Authors.
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Affiliation(s)
- Brian L Furman
- Strathclyde Institute of Pharmacy & Biomedical Sciences, Glasgow, Scotland, United Kingdom
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14
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Wang K, Cui Y, Lin P, Yao Z, Sun Y. JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation. Front Endocrinol (Lausanne) 2021; 12:689845. [PMID: 34335468 PMCID: PMC8322846 DOI: 10.3389/fendo.2021.689845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/04/2021] [Indexed: 12/28/2022] Open
Abstract
The impairment of pancreatic β-cells function is partly caused by lipotoxicity, which aggravates the development of type 2 diabetes mellitus. Activator Protein 1 member JunD modulates apoptosis and oxidative stress. Recently, it has been found that JunD regulates lipid metabolism in hepatocytes and cardiomyocytes. Here, we studied the role of JunD in pancreatic β-cells. The lipotoxic effects of palmitic acid on INS-1 cells were measured, and JunD small-interfering RNA was used to assess the effect of JunD in regulating lipid metabolism and insulin secretion. The results showed that palmitic acid stimulation induced the overexpression of JunD, impaired glucose-stimulated insulin secretion, and increased intracellular lipid accumulation of β-cells. Moreover, the gene expression involved in lipid metabolism (Scd1, Fabp4, Fas, Cd36, Lpl, and Plin5) was upregulated, while gene expression involved in the pancreatic β-cells function (such as Pdx1, Nkx6.1, Glut2, and Irs-2) was decreased. Gene silencing of JunD reversed the lipotoxic effects induced by PA on β-cells. These results suggested that JunD regulated the function of pancreatic β-cells by altering lipid accumulation.
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Affiliation(s)
- Kexin Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yixin Cui
- Department of Endocrinology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
| | - Peng Lin
- Department of Endocrinology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
| | - Zhina Yao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Zhina Yao, ; Yu Sun,
| | - Yu Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- *Correspondence: Zhina Yao, ; Yu Sun,
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Tristão Pereira C, Diao Y, Yin T, da Silva AR, Lanz B, Pierzchala K, Poitry-Yamate C, Jelescu IO. Synchronous nonmonotonic changes in functional connectivity and white matter integrity in a rat model of sporadic Alzheimer's disease. Neuroimage 2020; 225:117498. [PMID: 33164858 DOI: 10.1016/j.neuroimage.2020.117498] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 09/16/2020] [Accepted: 10/18/2020] [Indexed: 12/17/2022] Open
Abstract
Brain glucose hypometabolism has been singled out as an important contributor and possibly main trigger to Alzheimer's disease (AD). Intracerebroventricular injections of streptozotocin (icv-STZ) cause brain glucose hypometabolism without systemic diabetes. Here, a first-time longitudinal study of brain glucose metabolism, functional connectivity and white matter microstructure was performed in icv-STZ rats using PET and MRI. Histological markers of pathology were tested at an advanced stage of disease. STZ rats exhibited altered functional connectivity and intra-axonal damage and demyelination in brain regions typical of AD, in a temporal pattern of acute injury, transient recovery/compensation and chronic degeneration. In the context of sustained glucose hypometabolism, these nonmonotonic trends - also reported in behavioral studies of this animal model as well as in human AD - suggest a compensatory mechanism, possibly recruiting ketone bodies, that allows a partial and temporary repair of brain structure and function. The early acute phase could thus become a valuable therapeutic window to strengthen the recovery phase and prevent or delay chronic degeneration, to be considered both in preclinical and clinical studies of AD. In conclusion, this work reveals the consequences of brain insulin resistance on structure and function, highlights signature nonmonotonic trajectories in their evolution and proposes potent MRI-derived biomarkers translatable to human AD and diabetic populations.
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Affiliation(s)
- Catarina Tristão Pereira
- Centre d'Imagerie Biomédicale, EPFL, Station 6, Lausanne 1015, Switzerland; Faculdade de Ciências da Universidade de Lisboa, Lisbon, Portugal
| | - Yujian Diao
- Centre d'Imagerie Biomédicale, EPFL, Station 6, Lausanne 1015, Switzerland; Laboratoire d'Imagerie Fonctionnelle et Métabolique, EPFL, Lausanne, Switzerland
| | - Ting Yin
- Centre d'Imagerie Biomédicale, EPFL, Station 6, Lausanne 1015, Switzerland
| | - Analina R da Silva
- Centre d'Imagerie Biomédicale, EPFL, Station 6, Lausanne 1015, Switzerland
| | - Bernard Lanz
- Laboratoire d'Imagerie Fonctionnelle et Métabolique, EPFL, Lausanne, Switzerland
| | | | | | - Ileana O Jelescu
- Centre d'Imagerie Biomédicale, EPFL, Station 6, Lausanne 1015, Switzerland.
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Anti-diabetic activity of crude polysaccharide and rhamnose-enriched polysaccharide from G. lithophila on Streptozotocin (STZ)-induced in Wistar rats. Sci Rep 2020; 10:556. [PMID: 31953455 PMCID: PMC6969100 DOI: 10.1038/s41598-020-57486-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 10/15/2019] [Indexed: 12/14/2022] Open
Abstract
The aim of the present study was to elucidate the anti-diabetic effects of the crude polysaccharide and rhamnose-enriched polysaccharide derived from G. lithophila on streptozotocin (STZ)-induced diabetic Wistar rats. Treatment with crude polysaccharide and rhamnose-enriched polysaccharide showed increases in body weight and pancreatic insulin levels and a decrease in blood glucose levels compared with control diabetic rats. The blood concentrations of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) decreased, and high-density lipoprotein (HDL) increased both in the crude polysaccharide- and rhamnose-enriched polysaccharide-treated rats. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels increased, and malondialdehyde (MDA) levels decreased in the livers, kidneys and pancreases of crude polysaccharide- and rhamnose-enriched polysaccharide-treated rats. Immunohistological examination further confirmed that restoration of the normal cellular size of the islets of Langerhans and the rebirth of β-cells were found to be greater in the body region than in the head and tail regions of the pancreas. The crude polysaccharide- and rhamnose-enriched polysaccharide-treated diabetic rats showed normal blood glucose levels and insulin production, and reversed cholesterol levels and enzymatic actions. Therefore, rhamnose-enriched polysaccharide from G. lithophila acts as a potent anti-diabetic agent to treat diabetes and can lead to the development of an alternative medicine for diabetes in the future.
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Liu P, Cui L, Liu B, Liu W, Hayashi T, Mizuno K, Hattori S, Ushiki-Kaku Y, Onodera S, Ikejima T. Silibinin ameliorates STZ-induced impairment of memory and learning by up- regulating insulin signaling pathway and attenuating apoptosis. Physiol Behav 2020; 213:112689. [DOI: 10.1016/j.physbeh.2019.112689] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/30/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023]
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Ahmad Hajam Y, Rai S, Basheer M, Ghosh H, Singh S. Protective Role of Melatonin in Streptozotocin Induced Pancreatic Damages in Diabetic Wistar Rat. Pak J Biol Sci 2019; 21:423-431. [PMID: 30724043 DOI: 10.3923/pjbs.2018.423.431] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND OBJECTIVE Hyperglycemia is a representative hallmark and risk factor for diabetes and is closely linked to diabetes associated complications. The aim of the present study was to evaluate the therapeutic potential of exogenous melatonin against the streptozotocin induced pancreatic damages in rats. MATERIALS AND METHODS Streptozotocin was injected for consecutive 6 days. Diabetes was confirmed by blood glucose measurement after 72 h and on 7th day after injection. Animals having blood glucose level above 250 mg dL-1 were considered as diabetic and were administered exogenous melatonin for 4 weeks. Animals were euthanized after last dose, pancreas were dissected out, weighed and fixed in Bouin's fixative for histology and further tissues were kept at -20°C for biochemistry. RESULTS Diabetic rats displayed significant increase in lipid peroxidation, but pancreatic weight index, antioxidant system (GSH, SOD and CAT) showed decrease. Melatonin treatment to diabetic rats restored the alteration in physiological and biochemical markers. Results were supported by the histopathological observations, STZ treated pancreas showed damage in islets of langerhans, while as melatonin treated diabetic rats recovered the cellular architecture which inturn normalize the function of the pancreas. CONCLUSION Therefore, melatonin might be considered as a molecule to protect the pancreatic damages.
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Hormay E, László B, Szabó I, Ollmann T, Nagy B, Péczely L, Mintál K, Karádi Z. The effect of loss of the glucose-monitoring neurons in the anterior cingulate cortex: Physiologic challenges induce complex feeding-metabolic alterations after local streptozotocin microinjection in rats. Neurosci Res 2019; 149:50-60. [PMID: 30685493 DOI: 10.1016/j.neures.2019.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/14/2019] [Accepted: 01/21/2019] [Indexed: 10/27/2022]
Abstract
The anterior cingulate cortex (ACC) is interrelated to limbic structures, parts of the central glucose-monitoring (GM) network. GM neurons, postulated to exist here, are hypothesised to participate in regulatory functions, such as the central control of feeding and metabolism. In the present experiments, GM neurons were identified and examined in the ACC by means of the multibarreled microelectrophoretic technique. After bilateral ACC microinjection of streptozotocin (STZ), glucose tolerance tests (GTTs), and determination of relevant plasma metabolite concentrations were performed. Body weights were measured at regular time points during the GTT experiment. Ten percent of the neurons - 30 of 282 recorded cells - responded to the administration of D-glucose, thus, declared to be the GM units. The peak values and dynamics of the GTT blood glucose curves, the plasma metabolite concentrations, and the weight gain were pathologically altered in the STZ treated animals. Our recording experiments revealed the existence of GM neurons in the anterior cingulate cortex. STZ induced selective destruction of these chemosensory cells resulted in feeding and metabolic alterations. The present findings indicate distinguished significance of the cingulate cortical GM neurons in adaptive processes of maintenance of the homeostatic balance.
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Affiliation(s)
- Edina Hormay
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary.
| | - Bettina László
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary
| | - István Szabó
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary
| | - Tamás Ollmann
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary
| | - Bernadett Nagy
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary
| | - László Péczely
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary
| | - Kitti Mintál
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary
| | - Zoltán Karádi
- Institute of Physiology, Pécs University, Medical School, Pécs, Hungary; Neuroscience Centre, Pécs University, Pécs, Hungary; Molecular Neuroendocrinology and Neurophysiology Research Group, Szentágothai Research Center, Pécs University, Pécs, Hungary
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Fawzy Fahim V, Wadie W, Shafik AN, Ishak Attallah M. Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia. Brain Res Bull 2019; 144:21-27. [PMID: 30395886 DOI: 10.1016/j.brainresbull.2018.10.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/21/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The memory protective role of simvastatin and/or insulin, in a rat model of diabetes mellitus (DM) and dementia was examined. METHODS DM was induced by an intraperitoneal injection of streptozotocin. Diabetic rats were divided into untreated; insulin treated; simvastatin treated with 10 and 20 mg/kg/day; and combined insulin plus simvastatin treatment in the previous doses. Treatment started after blood glucose elevation and persisted for 6 weeks. Morris water maze and Y maze tests were held to detect behavioral changes. Serum glucose, cholesterol and insulin levels, the hippocampi insulin, amyloid beta (Aß) 1-42 and oxidative stress markers were measured. RESULTS Insulin increased the time spent in the target quadrant in the Morris water maze test and the percentage of alternations in the Y maze test, despite the mild improvements in brain parameters demonstrated by amyloid beta 1-42, malondialdehyde and reduced glutathione levels; while simvastatin in both doses improved brain parameters with no positive impact on behavioral tests. Insulin combined with simvastatin 20 mg/kg/day was effective in enhancing the behavioral tests and the measured brain parameters. CONCLUSIONS Treatment with insulin and simvastatin could provide a promising memory protective effect in diabetics.
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Affiliation(s)
- Veronia Fawzy Fahim
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Walaa Wadie
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Amani Nabil Shafik
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Magdy Ishak Attallah
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Takeda K, Mizutani K, Matsuura T, Kido D, Mikami R, Noda M, Buranasin P, Sasaki Y, Izumi Y. Periodontal regenerative effect of enamel matrix derivative in diabetes. PLoS One 2018; 13:e0207201. [PMID: 30439990 PMCID: PMC6237339 DOI: 10.1371/journal.pone.0207201] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/26/2018] [Indexed: 12/19/2022] Open
Abstract
The present study aimed to investigate the periodontal regenerative effect of enamel matrix derivative (EMD) in diabetes. Thirty-six rats were assigned to streptozotocin-induced diabetes or control (non-diabetic) groups. Three-wall intrabony defects were surgically generated in the bilateral maxilla molar, followed by application of EMD or saline. Primary wound closure and defect fill were evaluated via histomorphological analysis and micro-computed tomography. mRNA expression levels of inflammatory and angiogenic factors in the defects were quantified via real-time polymerase chain reaction. Gingival fibroblasts were isolated from control animals and cultured in high-glucose (HG) or control medium. The effects of EMD on insulin resistance and PI3K/Akt/VEGF signaling were evaluated. The achievement rate of primary closure and the parameters of defect fill were significantly higher at EMD-treated site than at EMD-untreated sites in both diabetic and non-diabetic rats, although defect fill in the diabetic groups was significantly lower in the control groups on two-way repeated-measures analysis of variance (for both, p<0.05). Newly formed bone and cementum were significantly increased at EMD-treated sites in diabetic rats than at EMD-untreated sites in control rats (for both, p<0.05). Vegf was significantly upregulated at EMD-treated sites in both diabetic and non-diabetic rats (for both, p<0.05). In vitro, insulin or EMD-induced Akt phosphorylation was significantly lower in cells cultured in HG medium (p<0.05). EMD-mediated Vegf upregulation was suppressed by the Akt inhibitor wortmannin, although the effect was significantly lower in HG medium (p<0.01). In conclusion, EMD might promote periodontal tissue regeneration via Akt/VEGF signaling, even in a diabetic condition.
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Affiliation(s)
- Kohei Takeda
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Koji Mizutani
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- * E-mail:
| | - Takanori Matsuura
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Daisuke Kido
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Risako Mikami
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Masahiro Noda
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Prima Buranasin
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yoshiyuki Sasaki
- Medical Innovation Promotion Center, Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yuichi Izumi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Li Y, Xiao L, Li J, Sun P, Shang L, Zhang J, Zhao Q, Ouyang Y, Li L, Gong K. MicroRNA profiling of diabetic atherosclerosis in a rat model. Eur J Med Res 2018; 23:55. [PMID: 30390707 PMCID: PMC6215356 DOI: 10.1186/s40001-018-0354-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 10/29/2018] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The incidence of diabetic atherosclerosis (DA) is increasing worldwide. The study aim was to identify differentially expressed microRNAs (DE-miRs) potentially associated with the initiation and/or progression of DA, thereby yielding new insights into this disease. METHODS Matched iliac artery tissue samples were isolated from 6 male rats with or without DA. The Affymetrix GeneChip microRNA 4.0 Array was used to detect miRs. Differential expression between atherosclerotic group and non-atherosclerotic group samples was analyzed using the Gene-Cloud of Biotechnology Information platform. Targetscan and miRanda were then used to predict targets of DE-miRs. Functions and pathways were identified for significantly enriched candidate target genes and a DE-miR functional regulatory network was assembled to identify DA-associated core target genes. RESULTS A total of nine DE-miRs (rno-miR-206-3p, rno-miR-133a-5p, rno-miR-133b-3p, rno-miR-133a-3p, rno-miR-325-5p, rno-miR-675-3p, rno-miR-411-5p, rno-miR-329-3p, and rno-miR-126a-3p) were identified, all of which were up-regulated and together predicted to target 3349 genes. The target genes were enriched in known functions and pathways related to lipid and glucose metabolism. The functional regulatory network indicated a modulatory pattern of these metabolic functions with DE-miRs. The miR-gene network suggested arpp19 and MDM4 as possible DA-related core target genes. CONCLUSION The present study identified DE-miRs and miRNA-gene networks enriched for lipid and glucose metabolic functions and pathways, and arpp19 and MDM4 as potential DA-related core target genes, suggesting DE-miRs and/or arpp19 and MDM4 could act as potential diagnostic markers or therapeutic targets for DA.
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Affiliation(s)
- Yuejin Li
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Le Xiao
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Jinyuan Li
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan China
| | - Ping Sun
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Lei Shang
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Jian Zhang
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Quan Zhao
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Yiming Ouyang
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Linhai Li
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
| | - Kunmei Gong
- The First Department of General Surgery, The First People’s Hospital of Yunnan Province, 157 JinBi Road, Kunming, 650032 Yunnan People’s Republic of China
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Abdel-Mageid AD, Abou-Salem MES, Salaam NMHA, El-Garhy HAS. The potential effect of garlic extract and curcumin nanoparticles against complication accompanied with experimentally induced diabetes in rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 43:126-134. [PMID: 29747745 DOI: 10.1016/j.phymed.2018.04.039] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 02/07/2018] [Accepted: 04/16/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Modified herbal medicines implicate the combination of several therapeutic practices of native systems of medicine that may extend many earlier generations, which frequently afford valuable therapeutic benefits. PURPOSE In this study, the role of nano-curcumin and aged garlic extract (AGE) as two modified phytomedicines on alleviating both of advanced glycation end products (AGEPs) and oxidative stress (OS) in streptozotocin (STZ) induced diabetic rats were investigated during this study. METHOD Nano-curcumin and AGE suspension were orally administrated at a dose of 300, 500 mg/kg body weight respectively. Serum glucose, insulin, total cholesterol, triglycerides and myocardial enzyme activities including creatine kinase-isoenzyme (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were determined biochemically, while quantitative real-time polymerase chain reaction (qRT-PCR)-test had been used to determine relative of manganese-superoxide dismutase (Mn-SOD) and receptor for advanced glycation end products (RAGE) gene expressions in the heart tissue of rats. Structure of rat's heart tissue was examined by histopathological analysis (H&E). RESULTS AGE increased the body weight and insulin concentration, while, it decreased serum glucose concentration, CK-MB, and LDH enzyme activities in comparing with the diabetic group. In addition, total cholesterol, triglycerides, and AST didn't show any significant changes in serum values of AGE compared to diabetic rats. Nano-curcumin suspension decreased the serum levels of triglycerides, CK- MB, LDH, and AST. While, there were non-significant changes in the body weight, glucose, insulin, and total cholesterol level of the same group compared with the STZ- untreated induced diabetic rats. The transcript quantity of manganese-superoxide dismutase gene (Mn-SOD) was highly accumulated (3.25 and 3.87-fold) in the heart tissue sample of the induced diabetic rats in response to both nano-Curcumin and AGE suspension respectively. While AGE was the most potent treatment where it caused down regulation of the receptor for advanced glycation end products gene (RAGE) expression (1.79-fold). Results of histopathological analyses under the light microscope showed restoring the structural integrity of the myocytes towards normalization in diabetic hearts treated with each of nano-curcumin and AGE suspension compared with the untreated diabetic heart samples. CONCLUSION Nano-curcumin and AGE suspension have a great therapeutic potential in the treatment of DCM, Diabetic cardiomyopathy, by attenuating cardiac inflammation, myocardial fibrosis, and programmed myocardial cell deaths through inhibiting OS and AGEPs accumulation in diabetic heart tissue. Furthermore, the hypoglycemic antioxidant properties of AGE resulted in more potent therapeutic effect than nano-curcumin in the treatment of diabetic hearts.
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Affiliation(s)
- Afaf D Abdel-Mageid
- Biochemistry Department, Faculty of Vet. Med., Benha Universtiy, Moshtohor, Tukh, Qalubia, Egypt
| | - Mohamed E S Abou-Salem
- Department of Forensic Medicine and Toxicology, Faculty of Vet. Med., Benha University, Moshtohor, Tukh, Qalubia, Egypt
| | - Nancy M H A Salaam
- Biochemistry Department, Faculty of Vet. Med., Benha Universtiy, Moshtohor, Tukh, Qalubia, Egypt
| | - Hoda A S El-Garhy
- Genetics Department, Faculty of Agriculture, Benha University, Moshtohor 13736, Qalubia, Egypt.
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Omolaoye TS, Skosana BT, du Plessis SS. Diabetes mellitus- induction: Effect of different streptozotocin doses on male reproductive parameters. Acta Histochem 2018; 120:103-109. [PMID: 29277349 DOI: 10.1016/j.acthis.2017.12.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 11/28/2017] [Accepted: 12/12/2017] [Indexed: 12/27/2022]
Abstract
Diabetes mellitus (DM) is reported to be involved in male reproductive impairment, and its impact is evident in the increased prevalence of infertility. Various studies have reported that a single parenteral injection of <40 mg/kg Streptozotocin (STZ) is ineffective in ablating pancreatic β-cells and creating a rat model to investigate the effect of DM on the male reproductive system. This study therefore aims to validate these claims. Adult male Wistar rats received either a single intraperitoneal injection of STZ (30 mg/kg or 60 mg/kg) or saline (0.9%, Control). Diabetes was confirmed after 72 h if plasma glucose levels were ≥14 mmol/L. Body weight, glucose level, fluid and food intake were measured weekly. Animals were sacrificed after 8 weeks of treatment by an overdose of sodium pentobarbital (160 mg/kg body weight). The testis and epididymis were harvested and weighed prior to preparation for histological evaluation. Epididymal sperm morphology was analysed using computer aided sperm analysis (CASA). STZ60 animals presented with significantly lower body weights compared to both control and STZ30 groups. Animals in both STZ30 and STZ60 groups showed decreased normal sperm morphology compared to control. Histological evaluation of the testes showed a decrease in the number of spermatozoa in the seminiferous tubules of animals in the STZ30 and STZ60 groups compared to control. A complete absence of spermiogenesis was observed in the seminiferous tubules of STZ60 animals. These findings prove that an STZ concentration of 30 mg/kg, which is much lower than the reported 40 mg/kg, has adverse effects on the male reproductive system via its diabetogenic effect and can therefore be used to study the impact of DM on male fertility.
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25
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Szabó I, Hormay E, Csetényi B, Nagy B, Lénárd L, Karádi Z. Multiple functional attributes of glucose-monitoring neurons in the medial orbitofrontal (ventrolateral prefrontal) cortex. Neurosci Biobehav Rev 2018; 85:44-53. [DOI: 10.1016/j.neubiorev.2017.04.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 04/11/2017] [Accepted: 04/21/2017] [Indexed: 11/28/2022]
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26
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Kido D, Mizutani K, Takeda K, Mikami R, Matsuura T, Iwasaki K, Izumi Y. Impact of diabetes on gingival wound healing via oxidative stress. PLoS One 2017; 12:e0189601. [PMID: 29267310 PMCID: PMC5739411 DOI: 10.1371/journal.pone.0189601] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 11/28/2017] [Indexed: 12/21/2022] Open
Abstract
The aim of this study is to investigate the mechanisms linking high glucose to gingival wound healing. Bilateral wounds were created in the palatal gingiva adjacent to maxillary molars of control rats and rats with streptozotocin-induced diabetes. After evaluating postsurgical wound closure by digital imaging, the maxillae including wounds were resected for histological examinations. mRNA expressions of angiogenesis, inflammation, and oxidative stress markers in the surgical sites were quantified by real-time polymerase chain reaction. Primary fibroblast culture from the gingiva of both rats was performed in high glucose and normal medium. In vitro wound healing and cell proliferation assays were performed. Oxidative stress marker mRNA expressions and reactive oxygen species production were measured. Insulin resistance was evaluated via PI3K/Akt and MAPK/Erk signaling following insulin stimulation using Western blotting. To clarify oxidative stress involvement in high glucose culture and cells of diabetic rats, cells underwent N-acetyl-L-cysteine treatment; subsequent Akt activity was measured. Wound healing in diabetic rats was significantly delayed compared with that in control rats. Nox1, Nox2, Nox4, p-47, and tumor necrosis factor-α mRNA levels were significantly higher at baseline in diabetic rats than in control rats. In vitro study showed that cell proliferation and migration significantly decreased in diabetic and high glucose culture groups compared with control groups. Nox1, Nox2, Nox4, and p47 expressions and reactive oxygen species production were significantly higher in diabetic and high glucose culture groups than in control groups. Akt phosphorylation decreased in the high glucose groups compared with the control groups. Erk1/2 phosphorylation increased in the high glucose groups, with or without insulin treatment, compared with the control groups. Impaired Akt phosphorylation partially normalized after antioxidant N-acetyl-L-cysteine treatment. Thus, delayed gingival wound healing in diabetic rats occurred because of impaired fibroblast proliferation and migration. Fibroblast dysfunction may occur owing to high glucose-induced insulin resistance via oxidative stress.
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Affiliation(s)
- Daisuke Kido
- Department of Periodontology, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Koji Mizutani
- Department of Periodontology, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- * E-mail:
| | - Kohei Takeda
- Department of Periodontology, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Risako Mikami
- Department of Periodontology, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Takanori Matsuura
- Department of Periodontology, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kengo Iwasaki
- Department of Nanomedicine, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yuichi Izumi
- Department of Periodontology, Graduate school of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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27
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Simas JN, Mendes TB, Paccola CC, Vendramini V, Miraglia SM. Resveratrol attenuates reproductive alterations in type 1 diabetes-induced rats. Int J Exp Pathol 2017; 98:312-328. [PMID: 29285813 PMCID: PMC5826946 DOI: 10.1111/iep.12251] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 08/31/2017] [Indexed: 12/11/2022] Open
Abstract
The progression of diabetes mellitus leads to several complications including overproduction of reactive oxygen species and reproductive alterations. As resveratrol (RES) is a powerful anti-oxidant and an anti-apoptotic compound, we hypothesized that side effects of type-1 diabetes (DM1) on male reproduction could be reduced by the RES treatment. Eighty-four prepubertal male rats were distributed into seven groups: sham-control (SC), RES-treated (R), resveratrol-vehicle-treated (RV), diabetic (D), diabetic-insulin-treated (DI), diabetic-RES-treated (DR), diabetic-insulin and RES-treated (DIR). DM1 was induced by a single intraperitoneal streptozotocin (STZ) injection (65 mg/kg) on the 30th day postpartum (dpp). Animals of DR, DIR and R groups received 150 mg/day of RES by gavage for 43 consecutive days (from the 33 to 75 dpp). DI and DIR rats received subcutaneous injections of insulin (1 U/100 g b.w./day) from 5th day after the DM1 induction. The blood glucose level was monitored. At 75 dpp, the euthanasia was performed for morphometric and biometric testicular analyses, spermatic evaluation and hormonal doses. In the D group, the blood glucose level was higher than in the DR, DI and DIR groups. Besides morphometric testicular measurements, testosterone and estradiol doses were lower in D group than in DR and DIR groups; LH dose was also lower than in DR. The preputial separation age was delayed in diabetes-induced groups. The DR and DIR groups showed an improvement in sperm mitochondrial activity, epididymal sperm counts and the frequency of morphologically normal sperms. RES treatment improved glycaemic level, sperm quantitative and qualitative parameters and the hormonal profile in DM1-induced rats and seems to be a good reproductive protector.
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Affiliation(s)
- Joana Noguères Simas
- Laboratory of Developmental BiologyDepartment of Morphology and GeneticsFederal University of Sao Paulo (UNIFESP)Sao PauloSPBrazil
| | - Talita Biude Mendes
- Laboratory of Developmental BiologyDepartment of Morphology and GeneticsFederal University of Sao Paulo (UNIFESP)Sao PauloSPBrazil
| | - Camila Cicconi Paccola
- Laboratory of Developmental BiologyDepartment of Morphology and GeneticsFederal University of Sao Paulo (UNIFESP)Sao PauloSPBrazil
| | - Vanessa Vendramini
- Laboratory of Developmental BiologyDepartment of Morphology and GeneticsFederal University of Sao Paulo (UNIFESP)Sao PauloSPBrazil
| | - Sandra Maria Miraglia
- Laboratory of Developmental BiologyDepartment of Morphology and GeneticsFederal University of Sao Paulo (UNIFESP)Sao PauloSPBrazil
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28
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Végh D, Somogyi A, Bányai D, Lakatos M, Balogh M, Al-Khrasani M, Fürst S, Vizi E, Hermann P. Effects of articaine on [ 3 H]noradrenaline release from cortical and spinal cord slices prepared from normal and streptozotocin-induced diabetic rats and compared to lidocaine. Brain Res Bull 2017; 135:157-162. [DOI: 10.1016/j.brainresbull.2017.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 10/12/2017] [Accepted: 10/16/2017] [Indexed: 11/29/2022]
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29
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Nagy B, Szabó I, Takács G, Csetényi B, Hormay E, Karádi Z. Impaired glucose tolerance after streptozotocin microinjection into the mediodorsal prefrontal cortex of the rat. Physiol Int 2017; 103:403-412. [PMID: 28229628 DOI: 10.1556/2060.103.2016.4.5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The mediodorsal prefrontal cortex (mdPFC) is a key structure of the central glucose-monitoring (GM) neural network. Previous studies indicate that intracerebral streptozotocin (STZ) microinjection-induced destruction of local chemosensory neurons results in feeding and metabolic alterations. The present experiments aimed to examine whether STZ microinjection into the mdPFC causes metabolic deficits. To do so, glucose tolerance test (GTT) and measurements of plasma metabolites were performed in STZ-treated or control rats. Intraperitoneal D-glucose load was delivered 20 min or 4 weeks following the intracerebral microinjection of STZ or saline (acute or subacute GTT, respectively). The STZ-treated rats displayed acute glucose intolerance: at the 120th min of the test, blood glucose level of these rats was significantly higher than that of the ones in the control group. When determining the plasma level of various metabolites, 30 min following the intracerebral STZ or saline microinjection, the triglyceride concentration of the STZ-treated rats was found to be reduced compared with that of the control rats. The GM neurons of the mdPFC are suggested to be involved in the organization of complex metabolic processes by which these chemosensory cells contribute to adaptive control mechanisms of the maintenance of homeostasis.
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Affiliation(s)
- B Nagy
- 1 Institute of Physiology, School of Medicine, University of Pécs , Pécs, Hungary
| | - I Szabó
- 1 Institute of Physiology, School of Medicine, University of Pécs , Pécs, Hungary
| | - G Takács
- 1 Institute of Physiology, School of Medicine, University of Pécs , Pécs, Hungary
| | - B Csetényi
- 1 Institute of Physiology, School of Medicine, University of Pécs , Pécs, Hungary
| | - E Hormay
- 1 Institute of Physiology, School of Medicine, University of Pécs , Pécs, Hungary
| | - Z Karádi
- 1 Institute of Physiology, School of Medicine, University of Pécs , Pécs, Hungary
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30
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Pandey V, Gilhotra RM, Kohli S. Granulated colloidal silicon dioxide-based self-microemulsifying tablets, as a versatile approach in enhancement of solubility and therapeutic potential of anti-diabetic agent: formulation design and in vitro/in vivo evaluation. Drug Dev Ind Pharm 2017; 43:1023-1032. [PMID: 28276787 DOI: 10.1080/03639045.2017.1291668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The current research work was executed with an aim to explore and promote the potential of self-microemusifying drug delivery systems (SMEDDS) in the form of tablets, in order to enhance solubility and oral bioavailability of poorly aqueous soluble drug Repaglinide (RPG). RPG-loaded liquid SMEDDS were developed consisting Labrafil M 1944CS, Kolliphor EL and Propylene glycol, which were then characterized on various parameters. After characterization and optimization, liquid SMEDDS were converted into solid form by adsorbing on Aeroperl® 300 pharma and polyplasdoneTM XL. Further, selection of suitable excipients was done and mixed with prepared solidified SMEDDS powder followed by the preparation of self-microemulsifying tablets (SMET's) wet granulation-compression method. SMET's were subjected to differential scanning calorimetry (DSC) and particle X-ray diffraction (RXRD) studies, results of which indicated transformation of crystalline structure of RPG because of dispersion of RPG at molecular level in liquid SMEDDS. This was further assured by micrographs obtained from scanning electron microscope. SMET's shown more than 85% (30 min) of in vitro drug release in contrast to conventional marketed tablets (13.2%) and pure RPG drug (3.2%). Results of in vivo studies furnished that SMET's had shown marked decrease in the blood glucose level and prolonged duration of action (up to 8 h) in comparison with conventional marketed tablets and pure RPG drug. In conclusion, SMET's serves as a promising tool for successful oral delivery of poorly aqueous soluble drug(s) such as RPG.
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Affiliation(s)
- Vikas Pandey
- a Department of Pharmaceutics , Suresh Gyan Vihar University , Jaipur , Rajasthan , India
| | - Ritu M Gilhotra
- a Department of Pharmaceutics , Suresh Gyan Vihar University , Jaipur , Rajasthan , India
| | - Seema Kohli
- b Department of Pharmaceutical Sciences , Kalaniketan Polytechnic College , Jabalpur , Madhya Pradesh , India
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Altıparmak M, Eskitaşçıoğlu T. Comparison of Systemic and Topical Hypericum Perforatum on Diabetic Surgical Wounds. J INVEST SURG 2017; 31:29-37. [PMID: 28107097 DOI: 10.1080/08941939.2016.1272654] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Surgical wounds in diabetic patients still remain a problem till the present day. As a common plant found around the world, Hypericum perforatum L. (Hypericaceae) is traditionally prepared as an oily extract and used as a folk remedy for various diseases such as wounds, burns, cuts, etc. This study aims to evaluate the effect of St. John's wort (Hypericum perforatum) on problematic wounds while comparing oral and topical applications. METHODS Incisional and excisional wound models were made on the dorsal regions of 54 diabetic Spraque-Dawley rats. The rats were divided into the following six groups (n = 9): Group 1: control, Group 2: diabetic, Group 3: diabetic oral Hypericum perforatum, Group 4: diabetic topical Hypericum perforatum, Group 5: diabetic oral olive oil, and Group 6: diabetic topical olive oil. RESULTS Groups 3 and 4 had significantly higher tensile strength, tissue hydroxyproline concentration, and collagen density compared with Group 2. Inflammatory cell density and collagen density on day 3 were significantly higher in Groups 3 and 6 compared with Group 2. On day 21, Groups 3 and 6 had significantly higher fibroblastic activity compared with Group 2. CONCLUSIONS This study has proved that oral St. John's wort has more positive effects on problematic wounds compared with topical St. John's wort and olive oil, which is a vehicle. Hypericum perforatum results with faster inflammatory response and better healing. These results could be an addition to literature about the clinical usage of Hypericum perforatum on diabetic wounds.
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Affiliation(s)
- Mehmet Altıparmak
- a Muğla Sitki Koçman University, Faculty of Medicine, Department of Plastic , Reconstructive and Aesthetic Surgery , Muğla , Turkey
| | - Teoman Eskitaşçıoğlu
- b Erciyes University, Faculty of Medicine, Department of Plastic , Reconstructive and Aesthetic Surgery , Kayseri , Turkey
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Wang CY, Li XD, Hao ZH, Xu D. Insulin-like growth factor-1 improves diabetic cardiomyopathy through antioxidative and anti-inflammatory processes along with modulation of Akt/GSK-3β signaling in rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2016; 20:613-619. [PMID: 27847438 PMCID: PMC5106395 DOI: 10.4196/kjpp.2016.20.6.613] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 09/09/2016] [Accepted: 09/10/2016] [Indexed: 12/13/2022]
Abstract
Diabetic cardiomyopathy (DCM), a serious complication of diabetes mellitus, is associated with changes in myocardial structure and function. This study sought to explore the ability of insulin-like growth factor-1 (IGF-1) to modulate DCM and its related mechanisms. Twenty-four male Wistar rats were injected with streptozotocin (STZ, 60 mg/kg) to mimic diabetes mellitus. Myocardial fibrosis and apoptosis were evaluated by histopathologic analyses, and relevant proteins were analyzed by Western blotting. Inflammatory factors were assessed by ELISA. Markers of oxidative stress were tested by colorimetric analysis. Rats with DCM displayed decreased body weight, metabolic abnormalities, elevated apoptosis (as assessed by the bcl-2/bax ratio and TUNEL assays), increased fibrosis, increased markers of oxidative stress (MDA and SOD) and inflammatory factors (TNF-α and IL-1β), and decreased phosphorylation of Akt and glycogen synthase kinase (GSK-3β). IGF-1 treatment, however, attenuated the metabolic abnormalities and myocardial apoptosis, interstitial fibrosis, oxidative stress and inflammation seen in diabetic rats, while also increasing the phosphorylation levels of Akt and GSK-3β. These findings suggest that IGF-1 ameliorates the pathophysiological progress of DCM along with an activation of the Akt/GSK-3β signaling pathway. Our findings suggest that IGF-1 could be a potential therapeutic choice for controlling DCM.
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Affiliation(s)
- Cheng Yu Wang
- Center of Morphological Experiment, Medical College of Yanbian University, Yanji 133000, Jilin Province, China
| | - Xiang Dan Li
- Center of Morphological Experiment, Medical College of Yanbian University, Yanji 133000, Jilin Province, China
| | - Zhi Hong Hao
- Center of Morphological Experiment, Medical College of Yanbian University, Yanji 133000, Jilin Province, China
| | - Dongyuan Xu
- Center of Morphological Experiment, Medical College of Yanbian University, Yanji 133000, Jilin Province, China
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Antidiabetic and antioxidant effects of catalpol extracted from Rehmannia glutinosa (Di Huang) on rat diabetes induced by streptozotocin and high-fat, high-sugar feed. Chin Med 2016; 11:25. [PMID: 27175212 PMCID: PMC4864906 DOI: 10.1186/s13020-016-0096-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Accepted: 05/03/2016] [Indexed: 12/12/2022] Open
Abstract
Background Diabetes, associated with hyperlipidemia and oxidative stress, would lead to an increased production of reactive oxygen species. Rehmannia glutinosa (Di Huang) is widely used to nourish yin, invigorate the kidney (shen), and treat xiao ke (a diabetes-like syndrome in Chinese medicine). This study aims to investigate the antidiabetic and antioxidant effects of catalpol from R. glutinosa on rat diabetes induced by streptozotocin (STZ) and high-fat, high-sugar feed. Methods Rats (eight rats in each group at least) were induced diabetes by an initial high-fat high-sugar feed for 3 weeks, followed by an intraperitoneal injection of STZ (30 mg/kg) for 3 days, and rats were fasted overnight before treatments. Catalpol at a dose of 0, 5, 10, 20 or 50 mg/kg was administrated through bolus intravenous injection to the experimental rats to find the most effective anti-hyperglycemic dose of catalpol to further study body weight loss, water intake, and food intake. The most effective catalpol dose was given to the diabetic model rats with hyperlipidemia, and the levels of blood sugar, plasma total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) were measured after catalpol administration once a day for 2 weeks. An oral glucose challenge test (OGCT) was performed after above experiments in which the most effective dose of catalpol has been determined. Levels of glutathione peroxidase (GSH-PX), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured by corresponding reagent kits and morphological changes of the pancreas were observed with histopathological examination using H&E stain. Results Catalpol at a dose of 50 mg/kg ameliorated body weight loss and increased water and food intake. Catalpol also attenuated the increase of plasma TC (P = 0.0067) and TG (P = 0.0084) and increased HDL-C (P = 0.0336). The OGCT revealed that catalpol reduced the increase of plasma glucose. The activities of antioxidative enzymes (SOD, P = 0.0037; GSH-PX, P = 0.0066; CAT, P = 0.005) were enhanced and MDA was reduced (P = 0.003). Furthermore, catalpol reduced the morphological impairment of the pancreas. Conclusion Catalpol protected against STZ-induced diabetes with high-fat and high-sugar feed with ameliorated structural impairment of the pancreas and restored balance between oxidative enzymes and antioxidative enzymes.
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Grieb P. Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer's Disease: in Search of a Relevant Mechanism. Mol Neurobiol 2016; 53:1741-1752. [PMID: 25744568 PMCID: PMC4789228 DOI: 10.1007/s12035-015-9132-3] [Citation(s) in RCA: 255] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 02/22/2015] [Indexed: 01/26/2023]
Abstract
Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer's disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer's brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of these cells may be involved in glucose sensing. Thus, icv STZ may damage brain glucose insulin producing cells and/or brain glucose sensors. Mechanistic explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer's disease.
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Affiliation(s)
- Paweł Grieb
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Str. Pawinskiego 5, 02-106, Warsaw, Poland.
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Ergul A, Hafez S, Fouda A, Fagan SC. Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes. Transl Stroke Res 2016; 7:248-60. [PMID: 27026092 DOI: 10.1007/s12975-016-0464-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Revised: 03/15/2016] [Accepted: 03/21/2016] [Indexed: 10/22/2022]
Abstract
Human ischemic stroke is very complex, and no single preclinical model can comprise all the variables known to contribute to stroke injury and recovery. Hypertension, diabetes, and hyperlipidemia are leading comorbidities in stroke patients. The use of predominantly young adult and healthy animals in experimental stroke research has created a barrier for translation of findings to patients. As such, more and more disease models are being incorporated into the research design. This review highlights the major strengths and weaknesses of the most commonly used animal models of these conditions in preclinical stroke research. The goal is to provide guidance in choosing, reporting, and executing appropriate disease models that will be subjected to different models of stroke injury.
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Affiliation(s)
- Adviye Ergul
- Charlie Norwood Veterans Administration Medical Center, University of Georgia, Athens, GA, USA. .,Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, GA, USA. .,Department of Physiology, Augusta University, CA2094, Augusta, GA, 30912, USA.
| | - Sherif Hafez
- Charlie Norwood Veterans Administration Medical Center, University of Georgia, Athens, GA, USA.,Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, GA, USA.,Department of Physiology, Augusta University, CA2094, Augusta, GA, 30912, USA
| | - Abdelrahman Fouda
- Charlie Norwood Veterans Administration Medical Center, University of Georgia, Athens, GA, USA.,Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, GA, USA
| | - Susan C Fagan
- Charlie Norwood Veterans Administration Medical Center, University of Georgia, Athens, GA, USA.,Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, GA, USA.,Department of Neurology, Augusta University, Augusta, GA, USA
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Challenges and issues with streptozotocin-induced diabetes - A clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact 2015; 244:49-63. [PMID: 26656244 DOI: 10.1016/j.cbi.2015.11.032] [Citation(s) in RCA: 257] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 11/18/2015] [Accepted: 11/26/2015] [Indexed: 02/07/2023]
Abstract
Streptozotocin (STZ) has been extensively used over the last three decades to induce diabetes in various animal species and to help screen for hypoglycemic drugs. STZ induces clinical features in animals that resemble those associated with diabetes in humans. For this reason STZ treated animals have been used to study diabetogenic mechanisms and for preclinical evaluation of novel antidiabetic therapies. However, the physiochemical characteristics and associated toxicities of STZ are still major obstacles for researchers using STZ treated animals to investigate diabetes. Another major challenges in STZ-induced diabetes are sustaining uniformity, suitability, reproducibility and induction of diabetes with minimal animal lethality. Lack of appropriate use of STZ was found to be associated with increased mortality and animal suffering. During STZ use in animals, attention should be paid to several factors such as method of preparation of STZ, stability, suitable dose, route of administration, diet regimen, animal species with respect to age, body weight, gender and the target blood glucose level used to represent hyperglycemia. Therefore, protocol for STZ-induced diabetes in experimental animals must be meticulously planned. This review highlights specific skills and strategies involved in the execution of STZ-induced diabetes model. The present review aims to provide insight into diabetogenic mechanisms of STZ, specific toxicity of STZ with its significance and factors responsible for variations in diabetogenic effects of STZ. Further this review also addresses ways to minimize STZ-induced mortality, suggests methods to improve STZ-based experimental models and best utilize them for experimental studies purported to understand diabetes pathogenesis and preclinical evaluation of drugs.
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Bergamin CS, Dib SA. Enterovirus and type 1 diabetes: What is the matter? World J Diabetes 2015; 6:828-839. [PMID: 26131324 PMCID: PMC4478578 DOI: 10.4239/wjd.v6.i6.828] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 01/30/2015] [Accepted: 04/09/2015] [Indexed: 02/05/2023] Open
Abstract
A complex interaction of genetic and environmental factors can trigger the immune-mediated mechanism responsible for type 1 diabetes mellitus (T1DM) establishment. Environmental factors may initiate and possibly sustain, accelerate, or retard damage to β-cells. The role of environmental factors in this process has been exhaustive studied and viruses are among the most probable ones, especially enteroviruses. Improvements in enterovirus detection methods and randomized studies with patient follow-up have confirmed the importance of human enterovirus in the pathogenesis of T1DM. The genetic risk of T1DM and particular innate and acquired immune responses to enterovirus infection contribute to a tolerance to T1DM-related autoantigens. However, the frequency, mechanisms, and pathways of virally induced autoimmunity and β-cell destruction in T1DM remain to be determined. It is difficult to investigate the role of enterovirus infection in T1DM because of several concomitant mechanisms by which the virus damages pancreatic β-cells, which, consequently, may lead to T1DM establishment. Advances in molecular and genomic studies may facilitate the identification of pathways at earlier stages of autoimmunity when preventive and therapeutic approaches may be more effective.
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Ghosh S, Bhattacharyya S, Rashid K, Sil PC. Curcumin protects rat liver from streptozotocin-induced diabetic pathophysiology by counteracting reactive oxygen species and inhibiting the activation of p53 and MAPKs mediated stress response pathways. Toxicol Rep 2015; 2:365-376. [PMID: 28962370 PMCID: PMC5598222 DOI: 10.1016/j.toxrep.2014.12.017] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 12/17/2014] [Accepted: 12/19/2014] [Indexed: 12/25/2022] Open
Abstract
Curcumin (CUR) is a highly pleiotropic molecule and possesses anti-inflammatory, hypoglycemic, antioxidative, wound-healing and antimicrobial activities. The present study was carried out to investigate whether CUR plays any beneficial role in streptozotocin (STZ) induced hepatic pathophysiology in diabetic rats. STZ exposure increased hepatic damage associated serum markers (ALT, ALP and LDH) as well as NO production in the liver tissue. Moreover, the same exposure enhanced ROS generation and lipid peroxidation; reduced GSH levels and antioxidant enzyme activities. Hyperglycemia induced hepatic pathophysiology also activated stress response pathways (involving phosphorylation of p38, ERK1/2 MAPKs and p53) and reduced mitochondrial membrane potential which in turn led to cellular apoptosis as evidenced from increased hepatic DNA fragmentation as well as FACS analysis. However, treatment with CUR effectively counteracts diabetes-induced, oxidative stress mediated hepatic damage and could act as a therapeutic in lessening liver dysfunction in diabetic subjects.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- Antioxidant
- Apoptosis
- CAT, catalase
- Curcumin
- Diabetes
- ERK1/2, extracellular signal regulated kinases 1/2
- FRAP, ferric reducing antioxidant power
- GPx, glutathione peroxidase
- GR, glutathione reductase
- GSH, glutathione
- GSSG, glutathione disulphide
- GST, glutathione S-transferase
- LDH, lactate dehydrogenase
- Liver
- MAPK, mitogen-activated protein kinases
- MDA, malondialdehyde
- NAPQI, N-acetyl-p-benzoquinone imine
- PSA, prostate-specific antigen
- ROS, reactive oxygen species
- Reactive oxygen species
- SOD, superoxide dismutase
- STZ, streptozotocin
- Streptozotocin
- TPTZ, 2,4,6-tripyridyl-s-triazine
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Affiliation(s)
| | | | | | - Parames C. Sil
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
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Samarji R, Balbaa M. Anti-diabetic activity of different oils through their effect on arylsulfatases. J Diabetes Metab Disord 2014; 13:116. [PMID: 25516848 PMCID: PMC4267437 DOI: 10.1186/s40200-014-0116-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 11/22/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diabetes mellitus (DM) is characterized by the overproduction of the reactive oxygen species which affects the integrity of the lysosomal membrane affecting lysosomal enzymes. The effect of these species is blocked by some natural products as antioxidants. In the current study, groups of normal and streptozotocin (STZ)-induced diabetic rats were treated by Nigella sativa (NS), olive and canola oils and subjected to the study of arylsulfatases as a model of lysosomal enzymes. The aim of the present study is to investigate the effect of STZ-induced diabetes on arylsulfatases in presence and absence of NS, olive and canola oils. METHODS Different groups of rats were induced by STZ, treated with different oils and compared to their corresponding control group. All groups were subjected for the assays of blood glucose, insulin, catalase and arylsulfatases. A comparative kinetic study of arylsulfatses was performed to detect the alteration of catalytic characterization. RESULTS The results demonstrated that diabetes causes a significant elevation in the level of hepatic arylsulfatase B and a significant reduction of hepatic catalase as an antioxidant enzyme. NS and olive oils returned catalase and arylsulfatase B activities back near to normal by fixing their catalytic properties. Furthermore, the maximum velocity of arylsulfatases A and B was significantly elevated in the induced diabetes, whereas their Km values were significantly changed. The treatment of diabetic rats by NS and olive oils reduced the degree of significance. CONCLUSION Diabetes induces significant alterations of the catalytic characters of arylsulfatases and some oils decrease this alteration through an antioxidant-mediated effect.
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Affiliation(s)
- Rima Samarji
- />Department of Biological & Environmental Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Mahmoud Balbaa
- />Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
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Guerrero-Berroa E, Schmeidler J, Beeri MS. Neuropathology of type 2 diabetes: a short review on insulin-related mechanisms. Eur Neuropsychopharmacol 2014; 24:1961-6. [PMID: 24529419 PMCID: PMC4116474 DOI: 10.1016/j.euroneuro.2014.01.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 01/23/2014] [Indexed: 12/20/2022]
Abstract
Postmortem studies have shown that cerebrovascular disease (CVD) neuropathology occurs frequently in type 2 diabetes (T2D) through mechanisms associated with chronic hyperglycemia such as advanced glycation end-products (AGEs). The involvement of T2D in Alzheimer׳s disease (AD)-type neuropathology has been more controversial. While postmortem data from animal studies have supported the involvement of T2D in AD-type neuropathology through insulin mechanism that may affect the development of neuritic plaques and neurofibrillary tangles (NFTs), findings from postmortem studies in humans, of the association of T2D with AD, have been mainly negative. To complicate matters, medications to treat T2D have been implicated in reduced AD-type neuropathology. In this review we summarize the literature on animal and human postmortem studies of T2D neuropathology, mainly the mechanisms involved in hyperglycemia-related CVD neuropathology and hyperinsulinemia-related AD-type neuropathology.
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Affiliation(s)
| | - James Schmeidler
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Michal Schnaider Beeri
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel
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. P, Anthony MWP, Rahman NA, . N, . S. Hypoglycemic and Antioxidative Effects of Pomegranate (Punica granatum L.) Juice in Streptozotocin Induced Diabetic Rats. ACTA ACUST UNITED AC 2014. [DOI: 10.3923/pjn.2014.567.572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Rajasekar N, Dwivedi S, Nath C, Hanif K, Shukla R. Protection of streptozotocin induced insulin receptor dysfunction, neuroinflammation and amyloidogenesis in astrocytes by insulin. Neuropharmacology 2014; 86:337-52. [PMID: 25158313 DOI: 10.1016/j.neuropharm.2014.08.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Revised: 08/12/2014] [Accepted: 08/14/2014] [Indexed: 01/04/2023]
Abstract
Impaired insulin signaling, amyloid pathology and neuroinflammation are closely associated with neurodegenerative disorder like Alzheimer's disease (AD). Our earlier studies showed that intracerebroventricular streptozotocin (STZ) induces insulin receptor (IR) signaling defect in the hippocampus, which is associated with memory impairment in rats. Astrocytes are the most abundant cells in the brain and play a major role in neuroinflammation. However, involvement of astrocytes in STZ induced IR dysfunction has not received much attention. Therefore, the present study was planned to explore the effect of STZ on IR signaling, proinflammatory markers and amyloidogenesis in rat astrocytoma cell line, (C6). STZ (100 μM) treatment in astrocytes (n = 3) for 24 h, resulted significant decrease in IR mRNA and protein expression, phosphorylation of IRS-1, Akt, GSK-3α and GSK-3β (p < 0.01). Further STZ induced amyloidogenic protein expression as evidenced by the increase in APP, BACE-1 and Aβ1-42 expression (p < 0.05) in astrocytes. STZ also significantly induced astrocytes activation as evidenced by increased expression of GFAP and p-P38 MAPK (p < 0.05). STZ treatment caused enhanced translocation of p65 NF-kB, triggered over expression of TNF-α, IL-1β, COX-2, oxidative/nitrosative stress and caspase activation (p < 0.05) in astrocytes. Insulin (25-100 nM) pretreatment (n = 3) significantly prevented changes in IR signaling, amyloidogenic protein expression and levels of proinflammatory markers (p < 0.05) in STZ treated astroglial cells. In the present study, the protective effect of insulin suggests that, IR dysfunction along with amyloidogenesis and neuroinflammation may have played a major role in STZ induced toxicity in astrocytes which are relevant to AD pathology.
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Affiliation(s)
- N Rajasekar
- Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), India
| | - Subhash Dwivedi
- Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Chandishwar Nath
- Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), India
| | - Kashif Hanif
- Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), India
| | - Rakesh Shukla
- Divisions of Pharmacology and Toxicology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), India.
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Kim JH, Lee DE, Gunawardhana KSND, Choi SH, Woo GH, Cha JH, Bak EJ, Yoo YJ. Effect of the interaction between periodontitis and type 1 diabetes mellitus on alveolar bone, mandibular condyle and tibia. Acta Odontol Scand 2014; 72:265-73. [PMID: 23931568 DOI: 10.3109/00016357.2013.822551] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE This study examined the effect of the interaction between periodontitis and type 1 diabetes mellitus on alveolar bone, mandibular condyle and tibia in animal models. MATERIALS AND METHODS Rats were divided into normal, periodontitis, diabetic and diabetic with periodontitis groups. After injection of streptozotocin to induce diabetes, periodontitis was induced by ligation of both lower-side first molars for 30 days. Alveolar bone loss and trabecular bone volume fraction (BVF) of the mandibular condyle and tibia were estimated via hematoxylin and eosin staining and micro-computed tomography, respectively. Osteoclastogenesis of bone marrow cells isolated from tibia and femur was assayed using tartrate-resistant acid phosphatase staining. RESULTS The cemento-enamel junction to the alveolar bone crest distance and ratio of periodontal ligament area in the diabetic with periodontitis group were significantly increased compared to those of the periodontitis group. Mandibular condyle BVF did not differ among groups. The BVF of tibia in the diabetic and diabetic with periodontitis groups was lower than that of the normal and periodontitis groups. Osteoclastogenesis of bone marrow cells in the diabetic groups was higher than that in the non-diabetic groups. However, the BVF of tibia and osteoclastogenesis in the diabetic with periodontitis group were not significantly different than those in the diabetic group. CONCLUSIONS Type 1 diabetes mellitus aggravates alveolar bone loss induced by periodontitis, but periodontitis does not alter the mandibular condyle and tibia bone loss induced by diabetes. Alveolar bone, mandibular condyle and tibia may have different responses to bone loss stimuli in the diabetic environment.
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Affiliation(s)
- Ji-Hye Kim
- Department of Applied Life Science, The Graduate School, Yonsei University , Seoul , Republic of Korea
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El Khoury NB, Gratuze M, Papon MA, Bretteville A, Planel E. Insulin dysfunction and Tau pathology. Front Cell Neurosci 2014; 8:22. [PMID: 24574966 PMCID: PMC3920186 DOI: 10.3389/fncel.2014.00022] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 01/16/2014] [Indexed: 01/26/2023] Open
Abstract
The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.
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Affiliation(s)
- Noura B El Khoury
- Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval Québec, QC, Canada ; Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Maud Gratuze
- Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval Québec, QC, Canada ; Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Marie-Amélie Papon
- Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Alexis Bretteville
- Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
| | - Emmanuel Planel
- Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval Québec, QC, Canada ; Axe Neurosciences, Centre Hospitalier de l'Université Laval Québec, QC, Canada
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Jo DH, Cho CS, Kim JH, Jun HO, Kim JH. Animal models of diabetic retinopathy: doors to investigate pathogenesis and potential therapeutics. J Biomed Sci 2013; 20:38. [PMID: 23786217 PMCID: PMC3694455 DOI: 10.1186/1423-0127-20-38] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2013] [Accepted: 06/17/2013] [Indexed: 12/20/2022] Open
Abstract
Effective and validated animal models are valuable to investigate the pathogenesis and potential therapeutics for human diseases. There is much concern for diabetic retinopathy (DR) in that it affects substantial number of working population all around the world, resulting in visual deterioration and social deprivation. In this review, we discuss animal models of DR based on different species of animals from zebrafish to monkeys and prerequisites for animal models. Despite criticisms on imprudent use of laboratory animals, we hope that animal models of DR will be appropriately utilized to deepen our understanding on the pathogenesis of DR and to support our struggle to find novel therapeutics against catastrophic visual loss from DR.
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Affiliation(s)
- Dong Hyun Jo
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University, Seoul 110-744, Republic of Korea
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Chaudhry ZZ, Morris DL, Moss DR, Sims EK, Chiong Y, Kono T, Evans-Molina C. Streptozotocin is equally diabetogenic whether administered to fed or fasted mice. Lab Anim 2013; 47:257-65. [PMID: 23760565 DOI: 10.1177/0023677213489548] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Streptozotocin (STZ) is a selective pancreatic β cell toxin used to generate experimental hyperglycemia in rodent models. Several laboratory animal protocols suggest that STZ be administered to fasted rodents to minimize competition between STZ and glucose for low affinity GLUT2 transporters on β cells. However, whether the diabetogenic effects of multiple low dose (MLD)-STZ administration are enhanced by fasting has not been addressed. Given that repeated bouts of fasting can cause undue metabolic stress in mice, we compared the efficacy of MLD-STZ injections (50 mg/kg body weight daily for 5 days) to induce experimental hyperglycemia in both NOD/SCID/γchain(null) and C57BL/6J mice that were either ad libitum fed (STZ-Fed) or that had been fasted for 6 h (STZ-Fasted) prior to the time of STZ administration. Both STZ-Fed and STZ-Fasted mice had significantly worse glucose tolerance than vehicle-treated control mice 10 days after initiation of the MLD-STZ regimen. In C57BL/6J mice, fasting glucose levels, serum insulin levels, β cell mass, and glucose disposal during intraperitoneal glucose tolerance tests (IPGTTs) were indistinguishable between STZ-Fed and STZ-Fasted mice 20 days after MLD-STZ. The glucose intolerant phenotypes persisted for 20 weeks thereafter, irrespective of whether C57BL/6J mice were fed or fasted at the time of STZ injections. However, STZ-Fasted C57BL/6J mice experienced significant weight loss during the repeated bouts of fasting/re-feeding that were required to complete the MLD-STZ protocol. In summary, induction of experimental hyperglycemia can be achieved using the MLD-STZ protocol without repeated bouts of fasting, which have the potential to cause metabolic stress in laboratory mice.
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Affiliation(s)
- Zunaira Z Chaudhry
- Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Gender and Contractile Functions of Slow and Fast Skeletal Muscles in Streptozotocin Induced Diabetic Sprague Dawley Rats. ROMANIAN JOURNAL OF DIABETES NUTRITION AND METABOLIC DISEASES 2012. [DOI: 10.2478/v10255-012-0048-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractObjectives: Diabetes mellitus has been linked with specific morphological andmetabolic abnormalities of skeletal muscle in a fiber specific manner. Aim: Thepresent study was designed to compare the contractile functions of slow and fastskeletal muscles in streptozotocin (STZ) induced diabetic male and female SpragueDawley rats. Material and methods: Thirty healthy Sprague Dawley rats (15 maleand 15 female) were divided into two groups and studied after four weeks followingdiabetes induction. The rats in group I (male diabetic; n = 15) and group II (femalediabetic; n = 15) were fed on normal pellet diet and water ad libitum and rendereddiabetic by single intraperitoneal injection of STZ 65 mg/kg body weight at the startof study (day 1). At the end of four weeks, the contractile parameters of slow soleusand fast extensor digitorum longus (EDL) muscles were recorded by iWorx advancedanimal/human physiology data acquisition unit (AHK/214). Results: At the end offour weeks, the weight of isolated soleus and EDL muscles in the male diabetic ratswas significantly higher (p < 0.001) as compared to the female diabetic rats.However, no significant difference was found in any of the contractile functions ofisolated soleus and EDL muscles when compared between the male and femalediabetic rats. Conclusion: No gender differences exist in the contractile functions ofslow and fast skeletal muscles in streptozotocin induced diabetic Sprague Dawleyrats.
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Whiley L, Godzien J, Ruperez FJ, Legido-Quigley C, Barbas C. In-Vial Dual Extraction for Direct LC-MS Analysis of Plasma for Comprehensive and Highly Reproducible Metabolic Fingerprinting. Anal Chem 2012; 84:5992-9. [DOI: 10.1021/ac300716u] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Luke Whiley
- Center for Metabolomics and
Bioanalysis (CEMBIO), Facultad
de Farmacia, Campus Monteprincipe, Universidad CEU San Pablo, 28668 Boadilla del Monte, Madrid, Spain
- Institute of Pharmaceutical
Sciences, King’s College London,
Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United
Kingdom
- Institute of Psychiatry, King’s College London, De Crespigny Park, London,
SE5 8AF, United Kingdom
| | - Joanna Godzien
- Center for Metabolomics and
Bioanalysis (CEMBIO), Facultad
de Farmacia, Campus Monteprincipe, Universidad CEU San Pablo, 28668 Boadilla del Monte, Madrid, Spain
- Department of Molecular Biology,
Faculty of Mathematics and Natural Sciences, The John Paul II Catholic University of Lublin, Krasnicka 102,
20-718 Lublin, Poland
| | - Francisco J Ruperez
- Center for Metabolomics and
Bioanalysis (CEMBIO), Facultad
de Farmacia, Campus Monteprincipe, Universidad CEU San Pablo, 28668 Boadilla del Monte, Madrid, Spain
| | - Cristina Legido-Quigley
- Institute of Pharmaceutical
Sciences, King’s College London,
Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United
Kingdom
| | - Coral Barbas
- Center for Metabolomics and
Bioanalysis (CEMBIO), Facultad
de Farmacia, Campus Monteprincipe, Universidad CEU San Pablo, 28668 Boadilla del Monte, Madrid, Spain
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Shafik AN. Effects of topiramate on diabetes mellitus induced by streptozotocin in rats. Eur J Pharmacol 2012; 684:161-167. [PMID: 22498001 DOI: 10.1016/j.ejphar.2012.03.042] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 03/14/2012] [Accepted: 03/23/2012] [Indexed: 12/18/2022]
Abstract
Topiramate currently approved for marketing as antiepileptic drug also possesses anti-diabetic activity. The aim of this study was to determine the antidiabetic effect of topiramate in a rat model of diabetes mellitus. Diabetes was induced by a single injection of streptozotocin to fasted rats. Diabetic animals were divided into untreated; insulin treated; topiramate treated with 25, 50 and 100 mg/kg; and combined insulin plus topiramate treatment in the previous doses. All medications were given once daily started after the rise of blood glucose for three weeks. Control rats were divided into untreated; vehicle treated and rats given topiramate in the previous doses. Body weight, blood-glucose and insulin levels were measured. Histopathological examination, immunohistochemical and morphometric studies of islets of the pancreas were done. Topiramate 50 and 100mg/kg resulted in a significant decrease in the blood glucose and increase in the insulin levels as well as the number of islets and the count and mass of beta cells. Combined treatment to diabetic rats with insulin and topiramate induced a better response than either alone. Further experimental and clinical studies are needed to explore the different mechanisms of action of topiramate as antidiabetic both in insulin dependent and non-insulin-dependent diabetes mellitus.
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Affiliation(s)
- Amani Nabil Shafik
- Department of Pharmacology, Faculty of Medicine, Cairo University, Egypt.
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Abstract
The zebrafish (Danio rerio) is an established model organism for the study of developmental processes, human disease, and tissue regeneration. We report that limb regeneration is severely impaired in our newly developed adult zebrafish model of type I diabetes mellitus. Intraperitoneal streptozocin injection of adult, wild-type zebrafish results in a sustained hyperglycemic state as determined by elevated fasting blood glucose values and increased glycation of serum protein. Serum insulin levels are also decreased and pancreas immunohistochemisty revealed a decreased amount of insulin signal in hyperglycemic fish. Additionally, the diabetic complications of retinal thinning and glomerular basement membrane thickening (early signs of retinopathy and nephropathy) resulting from the hyperglycemic state were evident in streptozocin-injected fish at 3 weeks. Most significantly, limb regeneration, following caudal fin amputation, is severely impaired in diabetic zebrafish and nonspecific toxic effects outside the pancreas were not found to contribute to impaired limb regeneration. This experimental system using adult zebrafish facilitates a broad spectrum of genetic and molecular approaches to study regeneration in the diabetic background.
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Affiliation(s)
- Ansgar S. Olsen
- Department of Cell Biology and Anatomy at Rosalind Franklin University, North Chicago, Illinois, USA
- William M. Scholl College of Podiatric Medicine at Rosalind Franklin University, North Chicago, Illinois, USA
| | - Michael P. Sarras
- Department of Cell Biology and Anatomy at Rosalind Franklin University, North Chicago, Illinois, USA
| | - Robert V. Intine
- Department of Cell Biology and Anatomy at Rosalind Franklin University, North Chicago, Illinois, USA
- William M. Scholl College of Podiatric Medicine at Rosalind Franklin University, North Chicago, Illinois, USA
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