|
1
|
El-Remaily MAEAAA, Aboelez MO, Ezelarab HAA, Selim HMRM, Taha EA, Mohamed SK, Soliman AM, Abdallah MS, Fawy MA, Hassany MA, Ahmed N, Alsaggaf AT, El Hamd MA, Kamel MS. Guanidine dicycloamine-based analogs: green chemistry synthesis, biological investigation, and molecular docking studies as promising antibacterial and antiglycation leads. Mol Divers 2024; 28:4277-4299. [PMID: 38324159 DOI: 10.1007/s11030-024-10816-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 01/21/2024] [Indexed: 02/08/2024]
Abstract
Dicyandiamide (DCD) reacted with amino acids 1a-f to produce biguanides 2 and 4 and guanidine pyrazolones 3, 5, 6, 7, and 8, according to the reaction. DCD exhibited the following reactions: imidodicarbonimidicdiamide 9, diazocan-2-ylguanidine 10, methyl biguanidylthion 11, N-carbamothioylimidodicarbonimidicdiamide 12, 2-guanidinebenzoimidazole 13a, 2-guanidinylbenzoxazole 13b, and 2-guanidinylbenzothiazol 13c. These reactions were triggered by 6-amino caproic acid, thioacetamide, thiourea, o-aminophenol, o-aminothiophenol, and anthranilic acid, respectively. Compound 2 had the least antimicrobial activity, while compound 13c demonstrated the most antibacterial impact against all bacterial strains. Furthermore, in terms of antiglycation efficacy (AGEs), 12, 11, and 7 were the most effective AGE cross-linking inhibitors. Eight and ten, which showed a considerable inhibition on cross-linking AGEs, come next. Compounds 4 and 6 on the other hand have shown the least suppression of AGE production. The most promising antiglycation scaffolds 8, 11, and 12 in the Human serum albumin (HAS) active site were shown to be able to adopt crucial binding interactions with important amino acids based on the results of in silico molecular docking. The most promising antiglycation compounds 8, 11, and 12 were also shown to have better hydrophilicity, acceptable lipophilicity, gastrointestinal tract absorption (GIT), and blood-brain barrier penetration qualities when their physicochemical properties were examined using the egg-boiled method.
Collapse
Affiliation(s)
| | - Moustafa O Aboelez
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt.
| | - Hend A A Ezelarab
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
| | - Heba Mohammed Refat M Selim
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, AlMaarefa University, Diriyah, Riyadh, Saudi Arabia.
- Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
| | - Enas A Taha
- Department of Chemistry, Faculty of Pharmacy, October 6 University, 6 October City, Giza, Egypt
| | - Shaaban K Mohamed
- The Environment and School of Healthcare Science, Manchester Metropolitan University, Manchester, UK
| | - Ahmed M Soliman
- Department of Chemistry, Faculty of Science, Sohag University, Sohag, 82524, Egypt
| | - Mohamed S Abdallah
- The Environment and School of Healthcare Science, Manchester Metropolitan University, Manchester, UK
| | - Mariam A Fawy
- Department of Zoology, Faculty of Science, South Valley University, Qena, 83523, Egypt
| | - Mohamed A Hassany
- Department of Internal Medicine, Faculty of Medicine, Aswan University, Aswan, Egypt
| | - Nessar Ahmed
- The Environment and School of Healthcare Science, Manchester Metropolitan University, Manchester, UK
| | | | - Mohamed A El Hamd
- Department of Pharmaceutical Chemistry, College of Pharmacy, Shaqra University, 11961, Shaqra, Saudi Arabia.
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt.
| | - Moumen S Kamel
- Department of Chemistry, Faculty of Science, Sohag University, Sohag, 82524, Egypt.
| |
Collapse
|
|
2
|
Amorim de Souza Lima T, Raissa Ribeiro M, Carneiro de Brito M, Mitiko Kawamoto E. Impaired exploration induced by type 1 diabetes is related to locomotor activity rather than a reduction in motivation. Neuroscience 2024; 560:1-10. [PMID: 39293729 DOI: 10.1016/j.neuroscience.2024.09.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/11/2024] [Accepted: 09/14/2024] [Indexed: 09/20/2024]
Abstract
Type 1 diabetes mellitus (T1D) is associated with cognitive impairments in humans. A well-established animal model of T1D is induced through the administration of streptozotocin (STZ), a glucose analog that induces pancreatic β-cell death, resulting in hyperglycemia and cognitive impairment linked to neuroinflammation and oxidative stress. Tumor necrosis factor (TNF)-α, a key inflammatory mediator, is elevated in the central nervous system (CNS) of diabetic animals. In this study, we utilized TNFR1 knockout mice to investigate the role of TNFR1 signaling in short-term T1D-related cognitive impairment. Our findings showed that diabetic animals did not develop cognitive damage within the first 2 weeks of T1D but exhibited reduced exploration in all behavioral tests. Our findings suggest that this reduction in exploration was attributable to motor impairment, as there was no reduction in motivated novelty-seeking behavior. Additionally, deletion of TNFR1 signaling attenuated gait speed impairment in diabetic mice, but did not affect other motor-related or exploratory behaviors.
Collapse
MESH Headings
- Animals
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/complications
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Experimental/psychology
- Mice, Knockout
- Motivation/physiology
- Exploratory Behavior/physiology
- Male
- Mice
- Locomotion/physiology
- Mice, Inbred C57BL
- Cognitive Dysfunction/physiopathology
- Cognitive Dysfunction/etiology
- Streptozocin
Collapse
Affiliation(s)
- Thiago Amorim de Souza Lima
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil
| | - Martina Raissa Ribeiro
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil
| | - Malcon Carneiro de Brito
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil
| | - Elisa Mitiko Kawamoto
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP, Brazil.
| |
Collapse
|
|
3
|
Şancı E, Köksal Karayıldırım Ç, Dağdeviren M, Yiğittürk G, Buhur A, Erbaş O, Yavaşoğlu A, Karabay Yavaşoğlu NÜ. Oxidative stress and inflammatory markers in streptozotocin-induced acute and subacute toxicity response. Drug Chem Toxicol 2024; 47:933-948. [PMID: 38348650 DOI: 10.1080/01480545.2024.2315150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 02/01/2024] [Indexed: 11/21/2024]
Abstract
Streptozotocin (STZ) is used as a diabetes-inducing agent in experimental animal studies. However, it is known that STZ-induced diabetic animals show significant increases in oxidative stress parameters and neurodegeneration besides their blood glucose level. In this study, the acute and subacute toxic effects of STZ on the liver, sciatic nerve, and brain tissues were investigated in vivo rat model. Sprague-Dawley rats were divided into two groups; while 50 mg/kg STZ was administered ip to the STZ group, only saline was administered to the control group. After STZ administration, three units (100 U/mL) of subcutaneous insulin glargine were applied daily to prevent the formation of diabetes. At 24 h, 1,2, and 4 weeks after applications, rats from each group were sacrificed and tissues were removed under anesthesia. At the end of the study, compared to the control, a significant decrease in SOD and GST activity and an increase in lipid peroxidation were detected in the liver and sciatic tissues of rats in the STZ-treated group in the first 24h. Considering the TUNEL, NFκB, and NOS2 expressions, it was noted that while the effects of STZ on the liver were observed in the acute stage (24h), it had subacute effects on the brain. When apoptosis-related gene expression (Bcl-2, Bax, CASP3, CASP8, CASP9, TNF-α) and immunohistochemistry were evaluated, the apoptotic effect of STZ was observed mostly in sciatic nerve tissues. Within the scope of the study, it was revealed that STZ did not only show selective toxicity to pancreatic β cells but also very toxic to other tissues and organs.
Collapse
Affiliation(s)
- Ebru Şancı
- Center for Drug Development and Pharmacokinetic Applications, Ege University, Bornova Izmir, Turkey
| | | | | | - Gürkan Yiğittürk
- Department of Histology and Embryology, Muğla Sıtkı Koçman University, Mugla, Turkey
| | - Aylin Buhur
- Department of Histology and Embryology, Ege University, Bornova Izmir, Turkey
| | - Oytun Erbaş
- Department of Physiology, Demiroğlu Bilim University, Istanbul, Turkey
| | - Altuğ Yavaşoğlu
- Department of Histology and Embryology, Ege University, Bornova Izmir, Turkey
| | - Nefise Ülkü Karabay Yavaşoğlu
- Center for Drug Development and Pharmacokinetic Applications, Ege University, Bornova Izmir, Turkey
- Department of Biology, Ege University, Bornova Izmir, Turkey
| |
Collapse
|
|
4
|
Kusumo LE, Gilley-Connor KR, Johnson MG, Hall GM, Gillett AE, McCready RG, Vichaya EG. Hyperglycemia sensitizes female mice to stress-induced depressive-like behavior in an inflammation-independent manner. Psychoneuroendocrinology 2024; 169:107151. [PMID: 39098101 DOI: 10.1016/j.psyneuen.2024.107151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND Depression is a multifaceted disorder that represents one of the most common causes of disability. The risk for developing depression is increased in women and among individuals with chronic diseases. For example, individuals in the United States with diabetes mellitus (DM) are at a twofold increased risk of developing depression compared to the general population and approximately one-quarter of women with diabetes have comorbid depression. The neurobiological mechanisms underlying this association between diabetes and depression is not fully understood and is particularly under-investigated in female models. We sought to explore the role of neuroinflammation in diabetes-induced depression in a female mouse model of hyperglycemia. METHODS To this end, we utilized female C57BL/6 J mice to (1) characterize the depressive-like symptoms in response to 75 mg/kg/day dose of streptozotocin (STZ) over 5 days, a dose reported to induce hyperglycemia in female mice (n=20), (2) determine if female hyperglycemic mice are sensitized to unpredictable chronic mild stress (UCMS)-induced depressive-like behavior and neuroinflammation (n=28), and (3) investigate if female hyperglycemic mice are primed to respond to a subthreshold dose of lipopolysaccharide (LPS), an acute inflammatory challenge (n=21). RESULTS Our results demonstrate that female mice exhibit robust hyperglycemia but limited evidence of depressive-like behavior in response to 75 mg/kg STZ. Additionally, we observe that healthy female mice have limited response to our stress protocol; however, hyperglycemic mice display increased stress-sensitivity as indicated by increased immobility in the forced swim test. While STZ mice show evidence of mild neuroinflammation, this effect was blunted by stress. Further, STZ mice failed to display a sensitization to inflammation-induced depressive-like behavior. CONCLUSION We interpret this data to indicate that while STZ-induced hyperglycemia does increase vulnerability to stress-induced depressive-like behavior, this effect is not a consequence of neuroinflammatory priming. Future studies will seek to better understand the mechanisms underlying this sensitization.
Collapse
Affiliation(s)
- Laura E Kusumo
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, United States
| | - Kayla R Gilley-Connor
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, United States
| | - Madilyn G Johnson
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, United States
| | - Grace M Hall
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, United States
| | - Avery E Gillett
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, United States
| | - Riley G McCready
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, United States
| | - Elisabeth G Vichaya
- Department of Psychology & Neuroscience, Baylor University, Waco, TX 76798, United States.
| |
Collapse
|
|
5
|
Li H, Wang R, Chen Y, Zhao M, Lan S, Zhao C, Li X, Li W. Integrated network pharmacology and pharmacological investigations to discover the active compounds of Toona sinensis pericarps against diabetic nephropathy. JOURNAL OF ETHNOPHARMACOLOGY 2024; 333:118441. [PMID: 38851471 DOI: 10.1016/j.jep.2024.118441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/22/2024] [Accepted: 06/05/2024] [Indexed: 06/10/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Toona sinensis (A. Juss.) Roem. Is a deciduous woody plant native to Eastern and Southeastern Asia. Different parts of this plant have a long history of being applied as traditional medicines to treat various diseases. The fruits have been used for antidiabetic, antidiabetic nephropathy (anti-DN), antioxidant, anti-inflammatory, and other activities. AIM OF THE STUDY The purpose of this study was to investigate the effects of EtOAc (PEAE) and n-BuOH extracts (PNBE) from T. sinensis pericarps (TSP) on kidney injury in high-fat and high-glucose diet (HFD)/streptozotocin (STZ)-induced DN mice by network pharmacology and pharmacological investigations, as well as to further discover active compounds that could ameliorate oxidative stress and inflammation, thereby delaying DN progression by regulating the Nrf2/NF-κB pathway in high glucose (HG)-induced glomerular mesangial cells (GMCs). MATERIALS AND METHODS The targets of TSP 1-16 with DN were analyzed by network pharmacology. HFD/STZ-induced DN mouse models were established to evaluate the effects of PEAE and PNBE. Six groups were divided into normal, model, PEAE100, PEAE400, PNBE100, and PNBE400 groups. Fasting blood glucose (FBG) levels, organ indices, plasma MDA, SOD, TNF-α, and IL-6 levels, as well as renal tissue Nrf2, HO-1, NF-κB, TNF-α, and TGF-β1 levels were determined, along with hematoxylin-eosin (H&E) and immunohistochemical (IHC) analysis of kidney sections. Furthermore, GMC activity screening combined with molecular docking was utilized to discover active compounds targeting HO-1, TNF-α, and IL-6. Moreover, western blotting assays were performed to validate the mechanism of Nrf2 and NF-κB in HG-induced GMCs. RESULTS Network pharmacology predicted that the main targets of PEAE and PNBE in the treatment of DN include IL-6, INS, TNF, ALB, GAPDH, IL-1β, TP53, EGFR, and CASP3. Additionally, major pathways include AGE-RAGE and IL-17. In vivo experiments, treatment with PEAE and PNBE effectively reduced FBG levels and organ indices, while plasma MDA, SOD, TNF-α, and IL-6 levels, renal tissue Nrf2, HO-1, NF-κB, TNF-α, and TGF-β1 levels, and renal function were significantly improved. PEAE and PNBE significantly improved glomerular and tubule injury, and inhibited the development of DN by regulating the levels of oxidative stress and inflammation-related factors. In vitro experiments, compound 11 strongly activated HO-1 and inhibited TNF-α and IL-6. The molecular docking results revealed that compound 11 exhibited a high binding affinity towards the targets HO-1, TNF-α, and IL-6 (<-6 kcal/mol). Western blotting results showed compound 11 effectively regulated Nrf2 and NF-κB p65 protein levels, and significantly improved oxidative stress damage and inflammatory responses in HG-induced GMCs. CONCLUSION PEAE, PNBE, and their compounds, especially compound 11, may have the potential to prevent and treat DN, and are promising natural nephroprotective agents.
Collapse
Affiliation(s)
- Huiting Li
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China.
| | - Rongshen Wang
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China; Key Laboratory of Molecular Pharmacology and Translational Research, Shandong Second Medical University, Weifang, 261053, China.
| | - Ying Chen
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China.
| | - Mengyao Zhao
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China.
| | - Shuying Lan
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China.
| | - Chunzhen Zhao
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China; Key Laboratory of Molecular Pharmacology and Translational Research, Shandong Second Medical University, Weifang, 261053, China.
| | - Xu Li
- Affiliated Hospital of Shandong Second Medical University, Weifang, 261041, China.
| | - Wanzhong Li
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China; Key Laboratory of Molecular Pharmacology and Translational Research, Shandong Second Medical University, Weifang, 261053, China.
| |
Collapse
|
|
6
|
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.
Collapse
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.
| |
Collapse
|
|
7
|
Mathisen AF, Larsen U, Kavli N, Unger L, Daian LM, Vacaru AM, Vacaru AM, Herrera PL, Ghila L, Chera S. Moderate beta-cell ablation triggers synergic compensatory mechanisms even in the absence of overt metabolic disruption. Commun Biol 2024; 7:833. [PMID: 38982170 PMCID: PMC11233560 DOI: 10.1038/s42003-024-06527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/01/2024] [Indexed: 07/11/2024] Open
Abstract
Regeneration, the ability to replace injured tissues and organs, is a phenomenon commonly associated with lower vertebrates but is also observed in mammals, in specific tissues. In this study, we investigated the regenerative potential of pancreatic islets following moderate beta-cell loss in mice. Using a rapid model of moderate ablation, we observed a compensatory response characterized by transient inflammation and proliferation signatures, ultimately leading to the recovery of beta-cell identity and function. Interestingly, this proliferative response occurred independently of inflammation, as demonstrated in ablated immunodeficient mice. Furthermore, exposure to high-fat diet stimulated beta-cell proliferation but negatively impacted beta-cell function. In contrast, an equivalent slower ablation model revealed a delayed but similar proliferative response, suggesting proliferation as a common regenerative response. However, high-fat diet failed to promote proliferation in this model, indicating a differential response to metabolic stressors. Overall, our findings shed light on the complex interplay between beta-cell loss, inflammation, and stress in modulating pancreatic islet regeneration. Understanding these mechanisms could pave the way for novel therapeutic strategies based on beta-cell proliferation.
Collapse
Affiliation(s)
- Andreas Frøslev Mathisen
- Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Ulrik Larsen
- Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Natalie Kavli
- Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Lucas Unger
- Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Laura Maria Daian
- BetaUpreg Research Group, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Andrei Mircea Vacaru
- BetaUpreg Research Group, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Ana-Maria Vacaru
- BetaUpreg Research Group, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Pedro Luis Herrera
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Luiza Ghila
- Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Simona Chera
- Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
| |
Collapse
|
|
8
|
Safoine M, Paquette C, Gingras GM, Fradette J. Improving Cutaneous Wound Healing in Diabetic Mice Using Naturally Derived Tissue-Engineered Biological Dressings Produced under Serum-Free Conditions. Stem Cells Int 2024; 2024:3601101. [PMID: 38737365 PMCID: PMC11087150 DOI: 10.1155/2024/3601101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 02/13/2024] [Accepted: 04/23/2024] [Indexed: 05/14/2024] Open
Abstract
Long-term diabetes often leads to chronic wounds refractory to treatment. Cell-based therapies are actively investigated to enhance cutaneous healing. Various cell types are available to produce biological dressings, such as adipose-derived stem/stromal cells (ASCs), an attractive cell source considering their abundancy, accessibility, and therapeutic secretome. In this study, we produced human ASC-based dressings under a serum-free culture system using the self-assembly approach of tissue engineering. The dressings were applied every 4 days to full-thickness 8-mm splinted skin wounds created on the back of polygenic diabetic NONcNZO10/LtJ mice and streptozotocin-induced diabetic K14-H2B-GFP mice. Global wound closure kinetics evaluated macroscopically showed accelerated wound closure in both murine models, especially for NONcNZO10/LtJ; the treated group reaching 98.7% ± 2.3% global closure compared to 76.4% ± 11.8% for the untreated group on day 20 (p=0.0002). Histological analyses revealed that treated wounds exhibited healed skin of better quality with a well-differentiated epidermis and a more organized, homogeneous, and 1.6-fold thicker granulation tissue. Neovascularization, assessed by CD31 labeling, was 2.5-fold higher for the NONcNZO10/LtJ treated wounds. We thus describe the beneficial impact on wound healing of biologically active ASC-based dressings produced under an entirely serum-free production system facilitating clinical translation.
Collapse
|
|
9
|
Tan SC, Rajendran R, Bhattamisra SK, Krishnappa P, Davamani F, Chitra E, Ambu S, Furman B, Candasamy M. Protective effects of madecassoside, a triterpenoid from Centella asiatica, against oxidative stress in INS-1E cells. Nat Prod Res 2024:1-8. [PMID: 38340357 DOI: 10.1080/14786419.2024.2315499] [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: 10/06/2023] [Accepted: 02/01/2024] [Indexed: 02/12/2024]
Abstract
Progressive decline in β cell function and reduction in the β cell mass is important in type 2 diabetes. Here, we tested the hypothesis that madecassoside's previously demonstrated in vivo protective effects on the β cell in experimental diabetes were exerted directly. We investigated the effects of madecassoside in protecting a β cell line (INS-1E) against a variety of agents. INS-1E cells were treated with madecassoside in the presence of high glucose (HG), a cytokine mixture, hydrogen peroxide (H2O2), or streptozotocin (STZ). HG, the cytokine mixture, H2O2 and STZ each produced a significant decrease in cell viability; this was significantly reversed by madecassoside. Pre-treatment with madecassoside reduced the number of apoptotic cells induced by HG, the cytokine mixture, H2O2, and STZ, and concentration-dependently reduced ROS production. Madecassoside also significantly enhanced glucose-induced insulin secretion. The results suggest that madecassoside's in vivo effects are exerted directly on the β cell.
Collapse
Affiliation(s)
- Swee Ching Tan
- School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
| | - Ramkumar Rajendran
- Faculty of Medicine, University of Adelaide, Adelaide, Australia
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
- School of Pharmacy, GITAM (Deemed to be University), Visakhapatnam, India
| | - Purushotham Krishnappa
- Department of Pathology, School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Fabian Davamani
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Ebenezer Chitra
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Stephen Ambu
- School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
| | - Brian Furman
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Mayuren Candasamy
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
- Centre for Bioactive Molecules & Drug Delivery, Institute for Research, Development and Innovation, International Medical University, Kuala Lumpur, Malaysia
| |
Collapse
|
|
10
|
Cubillos S, Kazlauskas A. Manifestation of Pathology in Animal Models of Diabetic Retinopathy Is Delayed from the Onset of Diabetes. Int J Mol Sci 2024; 25:1610. [PMID: 38338889 PMCID: PMC10855501 DOI: 10.3390/ijms25031610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/18/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
Diabetic retinopathy (DR) is the most common complication that develops in patients with diabetes mellitus (DM) and is the leading cause of blindness worldwide. Fortunately, sight-threatening forms of DR develop only after several decades of DM. This well-documented resilience to DR suggests that the retina is capable of protecting itself from DM-related damage and also that accumulation of such damage occurs only after deterioration of this resilience. Despite the enormous translational significance of this phenomenon, very little is known regarding the nature of resilience to DR. Rodent models of DR have been used extensively to study the nature of the DM-induced damage, i.e., cardinal features of DR. Many of these same animal models can be used to investigate resilience because DR is delayed from the onset of DM by several weeks or months. The purpose of this review is to provide a comprehensive overview of the literature describing the use of rodent models of DR in type-1 and type-2 diabetic animals, which most clearly document the delay between the onset of DM and the appearance of DR. These readily available experimental settings can be used to advance our current understanding of resilience to DR and thereby identify biomarkers and targets for novel, prevention-based approaches to manage patients at risk for developing DR.
Collapse
Affiliation(s)
- Samuel Cubillos
- University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA;
| | | |
Collapse
|
|
11
|
Watanabe H, Fujishima F, Unno M, Sasano H, Suzuki T. Immunohistochemical and in situ hybridization analyses of glucose transporter 2 in pancreatic neuroendocrine tumors: Possible glucose transporter 2 association with neoplastic insulin production. Pathol Res Pract 2024; 253:154966. [PMID: 38043192 DOI: 10.1016/j.prp.2023.154966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/18/2023] [Accepted: 11/21/2023] [Indexed: 12/05/2023]
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms. Additionally, glucose transporter 2 (GLUT2) is associated with insulin production and is essential for glucose transport to normal pancreatic β-cells. Neoplastic cell GLUT2 expression may also influence insulin production by using this transporter. GLUT2 expression and its clinical significance remain unclear in PanNETs. This study aimed to provide GLUT2 expression profiles and evidence of correlation with insulin in PanNETs. METHODS Clinical data were retrieved from 113 surgically resected paraffin-embedded PanNET tissue samples fixed with 10% formalin. PanNETs are categorized as insulinoma, non-functional (NF)-PanNET, or PanNET-not otherwise specified (NOS). A GLUT2 score was used to evaluate cytoplasmic GLUT2 immunoreactivity. The immunoreactive score (IRS) was used to determine membranous GLUT2, cytoplasmic insulin, and proinsulin immunoreactivities. A commercially available in situ hybridization (ISH) kit detected human SLC2A2 (GLUT2) mRNA on tissues in all seven positive- and 20 negative-GLUT2 IRS cases. RESULTS GLUT2 and IRSs significantly differed among insulinoma, NF-PanNET, and PanNET-NOS. Insulinomas exhibited significantly higher GLUT2 scores and IRSs than did NF-PanNETs. GLUT2 IRS positive cases demonstrated significantly higher insulin and proinsulin IRSs than did negative cases. Additionally, GLUT2 ISH-positive cases demonstrated positive GLUT2 scores and IRSs, with significantly higher GLUT2 IRSs than did negative cases. PanNET histological grade categories did not significantly affect GLUT2 scores and IRSs. CONCLUSION The first evidence of a correlation between GLUT2 expressions and insulin in PanNETs is shown in this study.
Collapse
Affiliation(s)
- Hirofumi Watanabe
- Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | | | - Michiaki Unno
- Department of Surgery, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Takashi Suzuki
- Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan
| |
Collapse
|
|
12
|
Chen X, Zhang Z, Niu H, Tian X, Tian H, Yao W, He H, Shi H, Li C, Luo J. Goat Milk Improves Glucose Metabolism in Type 2 Diabetic Mice and Protects Pancreatic β-Cell Functions. Mol Nutr Food Res 2024; 68:e2200842. [PMID: 37990402 DOI: 10.1002/mnfr.202200842] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 07/13/2023] [Indexed: 11/23/2023]
Abstract
SCOPE Consuming goat milk is known to benefit high-fat diet-fed and streptozocin (STZ)-induced diabetic rats, but the underlying mechanisms are unknown. This study is conducted to investigate the metabolic effects of a goat milk diet (a form of goat milk powder) on glucose homeostasis and pancreatic conditions in a mouse model of Type 2 diabetes mellitus (T2DM) induced by STZ. METHODS AND RESULTS T2DM mice are fed with a goat-milk-based diet containing 10.3% w/w goat milk powder for 10 weeks for investigating the in vivo effects; a β-cell line MIN6 cells are used to test the in vitro effects of digested goat milk (DGM). Goat milk diet improves the deleterious effects of STZ on fasting glucose levels and glucose tolerance, accelerates pancreatic structure recovery, and alters blood metabolites in mice. Based on the significant differences observed in metabolites, the key pathways, metabolite regulatory enzymes, metabolite molecular modules, and biochemical reactions are identified as critical integrated pathways. DGM promotes the cell activity, glucose transportation, and AKT activation in cultured STZ-treated MIN6 cells in vitro. CONCLUSIONS Goat milk diet improves glucose homeostasis and pancreatic conditions of T2DM mice, in association with improved blood metabolite profiles and activation of pancreatic AKT pathway.
Collapse
Affiliation(s)
- Xiaoying Chen
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Zhifei Zhang
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Huiming Niu
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Xinmiao Tian
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Huibin Tian
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Weiwei Yao
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Huanshan He
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Huaiping Shi
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Cong Li
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jun Luo
- Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| |
Collapse
|
|
13
|
Zhao Y, Niu M, Jia Y, Yuan J, Xiang L, Dai X, Wang G, Chen H. Establishment of type 2 diabetes mellitus models using streptozotocin after 3 months high-fat diet in Bama minipigs. Anim Biotechnol 2023; 34:2295-2312. [PMID: 35749713 DOI: 10.1080/10495398.2022.2088548] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
In the past twenty years, the number of adults with diabetes has tripled. Most studies have been conducted using rodent models of type 2 diabetes mellitus (T2DM), and the developed drugs have low clinical conversion efficiency. Therefore, it is urgent to establish a more human-like large animal model to explore T2DM pathogenesis and formulate new disease prevention and control strategies. This study was designed to establish and validate a T2DM model using minipigs fed a high-fat or high-cholesterol/high-fat diet and injected with low-dose streptozotocin (STZ). We examined the influence of the STZ injection timing with a diet high in fat (HFD) compared with one high in cholesterol and fat (HCFD) on the atherosclerotic lesions accelerated by T2DM. Male Bama minipigs (n = 24) were randomly divided into five groups. The control group was fed a normal diet for 9 months. The STZ + HFD and STZ + HCFD groups were infused with 90 mg/kg STZ and then fed a high-fat diet or high-cholesterol and high-fat diet for 9 months, respectively. The HFD + STZ and HCFD + STZ groups were fed a high-fat diet or a high-cholesterol and high-fat diet, respectively, for 9 months (after 3 months, these pigs were injected intravenously with 90 mg/kg STZ). During the induction period, animal body weight, BMI, and serum GLU, INS, TG, TC, HDL-C, LDL-C, FFA, ALT, AST, CRE, and BUN were detected monthly intervals. IVGTT and insulin release tests were performed at 3-month intervals. At the end of the test, the coronary artery and abdominal aorta were examined by computed tomography and pathological observations, and the thickness of the basement membrane of the capillary of the retina and kidney glomerulus was measured under a transmission electron microscope. The serum glucose concentrations were normal in all groups except the HFD + STZ and HCFD + STZ groups. Animals fed an HFD for 9 months did not develop apparent atherosclerotic lesions, but atherosclerotic lesions were seen in the animals fed an HCFD. Hyperglycemia accelerated the formation of atherosclerotic lesions on the intimal surface of the abdominal aorta. Low-dose STZ after 3 months of HFD or HCFD successfully established a T2DM model in minipigs. The HFD did not induce apparent atherosclerotic lesions, but these were seen with the HCFD. Hyperglycemia accelerated atherosclerosis in the minipigs.
Collapse
Affiliation(s)
- Yuqiong Zhao
- Laboratory Animal Center, Chinese PLA General Hospital, Beijing, China
| | - Miaomiao Niu
- Laboratory Animal Center, Chinese PLA General Hospital, Beijing, China
| | - Yunxiao Jia
- Laboratory Animal Center, Chinese PLA General Hospital, Beijing, China
| | - Jifang Yuan
- Laboratory Animal Center, Chinese PLA General Hospital, Beijing, China
| | - Lei Xiang
- Laboratory Animal Center, Chinese PLA General Hospital, Beijing, China
| | - Xin Dai
- Laboratory Animal Center, Chinese PLA General Hospital, Beijing, China
| | - Guisheng Wang
- Radiology Department of No. 3 Clinical Center, Chinese PLA General Hospital, Beijing, China
| | - Hua Chen
- Laboratory Animal Center, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
14
|
Wang J, Qi Z, Wu Y, Wang A, Liu Q, Zou F, Wang B, Qi S, Cao J, Hu C, Shi C, Liang Q, Wang L, Liu J, Wang W, Liu Q. Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus. Signal Transduct Target Ther 2023; 8:143. [PMID: 37015918 PMCID: PMC10073293 DOI: 10.1038/s41392-023-01352-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 01/03/2023] [Accepted: 02/01/2023] [Indexed: 04/06/2023] Open
Abstract
Insulin-producing pancreatic β cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic β cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic β cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.
Collapse
Affiliation(s)
- Junjie Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Ziping Qi
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Yun Wu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Aoli Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Qingwang Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Fengming Zou
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Beilei Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Shuang Qi
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Jiangyan Cao
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Chen Hu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Chenliang Shi
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Qianmao Liang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Li Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China
| | - Jing Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
| | - Wenchao Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
| | - Qingsong Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
- Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
- Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, P. R. China.
| |
Collapse
|
|
15
|
Kamli-Salino SEJ, Brown PAJ, Haschler TN, Liang L, Feliers D, Wilson HM, Delibegovic M. Induction of experimental diabetes and diabetic nephropathy using anomer-equilibrated streptozotocin in male C57Bl/6J mice. Biochem Biophys Res Commun 2023; 650:109-116. [PMID: 36774688 DOI: 10.1016/j.bbrc.2023.01.089] [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: 01/10/2023] [Revised: 01/20/2023] [Accepted: 01/28/2023] [Indexed: 02/08/2023]
Abstract
Streptozotocin (STZ) is widely used to induce experimental diabetes in murine models. However, the ability to induce diabetic nephropathy (DN) is more challenging. It has been recommended to inject STZ at multiple low doses within 15 min after dissolution due to its alleged instability. However, some studies suggest that STZ is stable for days due to equilibration of its two anomers (α and β), 90 min after dissolution, and that this anomer-equilibrated STZ leads to higher survival rates and persistent hyperglycaemia with minimal weight loss. The aim of this study was to determine an optimal dose of anomer-equilibrated STZ to induce kidney tubular damage and compare it with the more commonly used freshly prepared STZ. We hypothesised that anomer-equilibrated STZ provides a better, reproducible experimental model of diabetes-induced kidney damage with improved animal welfare. Body measurements, fasting glycaemia, insulinemia and renal histology were assessed in male C57Bl/6J at two and six months of age treated with fresh (50 mg/kg) or anomer-equilibrated (dose ranging 35-50 mg/kg) STZ or vehicle control. We demonstrated a dose-dependent effect of anomer-equilibrated STZ on the induction of hypo-insulinaemia and hyperglycaemia, as well as body weight in two-month-old mice. Interestingly, in six-month-old mice STZ leads to body weight loss, independently of STZ preparation mode. Anomer-equilibrated STZ provoked moderate to severe kidney tubule structural damage, resulting in significant kidney hypertrophy, whereas freshly prepared STZ only caused mild alterations. In conclusion, our study proposes that anomer-equilibrated STZ provides a robust murine model of diabetes and early-stage diabetic nephropathy, which can be used to test therapeutic approaches to treat and/or prevent renal damage.
Collapse
Affiliation(s)
- Sarah E J Kamli-Salino
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK.
| | - Paul A J Brown
- Department of Pathology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland, UK
| | - Timo N Haschler
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Lihuan Liang
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Denis Feliers
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Heather M Wilson
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
| | - Mirela Delibegovic
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK
| |
Collapse
|
|
16
|
Humphrey CM, Hooker JW, Thapa M, Wilcox MJ, Ostrowski D, Ostrowski TD. Synaptic loss and gliosis in the nucleus tractus solitarii with streptozotocin-induced Alzheimer's disease. Brain Res 2023; 1801:148202. [PMID: 36521513 PMCID: PMC9840699 DOI: 10.1016/j.brainres.2022.148202] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/21/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022]
Abstract
Obstructive sleep apnea is highly prevalent in Alzheimer's disease (AD). However, brainstem centers controlling respiration have received little attention in AD research, and mechanisms behind respiratory dysfunction in AD are not understood. The nucleus tractus solitarii (nTS) is an important brainstem center for respiratory control and chemoreflex function. Alterations of nTS integrity, like those shown in AD patients, likely affect neuronal processing and adequate control of breathing. We used the streptozotocin-induced rat model of AD (STZ-AD) to analyze cellular changes in the nTS that corroborate previously documented respiratory dysfunction. We used 2 common dosages of STZ (2 and 3 mg/kg STZ) for model induction and evaluated the early impact on cell populations in the nTS. The hippocampus served as control region to identify site-specific effects of STZ. There was significant atrophy in the caudal nTS of the 3 mg/kg STZ-AD group only, an area known to integrate chemoafferent information. Also, the hippocampus had significant atrophy with the highest STZ dosage tested. Both STZ-AD groups showed respiratory dysfunction along with multiple indices for astroglial and microglial activation. These changes were primarily located in the caudal and intermediate nTS. While there was no change of astrocytes in the hippocampus, microglial activation was accompanied by a reduction in synaptic density. Together, our data demonstrate that STZ-AD induces site-specific effects on all major cell types, primarily in the caudal/intermediate nTS. Both STZ dosages used in this study produced a similar outcome and can be used for future studies examining the initial symptoms of STZ-AD.
Collapse
Affiliation(s)
- Chuma M Humphrey
- Department of Physiology, Kirksville College of Osteopathic Medicine, A.T. Still University, 800 W. Jefferson St., Kirksville, MO, USA
| | - John W Hooker
- Department of Physiology, Kirksville College of Osteopathic Medicine, A.T. Still University, 800 W. Jefferson St., Kirksville, MO, USA
| | - Mahima Thapa
- Department of Biology, Truman State University, 100 E. Normal Ave., Kirksville, MO, USA
| | - Mason J Wilcox
- Department of Biology, Truman State University, 100 E. Normal Ave., Kirksville, MO, USA
| | - Daniela Ostrowski
- Department of Biology, Truman State University, 100 E. Normal Ave., Kirksville, MO, USA
| | - Tim D Ostrowski
- Department of Physiology, Kirksville College of Osteopathic Medicine, A.T. Still University, 800 W. Jefferson St., Kirksville, MO, USA.
| |
Collapse
|
|
17
|
Puris E, Fricker G, Gynther M. The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy. Pharmaceutics 2023; 15:pharmaceutics15020364. [PMID: 36839686 PMCID: PMC9966068 DOI: 10.3390/pharmaceutics15020364] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells.
Collapse
|
|
18
|
Attrill E, Richards SM, Ross RM, Sutherland BA, Premilovac D. Induction of Type 2 Diabetes in Mice to Understand Vascular Changes That Drive Diabetic Retinopathy. Methods Mol Biol 2023; 2678:1-12. [PMID: 37326701 DOI: 10.1007/978-1-0716-3255-0_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Diabetic retinopathy is a common complication of type 2 diabetes. Research into this comorbidity is challenging due to the slow progression of pathological changes and the limited transgenic models available to study disease progression and mechanistic changes. Here, we describe a non-transgenic mouse model of accelerated type 2 diabetes using a high-fat diet in combination with streptozotocin delivered via osmotic mini pump. This model, when subjected to fluorescent gelatin vascular casting, can be used to study vascular changes in type 2 diabetic retinopathy.
Collapse
Affiliation(s)
- Emily Attrill
- Tasmanian School of Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Stephen M Richards
- Tasmanian School of Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Renee M Ross
- Tasmanian School of Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Brad A Sutherland
- Tasmanian School of Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Dino Premilovac
- Tasmanian School of Medicine, University of Tasmania, Hobart, TAS, Australia.
| |
Collapse
|
|
19
|
Lu JS, Yang L, Chen J, Xiong FF, Cai P, Wang XY, Xiong BJ, Chen ZH, Chen L, Yang J, Yu CX. Basolateral amygdala astrocytes modulate diabetic neuropathic pain and may be a potential therapeutic target for koumine. Br J Pharmacol 2022; 180:1408-1428. [PMID: 36519959 DOI: 10.1111/bph.16011] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 10/20/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND AND PURPOSE New remedies are required for the treatment of diabetic neuropathic pain (DNP) due to insufficient efficacy of available therapies. Here, we used chemogenetic approaches combined with in vivo pharmacology to elucidate the role of basolateral amygdala (BLA) astrocytes in DNP pathogenesis and provide new insights into therapeutic strategies for DNP. EXPERIMENTAL APPROACH A streptozotocin-induced DNP model was established. Designer receptors exclusively activated by designer drugs (DREADDs) were used to regulate astrocyte activity. Mechanical hyperalgesia was assessed using the electronic von Frey test. Anxiety-like behaviours were detected using open field and elevated plus maze tests. Astrocytic activity was detected by immunofluorescence, and cytokine content was determined by ELISA. KEY RESULTS BLA astrocytes were regulated by DREADDs, and inhibition of BLA astrocytes attenuated mechanical allodynia and pain-related negative emotions in DNP rats. In contrast, temporary activation of BLA astrocytes induced allodynia without anxious behaviours in naive rats. In addition, koumine (KM) alleviated mechanical allodynia and anxiety-like behaviours in DNP rats, inhibited the activation of BLA astrocytes and suppressed the inflammatory response. Furthermore, persistent activation of BLA astrocytes through chemogenetics mimicked chronic pain, and KM alleviated the pain hypersensitivity and anxiety-like behaviours. CONCLUSION AND IMPLICATIONS DREADDs bidirectionally regulate the activity of BLA astrocytes, which proves for the first time the role of BLA astrocyte activation in the pathogenesis of DNP and represents a novel therapeutic strategy for DNP. KM ameliorates DNP, perhaps by inhibiting the activation of BLA astrocytes and reveal KM as a potential candidate for treating DNP.
Collapse
Affiliation(s)
- Jing-Shan Lu
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China.,Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China
| | - Lan Yang
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Jian Chen
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Fang-Fang Xiong
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Ping Cai
- Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Xin-Yao Wang
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Bo-Jun Xiong
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Ze-Hong Chen
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Li Chen
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Jian Yang
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Chang-Xi Yu
- Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China
| |
Collapse
|
|
20
|
Kisacam MA, Kocamuftuoglu GO, Ufat H, Ozan ST. The evaluation of early stage oxidative status in streptozotocin induced diabetes in rats. Arch Physiol Biochem 2022; 128:1474-1478. [PMID: 32521173 DOI: 10.1080/13813455.2020.1776736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Early-stage diabetes can be defined as the stages before absolute insulin deficiency in patients. In this study, the early stage oxidative effect of streptozotocin(STZ) induced diabetes mellitus was evaluated. 28 male adult Sprague-Dawley rats were divided into four groups; control group and 7th, 14th, 21st days diabetic groups. Diabetic groups received single 65 mg/kg STZ injection intraperitoneally. Rats were decapitated at 7th, 14th and 21st days, liver tissues were taken. Nitric oxide(NO), malondialdehyde(MDA) levels and catalase, arginase activities were measured. MDA and NO levels were increased (respectively p < .001 and p < .01), mainly 14 and 21 days after STZ administration; moreover, while liver catalase activity was progressively decreased (p < .001), oppositely arginase was increased in the same time period (p < .01). Results show that MDA and nitric oxide together with catalase and arginase switch at an early stage of diabetes and they may contribute to subsequent complications related to diabetes via increased oxidative damage.
Collapse
Affiliation(s)
- Mehmet Ali Kisacam
- Department of Biochemistry, Faculty of Veterinary Medicine, Mustafa Kemal University, Hatay, Turkey
| | - Gonca Ozan Kocamuftuoglu
- Department of Biochemistry, Faculty of Veterinary Medicine, Mehmet Akif Ersoy University, Burdur, Turkey
| | - Hakan Ufat
- Department of Biochemistry, Faculty of Veterinary Medicine, Firat University, Elazig, Turkey
| | - Sema Temizer Ozan
- Department of Biochemistry, Faculty of Veterinary Medicine, Firat University, Elazig, Turkey
| |
Collapse
|
|
21
|
Effects of Rice-Husk Silica Liquid in Streptozotocin-Induced Diabetic Mice. Metabolites 2022; 12:metabo12100964. [PMID: 36295866 PMCID: PMC9611213 DOI: 10.3390/metabo12100964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/08/2022] [Accepted: 10/09/2022] [Indexed: 11/16/2022] Open
Abstract
Type 2 diabetes mellitus is a complex multifactorial disease characterized by poor glucose tolerance and insulin resistance. Rice-husk silica liquid (RHSL) derived from rice husk has the ability to improve the dysfunction of pancreatic β-cells. This study aimed to confirm the potential protective effects of RHSL in streptozotocin (STZ)-induced diabetic mice. Diabetes was induced in male C57BL/6J mice by intraperitoneal administration of STZ (200 mg/kg BW). RHSL, food-grade silica liquid (FDSL), and rosiglitazone (RSG) were administered to diabetic mice for 12 weeks after successful induction of diabetes. During the experiment, fasting blood glucose, serum insulin, and organ weights were measured. The histopathology of liver tissue was evaluated by H&E staining. Western blotting was performed to assess protein expression levels. The results showed that RHSL significantly reversed the serum insulin levels and improved oral glucose tolerance test (OGTT) results (p < 0.05). In addition, liver sections of STZ-induced diabetic mice after RHSL treatment showed neatly arranged and intact hepatocytes. Furthermore, RHSL was more effective than FDSL in increasing the expression of SIRT1 and decreasing the expression of the PPAR-γ and p-NF-κB proteins. Taken together, this study demonstrated that RHSL ameliorated STZ-induced insulin resistance and liver tissue damage in C57BL/6J mice.
Collapse
|
|
22
|
Liu F, Cai Z, Yang Y, Plasko G, Zhao P, Wu X, Tang C, Li D, Li T, Hu S, Song L, Yu S, Xu R, Luo H, Fan L, Wang E, Xiao Z, Ji Y, Zeng R, Li R, Bai J, Zhou Z, Liu F, Zhang J. The adipocyte-enriched secretory protein tetranectin exacerbates type 2 diabetes by inhibiting insulin secretion from β cells. SCIENCE ADVANCES 2022; 8:eabq1799. [PMID: 36129988 PMCID: PMC9491725 DOI: 10.1126/sciadv.abq1799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 08/04/2022] [Indexed: 06/15/2023]
Abstract
Pancreatic β cell failure is a hallmark of diabetes. However, the causes of β cell failure remain incomplete. Here, we report the identification of tetranectin (TN), an adipose tissue-enriched secretory molecule, as a negative regulator of insulin secretion in β cells in diabetes. TN expression is stimulated by high glucose in adipocytes via the p38 MAPK/TXNIP/thioredoxin/OCT4 signaling pathway, and elevated serum TN levels are associated with diabetes. TN treatment greatly exacerbates hyperglycemia in mice and suppresses glucose-stimulated insulin secretion in islets. Conversely, knockout of TN or neutralization of TN function notably improves insulin secretion and glucose tolerance in high-fat diet-fed mice. Mechanistically, TN binds with high selectivity to β cells and inhibits insulin secretion by blocking L-type Ca2+ channels. Our study uncovers an adipocyte-β cell cross-talk that contributes to β cell dysfunction in diabetes and suggests that neutralization of TN levels may provide a new treatment strategy for type 2 diabetes.
Collapse
Affiliation(s)
- Fen Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Zixin Cai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Yan Yang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - George Plasko
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
| | - Piao Zhao
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China
| | - Xiangyue Wu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China
| | - Cheng Tang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China
| | - Dandan Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ting Li
- Department of Liver Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Shanbiao Hu
- Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Lei Song
- Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Shaojie Yu
- Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ran Xu
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Hairong Luo
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Libin Fan
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ersong Wang
- Department of Neurosurgery, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Zhen Xiao
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China
| | - Yujiao Ji
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Rong Zeng
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Rongxia Li
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Juli Bai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| |
Collapse
|
|
23
|
Yuan J, Li S, Peng H, Ma Y, Li L, Fu L, Liu J, Jiang H. Artesunate protects pancreatic β-cells from streptozotocin-induced diabetes via inhibition of the NLRP3/caspase-1/GSDMD pathway. Gen Comp Endocrinol 2022; 326:114068. [PMID: 35671834 DOI: 10.1016/j.ygcen.2022.114068] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/16/2022] [Accepted: 06/02/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND Reports in recent years have shown that pancreatic β-cell pyroptosis represents a critical mechanism involved with the progressive failure of pancreatic function. Previous research from our laboratory has indicated that artemether can increase the number of cells in pancreatic islets of db/db mice. In this study, we further examined whether artesunate (ART) protects pancreatic β-cells from the damage of streptozotocin (STZ) by inhibiting pyroptosis. MATERIALS AND METHODS In vitro, MIN6 cells exposed to 1 mM STZ were treated with ART (0.8 or 1.6 μM). The effects of ART on STZ-treated cells were evaluated through CCK-8 assay, flow cytometry and western blot, and further compared the effects of ART with the NLRP3 inhibitor, Mcc950 upon pyroptosis pathway proteins using western blot. In vivo, Male C57 mice were administered with a single intraperitoneal injection of STZ, and those with confirmed diabetes mellitus were given ART (0.5 or 1.0 mg/ml in drinking water) for 18 days. The effects of ART on STZ-induced diabetes were assessed by the observation of the general situation, glucose tolerance test, hematoxylin-eosin (HE) staining and immunohistochemistry. RESULTS In MIN6 cells treated with STZ, we found that ART increased cell viability, decreased the number of late apoptotic cells (including pyroptosis cells) and inhibited the expression of proteins associated with the pyroptosis pathway. In STZ-induced animal model, the administration of ART reduced blood glucose levels, improved the consumption status within this diabetic mouse model and inhibited the expression of proteins include in the pyroptosis pathway in mice pancreats. CONCLUSIONS Inhibition of pyroptosis may be a critical mechanism through which artesunate exerts protective effects upon pancreatic β cells.
Collapse
Affiliation(s)
- Jingya Yuan
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Shipeng Li
- Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo 454002, China
| | - Huifang Peng
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Yujin Ma
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Liping Li
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Liujun Fu
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Jie Liu
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Hongwei Jiang
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China.
| |
Collapse
|
|
24
|
Marissal-Arvy N, Moisan MP. Diabetes and associated cognitive disorders: Role of the Hypothalamic-Pituitary Adrenal axis. Metabol Open 2022; 15:100202. [PMID: 35958117 PMCID: PMC9357829 DOI: 10.1016/j.metop.2022.100202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 11/12/2022] Open
Abstract
Both diabetes types, types 1 and 2, are associated with cognitive impairments. Each period of life is concerned, and this is an increasing public health problem. Animal models have been developed to investigate the biological actors involved in such impairments. Many levels of the brain function (structure, volume, neurogenesis, neurotransmission, behavior) are involved. In this review, we detailed the part potentially played by the Hypothalamic-Pituitary Adrenal axis in these dysfunctions. Notably, regulating glucocorticoid levels, their receptors and their bioavailability appear to be relevant for future research studies, and treatment development.
Collapse
Affiliation(s)
- Nathalie Marissal-Arvy
- INRAE, Laboratoire de Nutrition et Neurobiologie Intégrée, UMR 1286, UFR de Pharmacie, 146 Rue Léo Saignat, 33076, Bordeaux Cedex, France
| | - Marie-Pierre Moisan
- University of Bordeaux, Nutrition et Neurobiologie Intégrée, UMR 1286, 33000, Bordeaux, France
| |
Collapse
|
|
25
|
Female Wistar rats present particular glucose flux when submitted to classic protocols of experimental diabetes. Biomed J 2022; 46:100539. [DOI: 10.1016/j.bj.2022.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 05/02/2022] [Accepted: 05/12/2022] [Indexed: 11/17/2022] Open
|
|
26
|
Komoto I, Kokudo N, Aoki T, Morizane C, Ito T, Hashimoto T, Kimura W, Inoue N, Hasegawa K, Kondo S, Ueno H, Igarashi H, Oono T, Makuuchi M, Takamoto T, Hirai I, Takeshita A, Imamura M. Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. Jpn J Clin Oncol 2022; 52:716-724. [PMID: 35411926 PMCID: PMC9264336 DOI: 10.1093/jjco/hyac048] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.
Collapse
Affiliation(s)
- Izumi Komoto
- Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, University of Tokyo Hospital, Tokyo, Japan.,National Center for Global Health and Medicine, Tokyo, Japan
| | - Taku Aoki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, University of Tokyo Hospital, Tokyo, Japan.,Dokkyo Medical University Hospital, Tochigi, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Fukuoka Sanno Hospital, International University of Health and Welfare, Fukuoka, Japan
| | - Takuya Hashimoto
- Division of Hepato-Biliary-Pancreatic Surgery, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Wataru Kimura
- Department of Gastroenterological, Breast, Thyroid, and General Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Naoya Inoue
- Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, University of Tokyo Hospital, Tokyo, Japan
| | - Shunsuke Kondo
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hideki Ueno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hisato Igarashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Igarashi Medical Clinic, Yamaguchi, Japan
| | - Takamasa Oono
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Masatoshi Makuuchi
- Division of Hepato-Biliary-Pancreatic Surgery, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Takeshi Takamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Ichiro Hirai
- Department of Gastroenterological, Breast, Thyroid, and General Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Akiko Takeshita
- Department of Gastroenterological, Breast, Thyroid, and General Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan.,Okitama Public General Hospital, Yamagata, Japan
| | - Masayuki Imamura
- Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan.,Neuroendocrine Tumor Center, Kansai Electric Power Hospital, Osaka, Japan
| |
Collapse
|
|
27
|
Erichsen JM, Fadel JR, Reagan LP. Peripheral versus central insulin and leptin resistance: Role in metabolic disorders, cognition, and neuropsychiatric diseases. Neuropharmacology 2022; 203:108877. [PMID: 34762922 PMCID: PMC8642294 DOI: 10.1016/j.neuropharm.2021.108877] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/14/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
Insulin and leptin are classically regarded as peptide hormones that play key roles in metabolism. In actuality, they serve several functions in both the periphery and central nervous system (CNS). Likewise, insulin and leptin resistance can occur both peripherally and centrally. Metabolic disorders such as diabetes and obesity share several key features including insulin and leptin resistance. While the peripheral effects of these disorders are well-known (i.e. cardiovascular disease, hypertension, stroke, dyslipidemia, etc.), the CNS complications of leptin and insulin resistance have come into sharper focus. Both preclinical and clinical findings have indicated that insulin and leptin resistance are associated with cognitive deficits and neuropsychiatric diseases such as depression. Importantly, these studies also suggest that these deficits in neuroplasticity can be reversed by restoration of insulin and leptin sensitivity. In view of these observations, this review will describe, in detail, the peripheral and central functions of insulin and leptin and explain the role of insulin and leptin resistance in various metabolic disorders, cognition, and neuropsychiatric diseases.
Collapse
Affiliation(s)
- Jennifer M Erichsen
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA.
| | - Jim R Fadel
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA
| | - Lawrence P Reagan
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA; Columbia VA Health Care System, Columbia, SC, 29208, USA
| |
Collapse
|
|
28
|
Zhu BT. Pathogenic Mechanism of Autoimmune Diabetes Mellitus in Humans: Potential Role of Streptozotocin-Induced Selective Autoimmunity against Human Islet β-Cells. Cells 2022; 11:cells11030492. [PMID: 35159301 PMCID: PMC8834428 DOI: 10.3390/cells11030492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/22/2022] [Accepted: 01/22/2022] [Indexed: 12/22/2022] Open
Abstract
Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing β-cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet β-cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ. In addition, the potential presence of the STZ-producing bacteria in the gut microbiota of some individuals might be another source of long-term STZ exposure. Because of the high chemical reactivity of STZ and its breakdown products, these chemicals can covalently modify certain cellular macromolecules (e.g., DNA and proteins), and the covalently modified cellular components would serve as new antigens, potentially capable of inducing both humoral and cellular autoimmune responses in the islets of certain individuals. In addition to STZ exposure, the eventual development of autoimmunity against STZ-exposed islet β-cells also depends critically on the genetic predisposition of the susceptible individuals plus the opportunistic presence of a conducive, strong environmental trigger, which often is presented as severe febrile viral infections subsequently inducing strong aberrant reactions of the body’s immune system. The proposed pathogenic hypothesis is supported by a considerable body of direct and indirect evidence from laboratory animal studies and clinical observations. Certainly, more experimental and clinical studies are needed to carefully further examine each of the key components of the proposed pathogenic hypothesis.
Collapse
Affiliation(s)
- Bao Ting Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China;
- Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| |
Collapse
|
|
29
|
Gonçalves MG, Medeiros MA, de Lemos LIC, de Fátima Campos Pedrosa L, de Andrade Santos PP, Abreu BJ, Lima JPMS. Effects of Creatine Supplementation on Histopathological and Biochemical Parameters in the Kidney and Pancreas of Streptozotocin-Induced Diabetic Rats. Nutrients 2022; 14:nu14030431. [PMID: 35276790 PMCID: PMC8840440 DOI: 10.3390/nu14030431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/29/2021] [Accepted: 12/29/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus (DM) is a worldwide health concern, and projections state that cases will reach 578 million by 2030. Adjuvant therapies that can help the standard treatment and mitigate DM effects are necessary, especially those using nutritional supplements to improve glycemic control. Previous studies suggest creatine supplementation as a possible adjuvant therapy for DM, but they lack the evaluation of potential morphological parameters alterations and tissue injury caused by this compound. The present study aimed to elucidate clinical, histomorphometric, and histopathological consequences and the cellular oxidative alterations of creatine supplementation in streptozotocin (STZ)-induced type 1 DM rats. We could estimate whether the findings are due to DM or the supplementation from a factorial experimental design. Although creatine supplementation attenuated some biochemical parameters, the morphological analyses of pancreatic and renal tissues made clear that the supplementation did not improve the STZ-induced DM1 injuries. Moreover, creatine-supplemented non-diabetic animals were diagnosed with pancreatitis and showed renal tubular necrosis. Therefore, even in the absence of clinical symptoms and unaltered biochemical parameters, creatine supplementation as adjuvant therapy for DM should be carefully evaluated.
Collapse
Affiliation(s)
- Meline Gomes Gonçalves
- Biochemistry and Molecular Biology Graduate Program, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, RN, Brazil;
| | - Matheus Anselmo Medeiros
- Bioinformatics Graduate Program, Digital Metropolis Institute, Federal University of Rio Grande do Norte, Natal 59078-400, RN, Brazil;
| | | | - Lucia de Fátima Campos Pedrosa
- Graduate Program in Nutrition, Federal University of Rio Grande do Norte, Natal 59.078-970, RN, Brazil; (L.I.C.d.L.); (L.d.F.C.P.)
| | - Pedro Paulo de Andrade Santos
- Structural and Functional Biology Graduate Program, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, RN, Brazil;
- Biosciences Center, Morphology Department, Federal University of Rio Grande do Norte, Natal 59078-970, RN, Brazil;
| | - Bento João Abreu
- Biosciences Center, Morphology Department, Federal University of Rio Grande do Norte, Natal 59078-970, RN, Brazil;
| | - João Paulo Matos Santos Lima
- Biochemistry and Molecular Biology Graduate Program, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, RN, Brazil;
- Bioinformatics Graduate Program, Digital Metropolis Institute, Federal University of Rio Grande do Norte, Natal 59078-400, RN, Brazil;
- Correspondence:
| |
Collapse
|
|
30
|
Márquez-Quiroga LV, Arellanes-Robledo J, Vásquez-Garzón VR, Villa-Treviño S, Muriel P. Models of nonalcoholic steatohepatitis potentiated by chemical inducers leading to hepatocellular carcinoma. Biochem Pharmacol 2021; 195:114845. [PMID: 34801522 DOI: 10.1016/j.bcp.2021.114845] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC), the most common primary liver cancer, arises after a long period of exposure to etiological factors. Nonalcoholic steatohepatitis (NASH) is ranked as the main risk factor for developing HCC; hence, experimental models of NASH leading to HCC have become key tools both to investigate the molecular mechanisms underlying the pathophysiology and to evaluate new putative drugs for treating chronic liver diseases in humans. Animal models of NASH induced by a high-fat diet (HFD) plus chemical inducers, such as the NASH-HCC (STAM), high-fat diet/diethylnitrosamine (HFD/DEN), choline-deficient high-fat diet/DEN (CDHFD/DEN), and Western diet/carbon tetrachloride (WD/CCl4) models, are promising because they exacerbate liver damage and significantly shorten the experimental time. In this review, we critically summarize and discuss the ability of these models to recapitulate the liver alterations that precede and lead to HCC progression, as well as the impact of the diet in promoting liver injury progression. We also emphasize the strengths and weaknesses of the models' ability to closely mimic the stages of liver injury development that occur in humans. Based on the molecular mechanisms induced by the currently available NASH models leading to HCC, we argue that although several NASH models have importantly contributed to describing the disease chronology, the progress in emulating the progression from NASH to HCC has been partial. Thus, the development of novel NASH/HCC models remains an unmet need.
Collapse
Affiliation(s)
- Linda Vanessa Márquez-Quiroga
- Laboratorio de Hepatología Experimental, Departamento de Farmacología, Cinvestav-IPN, Apartado Postal 14-740, Ciudad de México, Mexico
| | - Jaime Arellanes-Robledo
- Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica - INMEGEN, Ciudad de México, Mexico; Dirección de Cátedras, Consejo Nacional de Ciencia y Tecnología - CONACYT, Ciudad de México, Mexico.
| | - Verónica Rocío Vásquez-Garzón
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Mexico; Dirección de Cátedras, Consejo Nacional de Ciencia y Tecnología - CONACYT, Ciudad de México, Mexico
| | - Saul Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Pablo Muriel
- Laboratorio de Hepatología Experimental, Departamento de Farmacología, Cinvestav-IPN, Apartado Postal 14-740, Ciudad de México, Mexico.
| |
Collapse
|
|
31
|
Yang M, Chen Y, Vagionitis S, Körtvely E, Ueffing M, Schmachtenberg O, Hu Z, Jiao K, Paquet-Durand F. Expression of glucose transporter-2 in murine retina: Evidence for glucose transport from horizontal cells to photoreceptor synapses. J Neurochem 2021; 160:283-296. [PMID: 34726780 DOI: 10.1111/jnc.15533] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/12/2021] [Accepted: 10/18/2021] [Indexed: 01/30/2023]
Abstract
The retina has the highest relative energy consumption of any tissue, depending on a steady supply of glucose from the bloodstream. Glucose uptake is mediated by specific transporters whose regulation and expression are critical for the pathogenesis of many diseases, including diabetes and diabetic retinopathy. Here, we used immunofluorescence to show that glucose transporter-2 (GLUT2) is expressed in horizontal cells of the mouse neuroretina in proximity to inner retinal capillaries. To study the function of GLUT2 in the murine retina, we used organotypic retinal explants, cultivated under entirely controlled, serum-free conditions and exposed them to streptozotocin, a cytotoxic drug transported exclusively by GLUT2. Contrary to our expectations, streptozotocin did not measurably affect horizontal cell viability, while it ablated rod and cone photoreceptors in a concentration-dependent manner. Staining for poly-ADP-ribose (PAR) indicated that the detrimental effect of streptozotocin on photoreceptors may be associated with DNA damage. The negative effect of streptozotocin on the viability of rod photoreceptors was counteracted by co-administration of either the inhibitor of connexin-formed hemi-channels meclofenamic acid or the blocker of clathrin-mediated endocytosis dynasore. Remarkably, cone photoreceptors were not protected from streptozotocin-induced degeneration by neither of the two drugs. Overall, these data suggest the existence of a GLUT2-dependent glucose transport shuttle, from horizontal cells into photoreceptor synapses. Moreover, our study points at different glucose uptake mechanisms in rod and cone photoreceptors.
Collapse
Affiliation(s)
- Ming Yang
- Affiliated Hospital of Yunnan University & 2nd People's Hospital of Yunnan Province, Kunming, China.,Yunnan Eye Institute & Key Laboratory of Yunnan Province, Kunming, China.,1st Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yiyi Chen
- Institute for Ophthalmic Research, Eberhard-Karls-Universität, Tübingen, Germany
| | - Stavros Vagionitis
- Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany
| | - Elöd Körtvely
- Roche Pharma Research and Early Development, Immunology, Infectious Diseases and Ophthalmology (I2O), Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Marius Ueffing
- Institute for Ophthalmic Research, Eberhard-Karls-Universität, Tübingen, Germany
| | - Oliver Schmachtenberg
- CINV, Instituto de Biología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Zhulin Hu
- Affiliated Hospital of Yunnan University & 2nd People's Hospital of Yunnan Province, Kunming, China.,Yunnan Eye Institute & Key Laboratory of Yunnan Province, Kunming, China
| | - Kangwei Jiao
- Affiliated Hospital of Yunnan University & 2nd People's Hospital of Yunnan Province, Kunming, China.,Yunnan Eye Institute & Key Laboratory of Yunnan Province, Kunming, China
| | | |
Collapse
|
|
32
|
Intrauterine hyperglycemia impairs memory across two generations. Transl Psychiatry 2021; 11:434. [PMID: 34417446 PMCID: PMC8379206 DOI: 10.1038/s41398-021-01565-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/27/2021] [Accepted: 08/10/2021] [Indexed: 12/22/2022] Open
Abstract
Studies on humans and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, the molecular mechanisms underpinning the intergenerational effects remain unclear. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes (DEGs) were enriched in neurodevelopment and synaptic plasticity. The reduced representation bisulfite sequencing (RRBS) of sperm in F1 adult males showed that the intrauterine hyperglycemia exposure caused altered methylated modification of F1 sperm, which is a potential epigenetic mechanism for the intergenerational neurocognitive effects of GDM.
Collapse
|
|
33
|
Hijioka S, Morizane C, Ikeda M, Ishii H, Okusaka T, Furuse J. Current status of medical treatment for gastroenteropancreatic neuroendocrine neoplasms and future perspectives. Jpn J Clin Oncol 2021; 51:1185-1196. [PMID: 34038547 PMCID: PMC8326384 DOI: 10.1093/jjco/hyab076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/03/2021] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors. In this review, we summarize the results of various clinical trials that have been conducted to investigate the efficacy and safety of various therapeutic options for NENs. Based on the encouraging results obtained from these trials, various therapeutic options have been established for the treatment of NENs, including somatostatin analogs (SSAs), molecularly targeted drugs and cytotoxic agents. In addition, peptide receptor radionucleotide therapy has recently been evaluated for the treatment of various NENs. We also discuss the approach for selecting the appropriate drugs and sequence of treatment with the various drug classes, as recommended by different treatment guidelines. Finally, we discuss the scope for future research in this field, especially into the merits of combination therapy with molecularly targeted drugs plus SSAs, along with ongoing studies.
Collapse
Affiliation(s)
- Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroshi Ishii
- Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| |
Collapse
|
|
34
|
Fahie K, Narayanan B, Zahra F, Reeves R, Fernandes SM, Hart GW, Zachara NE. Detection and Analysis of Proteins Modified by O-Linked N-Acetylglucosamine. Curr Protoc 2021; 1:e129. [PMID: 34004049 DOI: 10.1002/cpz1.129] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
O-GlcNAc is a common post-translational modification of nuclear, mitochondrial, and cytoplasmic proteins that regulates normal physiology and the cell stress response. Dysregulation of O-GlcNAc cycling is implicated in the etiology of type II diabetes, heart failure, hypertension, and Alzheimer's disease, as well as cardioprotection. These protocols cover simple and comprehensive techniques for detecting proteins modified by O-GlcNAc and studying the enzymes that add or remove O-GlcNAc. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Increasing the stoichiometry of O-GlcNAc on proteins before analysis Basic Protocol 2: Detection of proteins modified by O-GlcNAc using antibodies Basic Protocol 3: Detection of proteins modified by O-GlcNAc using the lectin sWGA Support Protocol 1: Control for O-linked glycosylation Basic Protocol 4: Detection and enrichment of proteins using WGA-agarose Support Protocol 2: Digestion of proteins with hexosaminidase Alternate Protocol: Detection of proteins modified by O-GlcNAc using galactosyltransferase Support Protocol 3: Autogalactosylation of galactosyltransferase Support Protocol 4: Assay of galactosyltransferase activity Basic Protocol 5: Characterization of labeled glycans by β-elimination and chromatography Basic Protocol 6: Detection of O-GlcNAc in 96-well plates Basic Protocol 7: Assay for OGT activity Support Protocol 5: Desalting of O-GlcNAc transferase Basic Protocol 8: Assay for O-GlcNAcase activity.
Collapse
Affiliation(s)
- Kamau Fahie
- The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Fiddia Zahra
- The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Russell Reeves
- The Johns Hopkins University School of Medicine, Baltimore, Maryland.,Current address: Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | - Steve M Fernandes
- The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Gerald W Hart
- Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia
| | - Natasha E Zachara
- The Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
35
|
Fundamental changes in endogenous bone marrow mesenchymal stromal cells during Type I Diabetes is a pre-neuropathy event. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166187. [PMID: 34102256 DOI: 10.1016/j.bbadis.2021.166187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 06/01/2021] [Indexed: 12/12/2022]
Abstract
Deficiency of angiogenic and neurotrophic factors under long term diabetes is known to lead to Schwann cell degeneration, clinically manifested as Diabetic Neuropathy (DN). While the transplantation of exogenous allogenic Mesenchymal Stromal Cells (MSCs) has shown amelioration of DN through paracrine action, it is not known what functional changes occur in endogenous bone-marrow MSCs under chronic diabetes in terms of homing, migration and/or paracrine signalling with reference to the end-point clinical manifestation of Diabetic Neuropathy. We thus aimed at determining the changes in BM-MSCs under Type 1 Diabetes with respect to survival, self-renewal, oxidative status, paracrine activity, intracellular Ca2+ response and migration in response to pathological cytokine/chemokine, in reference to the time-point of decline in Nerve Conduction Velocity (NCV) in a rat model. Within one week of diabetes induction, BM-MSCs underwent apoptosis, and compromised their self-renewal capacity, antioxidant defence mechanism and migration toward cytokine/chemokine; whereas epineurial blood vessel thickening and demyelination resulting in NCV decline were observed only after three weeks. By two- and three-weeks post diabetes induction, BM-MSC apoptosis reduced and proliferative ability was restored; however, their self-renewal, migration and intracellular Ca2+ response toward pathological cytokine/chemokine remained impaired. These results indicate that T1D induced intrinsic functional impairments in endogenous BM-MSCs occur before neuropathy onset. This timeline of functional alterations in BM-MSCs also suggest that treatment strategies that target the bone marrow niche early on may help to modulate BM-MSC functional impairments and thus slow down the progression of neuropathy.
Collapse
|
|
36
|
Miranda MA, Macias-Velasco JF, Lawson HA. Pancreatic β-cell heterogeneity in health and diabetes: classes, sources, and subtypes. Am J Physiol Endocrinol Metab 2021; 320:E716-E731. [PMID: 33586491 PMCID: PMC8238131 DOI: 10.1152/ajpendo.00649.2020] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pancreatic β-cells perform glucose-stimulated insulin secretion, a process at the center of type 2 diabetes etiology. Efforts to understand how β-cells behave in healthy and stressful conditions have revealed a wide degree of morphological, functional, and transcriptional heterogeneity. Sources of heterogeneity include β-cell topography, developmental origin, maturation state, and stress response. Advances in sequencing and imaging technologies have led to the identification of β-cell subtypes, which play distinct roles in the islet niche. This review examines β-cell heterogeneity from morphological, functional, and transcriptional perspectives, and considers the relevance of topography, maturation, development, and stress response. It also discusses how these factors have been used to identify β-cell subtypes, and how heterogeneity is impacted by diabetes. We examine open questions in the field and discuss recent technological innovations that could advance understanding of β-cell heterogeneity in health and disease.
Collapse
Affiliation(s)
- Mario A Miranda
- Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri
| | - Juan F Macias-Velasco
- Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri
| | - Heather A Lawson
- Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri
| |
Collapse
|
|
37
|
Emerging Roles of Metallothioneins in Beta Cell Pathophysiology: Beyond and Above Metal Homeostasis and Antioxidant Response. BIOLOGY 2021; 10:biology10030176. [PMID: 33652748 PMCID: PMC7996892 DOI: 10.3390/biology10030176] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/17/2021] [Accepted: 02/22/2021] [Indexed: 12/15/2022]
Abstract
Simple Summary Defective insulin secretion by pancreatic beta cells is key for the development of type 2 diabetes but the precise mechanisms involved are poorly understood. Metallothioneins are metal binding proteins whose precise biological roles have not been fully characterized. Available evidence indicated that Metallothioneins are protective cellular effectors involved in heavy metal detoxification, metal ion homeostasis and antioxidant defense. This concept has however been challenged by emerging evidence in different medical research fields revealing novel negative roles of Metallothioneins, including in the context of diabetes. In this review, we gather and analyze the available knowledge regarding the complex roles of Metallothioneins in pancreatic beta cell biology and insulin secretion. We comprehensively analyze the evidence showing positive effects of Metallothioneins on beta cell function and survival as well as the emerging evidence revealing negative effects and discuss the possible underlying mechanisms. We expose in parallel findings from other medical research fields and underscore unsettled questions. Then, we propose some future research directions to improve knowledge in the field. Abstract Metallothioneins (MTs) are low molecular weight, cysteine-rich, metal-binding proteins whose precise biological roles have not been fully characterized. Existing evidence implicated MTs in heavy metal detoxification, metal ion homeostasis and antioxidant defense. MTs were thus categorized as protective effectors that contribute to cellular homeostasis and survival. This view has, however, been challenged by emerging evidence in different medical fields revealing novel pathophysiological roles of MTs, including inflammatory bowel disease, neurodegenerative disorders, carcinogenesis and diabetes. In the present focused review, we discuss the evidence for the role of MTs in pancreatic beta-cell biology and insulin secretion. We highlight the pattern of specific isoforms of MT gene expression in rodents and human beta-cells. We then discuss the mechanisms involved in the regulation of MTs in islets under physiological and pathological conditions, particularly type 2 diabetes, and analyze the evidence revealing adaptive and negative roles of MTs in beta-cells and the potential mechanisms involved. Finally, we underscore the unsettled questions in the field and propose some future research directions.
Collapse
|
|
38
|
Effects of Curcumin Treatment in a Diabetic Neuropathic Pain Model of Rats: Involvement of c-Jun N-Terminal Kinase Located in the Astrocytes and Neurons of the Dorsal Root Ganglion. Pain Res Manag 2021; 2021:8787231. [PMID: 33532012 PMCID: PMC7837777 DOI: 10.1155/2021/8787231] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/06/2020] [Accepted: 01/08/2021] [Indexed: 12/28/2022]
Abstract
Curcumin (diferuloylmethane) is a major component of turmeric, which is isolated from the rhizomes of Curcuma longa L. from the family Zingiberaceae. It is used as a dietary pigment for curry and in traditional Indian medicine for its anti-inflammatory and attenuating pain effects. This study aimed to evaluate the beneficial effects of curcumin in a rat model of diabetic neuropathic pain. Additionally, we investigated the involvement of the phosphorylated form of c-Jun N-terminal kinase (pJNK) located in the neurons and astrocytes of the dorsal root ganglion (DRG). To induce diabetic neuropathic pain in rats, 50 mg/kg of streptozotocin (STZ) was intraperitoneally injected. After 4 weeks, rats were administered the vehicle, 10 mg/kg/day curcumin, or 50 mg/kg/day curcumin orally for 4 consecutive weeks. One day after the final drug administration, we performed behavioral tests to measure responses of rats to mechanical, heat, cold, and acetone-induced cold stimuli. After behavioral tests, pJNK expression in the DRG was evaluated using western blot assay and immunohistochemistry. Curcumin treatment for 4 consecutive weeks in STZ-induced diabetic neuropathic pain rats improved behavioral responses to mechanical, cold, and thermal stimuli. Increased pJNK expression in the astrocytes and neurons of the DRG in STZ-induced diabetic neuropathic pain rats was reduced by curcumin treatment for 4 consecutive weeks. We suggest that curcumin can be an option for the treatment of diabetes-related neuropathic pain, and one of the mechanisms that underlie the action of curcumin may involve pJNK expression in the astrocytes and neurons of the DRG.
Collapse
|
|
39
|
Umezu T, Tsuneyama K, Kanekura K, Hayakawa M, Tanahashi T, Kawano M, Taguchi YH, Toyoda H, Tamori A, Kuroda M, Murakami Y. Comprehensive analysis of liver and blood miRNA in precancerous conditions. Sci Rep 2020; 10:21766. [PMID: 33303811 PMCID: PMC7728755 DOI: 10.1038/s41598-020-78500-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Streptozotocin administration to mice (STZ-mice) induces type I diabetes and hepatocellular carcinoma (HCC). We attempted to elucidate the carcinogenic mechanism and the miRNA expression status in the liver and blood during the precancerous state. Serum and liver tissues were collected from STZ-mice and non-treated mice (CTL-mice) at 6, 10, and 12 W. The exosome enriched fraction extracted from serum was used. Hepatic histological examination and hepatic and exosomal miRNA expression analysis were serially performed using next-generation sequencing (NGS). Human miRNA expression analysis of chronic hepatitis liver tissue and exosomes, which were collected before starting the antiviral treatment, were also performed. No inflammation or fibrosis was found in the liver of CTL-mice during the observation period. In STZ-mice, regeneration and inflammation of hepatocytes was found at 6 W and nodules of atypical hepatocytes were found at 10 and 12 W. In the liver tissue, during 6-12 W, the expression levels of let-7f-5p, miR-143-3p, 148a-3p, 191-5p, 192-5p, 21a-5p, 22-3p, 26a-5p, and 92a-3p was significantly increased in STZ-mice, and anti-oncogenes of their target gene candidates were down-regulated. miR-122-5p was also significantly down-regulated in STZ-mice. Fifteen exosomal miRNAs were upregulated in STZ-mice. Six miRNAs (let-7f-5p, miR-10b-5p, 143-3p, 191-5p, 21a-5p, and 26a-5p) were upregulated, similarly to human HCC cases. From the precancerous state, aberrant expression of hepatic miRNAs has already occurred, and then, it can promote carcinogenesis. In exosomes, the expression pattern of common miRNAs between mice and humans before carcinogenesis was observed and can be expected to be developed as a cancer predictive marker.
Collapse
Affiliation(s)
- Tomohiro Umezu
- Department of Molecular Pathology, Tokyo Medical University, Shinjuku 6-1-1, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Kohsuke Kanekura
- Department of Molecular Pathology, Tokyo Medical University, Shinjuku 6-1-1, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Michiyo Hayakawa
- Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan
| | | | - Mitsuoki Kawano
- Department of Human Nutrition, Faculty of Contemporary Life Science, Chugokugakuen University, Okayama, 701-0197, Japan
| | - Y-H Taguchi
- Department of Physics, Chuo University, Tokyo, 112-8551, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, 503-8502, Japan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Shinjuku 6-1-1, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Yoshiki Murakami
- Department of Molecular Pathology, Tokyo Medical University, Shinjuku 6-1-1, Shinjuku-ku, Tokyo, 160-8402, Japan.
| |
Collapse
|
|
40
|
Watanabe H, Yamazaki Y, Fujishima F, Izumi K, Imamura M, Hijioka S, Toriyama K, Yatabe Y, Kudo A, Motoi F, Unno M, Sasano H. O 6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms. BMC Cancer 2020; 20:1195. [PMID: 33287738 PMCID: PMC7720403 DOI: 10.1186/s12885-020-07579-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/27/2020] [Indexed: 01/25/2023] Open
Abstract
Background Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. Methods In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). Results In GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = − 0.4570; MGMT score: P = 0.0064, ρ = − 0.4399; H-score: P = 0.0110, ρ = − 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. Conclusion The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07579-6.
Collapse
Affiliation(s)
- Hirofumi Watanabe
- Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Yuto Yamazaki
- Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Komoto Izumi
- Department of Surgery, Kansai Electric Power Hospital, Osaka, 553-0003, Japan.,Kansai Electric Power Medical Research Institute, Osaka, 553-0003, Japan
| | - Masayuki Imamura
- Department of Surgery, Kansai Electric Power Hospital, Osaka, 553-0003, Japan
| | - Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center, Tokyo, 104-0045, Japan
| | - Kazuhiro Toriyama
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Aichi, 464-0021, Japan
| | - Yasushi Yatabe
- Department of Pathology and Clinical Laboratories, National Cancer Center, Tokyo, Japan
| | - Atsushi Kudo
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-0034, Japan
| | - Fuyuhiko Motoi
- Department of Surgery I, Yamagata University Graduate School of Medical Science, Yamagata, 990-9585, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan.
| |
Collapse
|
|
41
|
Elferink H, Bruekers JPJ, Veeneman GH, Boltje TJ. A comprehensive overview of substrate specificity of glycoside hydrolases and transporters in the small intestine : "A gut feeling". Cell Mol Life Sci 2020; 77:4799-4826. [PMID: 32506169 PMCID: PMC7658089 DOI: 10.1007/s00018-020-03564-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/21/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023]
Abstract
The human body is able to process and transport a complex variety of carbohydrates, unlocking their nutritional value as energy source or as important building block. The endogenous glycosyl hydrolases (glycosidases) and glycosyl transporter proteins located in the enterocytes of the small intestine play a crucial role in this process and digest and/or transport nutritional sugars based on their structural features. It is for these reasons that glycosidases and glycosyl transporters are interesting therapeutic targets to combat sugar related diseases (such as diabetes) or to improve drug delivery. In this review we provide a detailed overview focused on the molecular structure of the substrates involved as a solid base to start from and to fuel research in the area of therapeutics and diagnostics.
Collapse
Affiliation(s)
- Hidde Elferink
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, Nijmegen, The Netherlands
| | - Jeroen P J Bruekers
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, Nijmegen, The Netherlands
| | | | - Thomas J Boltje
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525, Nijmegen, The Netherlands.
| |
Collapse
|
|
42
|
Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice. Molecules 2020; 25:molecules25194381. [PMID: 32987643 PMCID: PMC7582334 DOI: 10.3390/molecules25194381] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 01/14/2023] Open
Abstract
Diabetes mellitus (DM) is one of the major causes of death in the world. There are two types of DM—type 1 DM and type 2 DM. Type 1 DM can only be treated by insulin injection whereas type 2 DM is commonly treated using anti-hyperglycemic agents. Despite its effectiveness in controlling blood glucose level, this therapeutic approach is not able to reduce the decline in the number of functional pancreatic β cells. MST1 is a strong pro-apoptotic kinase that is expressed in pancreatic β cells. It induces β cell death and impairs insulin secretion. Recently, a potent and specific inhibitor for MST1, called XMU-MP-1, was identified and characterized. We hypothesized that treatment with XMU-MP-1 would produce beneficial effects by improving the survival and function of the pancreatic β cells. We used INS-1 cells and STZ-induced diabetic mice as in vitro and in vivo models to test the effect of XMU-MP-1 treatment. We found that XMU-MP-1 inhibited MST1/2 activity in INS-1 cells. Moreover, treatment with XMU-MP-1 produced a beneficial effect in improving glucose tolerance in the STZ-induced diabetic mouse model. Histological analysis indicated that XMU-MP-1 increased the number of pancreatic β cells and enhanced Langerhans islet area in the severe diabetic mice. Overall, this study showed that MST1 could become a promising therapeutic target for diabetes mellitus.
Collapse
|
|
43
|
Ünver Saraydin S, Özdenoglu Kutlu B, Saraydın D. Effects of diabetes on apoptosis and mitosis in rat hippocampus. Biotech Histochem 2020; 96:460-467. [PMID: 32938250 DOI: 10.1080/10520295.2020.1818827] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Diabetes contributes to neurological dysfunction including peripheral nerve diseases, stroke and dementia. We investigated the effects of diabetes on apoptosis and mitosis in the hippocampal CA1 region. Rats were given diabetes by injection of streptozotocin (STZ). The mass and blood glucose levels of the rats were measured until day 7 of the experiment. The loss of mass index was approximately 10%, and the diabetogenic index was approximately 330% between nondiabetic and diabetic groups. We investigated caspase-3, caspase-7 and Ki 67 levels immunohistochemically for mitotic activity, the TUNEL method for apoptosis and GFAP for astrocyte cell density in the hippocampal CA1 region. We found that apoptotic cells and the number of astrocytes and mitotic activity in the diabetic group were increased significantly compared to controls. Diabetes stimulates apoptosis and promotes cell proliferation in the hippocampal CA1 region, which may impair its homeostasis and function.
Collapse
Affiliation(s)
- Serpil Ünver Saraydin
- Histology and Embryology Department, Medicine Faculty, Sivas Cumhuriyet University, Sivas, Turkey
| | - Berna Özdenoglu Kutlu
- Histology and Embryology Department, Medicine Faculty, Sivas Cumhuriyet University, Sivas, Turkey
| | - Dursun Saraydın
- Chemistry Department, Science Faculty, Sivas Cumhuriyet University, Sivas, Turkey
| |
Collapse
|
|
44
|
Berger C, Zdzieblo D. Glucose transporters in pancreatic islets. Pflugers Arch 2020; 472:1249-1272. [PMID: 32394191 PMCID: PMC7462922 DOI: 10.1007/s00424-020-02383-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023]
Abstract
The fine-tuning of glucose uptake mechanisms is rendered by various glucose transporters with distinct transport characteristics. In the pancreatic islet, facilitative diffusion glucose transporters (GLUTs), and sodium-glucose cotransporters (SGLTs) contribute to glucose uptake and represent important components in the glucose-stimulated hormone release from endocrine cells, therefore playing a crucial role in blood glucose homeostasis. This review summarizes the current knowledge about cell type-specific expression profiles as well as proven and putative functions of distinct GLUT and SGLT family members in the human and rodent pancreatic islet and further discusses their possible involvement in onset and progression of diabetes mellitus. In context of GLUTs, we focus on GLUT2, characterizing the main glucose transporter in insulin-secreting β-cells in rodents. In addition, we discuss recent data proposing that other GLUT family members, namely GLUT1 and GLUT3, render this task in humans. Finally, we summarize latest information about SGLT1 and SGLT2 as representatives of the SGLT family that have been reported to be expressed predominantly in the α-cell population with a suggested functional role in the regulation of glucagon release.
Collapse
Affiliation(s)
- Constantin Berger
- Tissue Engineering & Regenerative Medicine, University Hospital Würzburg, Röntgenring 11, 97070, Würzburg, Germany
| | - Daniela Zdzieblo
- Tissue Engineering & Regenerative Medicine, University Hospital Würzburg, Röntgenring 11, 97070, Würzburg, Germany.
- Fraunhofer Institute for Silicate Research (ISC), Translational Center Regenerative Therapies, Neunerplatz 2, 97082, Würzburg, Germany.
| |
Collapse
|
|
45
|
Uhlemeyer C, Müller N, Grieß K, Wessel C, Schlegel C, Kuboth J, Belgardt BF. ATM and P53 differentially regulate pancreatic beta cell survival in Ins1E cells. PLoS One 2020; 15:e0237669. [PMID: 32810137 PMCID: PMC7437460 DOI: 10.1371/journal.pone.0237669] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/30/2020] [Indexed: 01/09/2023] Open
Abstract
Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult.
Collapse
Affiliation(s)
- Celina Uhlemeyer
- Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Nadine Müller
- Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Kerstin Grieß
- Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Corinna Wessel
- Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Caroline Schlegel
- Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Jennifer Kuboth
- Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Bengt-Frederik Belgardt
- Institute for Vascular and Islet Cell Biology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- * E-mail:
| |
Collapse
|
|
46
|
Synthesis of 18F-labeled streptozotocin derivatives and an in-vivo kinetics study using positron emission tomography. Bioorg Med Chem Lett 2020; 30:127400. [PMID: 32738964 DOI: 10.1016/j.bmcl.2020.127400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 01/28/2023]
Abstract
Glucose transporter 2 (GLUT2) is involved in glucose uptake by hepatocytes, pancreatic beta cells, and absorptive cells in the intestine and proximal tubules in the kidney. Pancreatic GLUT2 also plays an important role in the mechanism of glucose-stimulated insulin secretion. In this study, novel Fluorine-18-labeled streptozotocin (STZ) derivatives were synthesized to serve as glycoside analogs for in-vivo GLUT2 imaging. Fluorine was introduced to hexyl groups at the 3'-positions of the compounds, and we aimed to synthesize compounds that were more stable than STZ. The nitroso derivatives exhibited relatively good stability during purification and purity analysis after radiosynthesis. We then evaluated the compounds in PET imaging and ex-vivo biodistribution studies. We observed high levels of radioactivity in the liver and kidney, which indicated accumulation in these organs within 5 min of administration. In contrast, the denitroso derivatives accumulated only in the kidney and bladder shortly after administration. Compounds with nitroso groups are thus expected to accumulate in GLUT2-expressing organs, and the presence of a nitroso group is essential for in-vivo GLUT2 imaging.
Collapse
|
|
47
|
Bisignano P, Lee MA, George A, Zuckerman DM, Grabe M, Rosenberg JM. A kinetic mechanism for enhanced selectivity of membrane transport. PLoS Comput Biol 2020; 16:e1007789. [PMID: 32614861 PMCID: PMC7331977 DOI: 10.1371/journal.pcbi.1007789] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 03/13/2020] [Indexed: 01/06/2023] Open
Abstract
Membrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from two different sides of the membrane to exchange substrates from the extracellular environment and the cytoplasm or from the cytoplasm and the intracellular matrix of the organelles (only in eukaryotes). In recent years, a number of high resolution structures have supported this general framework for a wide class of transport molecules, although additional states along the transport pathway are emerging as critically important. Given that substrate binding is often weak in order to enhance overall transport rates, there exists the distinct possibility that transporters may transport the incorrect substrate. This is certainly the case for many pharmaceutical compounds that are absorbed in the gut or cross the blood brain barrier through endogenous transporters. Docking studies on the bacterial sugar transporter vSGLT reveal that many highly toxic compounds are compatible with binding to the orthosteric site, further motivating the selective pressure for additional modes of selectivity. Motivated by recent work in which we observed failed substrate delivery in a molecular dynamics simulation where the energized ion still goes down its concentration gradient, we hypothesize that some transporters evolved to harness this 'slip' mechanism to increase substrate selectivity and reduce the uptake of toxic molecules. Here, we test this idea by constructing and exploring a kinetic transport model that includes a slip pathway. While slip reduces the overall productive flux, when coupled with a second toxic molecule that is more prone to slippage, the overall substrate selectivity dramatically increases, suppressing the accumulation of the incorrect compound. We show that the mathematical framework for increased substrate selectivity in our model is analogous to the classic proofreading mechanism originally proposed for tRNA synthase; however, because the transport cycle is reversible we identified conditions in which the selectivity is essentially infinite and incorrect substrates are exported from the cell in a 'detoxification' mode. The cellular consequences of proofreading and membrane slippage are discussed as well as the impact on future drug development.
Collapse
Affiliation(s)
- Paola Bisignano
- Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America
| | - Michael A. Lee
- Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America
| | - August George
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Daniel M. Zuckerman
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States of America
| | - Michael Grabe
- Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America
| | - John M. Rosenberg
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| |
Collapse
|
|
48
|
Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells. Antibiotics (Basel) 2020; 9:antibiotics9040182. [PMID: 32326389 PMCID: PMC7235802 DOI: 10.3390/antibiotics9040182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 03/31/2020] [Accepted: 04/10/2020] [Indexed: 01/26/2023] Open
Abstract
With the increasing resistance of bacteria to current antibiotics, novel compounds are urgently needed to treat bacterial infections. Streptozotocin (STZ) is a natural product that has broad-spectrum antibiotic activity, albeit with limited use because of its toxicity to pancreatic β cells. In an attempt to derivatize STZ through structural modification at the C3 position, we performed the synthesis of three novel STZ analogues by making use of our recently developed regioselective oxidation protocol. Keto-STZ (2) shows the highest inhibition of bacterial growth (minimum inhibitory concentration (MIC) and viability assays), but is also the most cytotoxic compound. Pre-sensitizing the bacteria with GlcNAc increased the antimicrobial effect, but did not result in complete killing. Interestingly, allo-STZ (3) revealed moderate concentration-dependent antimicrobial activity and no cytotoxicity towards β cells, and deoxy-STZ (4) showed no activity at all.
Collapse
|
|
49
|
SAYED N, ABDALLA O, KILANY O, DESSOUKI A, YOSHIDA T, SASAKI K, SHIMODA M. Effect of dapagliflozin alone and in combination with insulin in a rat model of type 1 diabetes. J Vet Med Sci 2020; 82:467-474. [PMID: 32161237 PMCID: PMC7192721 DOI: 10.1292/jvms.19-0450] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 02/12/2020] [Indexed: 11/22/2022] Open
Abstract
Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor; it reduces glucose reabsorption via the kidney and increases the glucose excretion in urine. This inhibitor functions through a unique insulin-independent mechanism, and is therefore a potential new approach for the treatment of hyperglycemia in patients with diabetes. In this study, we evaluated the effectiveness of the SGLT2 inhibitor, dapagliflozin, by using a rat model of type 1 diabetes. Type 1 diabetes was induced by a single intraperitoneal injection of 60 mg/kg streptozotocin (STZ). The STZ-induced rats showed marked hyperglycemia and other metabolic abnormalities. We clarified the hypoglycemic effect of the combination treatment of dapagliflozin with a low dose of insulin compared with dapagliflozin alone and insulin alone in 3-week and 8-week studies. Our results showed that dapagliflozin in combination with a low dose of insulin significantly lowered hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. Furthermore, the antioxidant status and body weight were improved. In contrast, treatment with dapagliflozin alone did not improve the blood glucose levels, lipid profile, antioxidant status, or body weight. These findings suggested that in type 1 diabetes, dapagliflozin was effective in combination with a low dose of insulin; however, the administration of dapagliflozin alone did not achieve a significant effect.
Collapse
Affiliation(s)
- Noha SAYED
- Laboratory of Veterinary Pharmacology, Department of
Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Tokyo
183-8509, Japan
- Clinical Pathology Department, Faculty of Veterinary
Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Osama ABDALLA
- Clinical Pathology Department, Faculty of Veterinary
Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Omnia KILANY
- Clinical Pathology Department, Faculty of Veterinary
Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Amina DESSOUKI
- Pathology Department, Faculty of Veterinary Medicine, Suez
Canal University, Ismailia 41522, Egypt
| | - Toshinori YOSHIDA
- Laboratory of Veterinary Pathology, Department of Veterinary
Medicine, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509,
Japan
| | - Kazuaki SASAKI
- Laboratory of Veterinary Pharmacology, Department of
Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Tokyo
183-8509, Japan
| | - Minoru SHIMODA
- Laboratory of Veterinary Pharmacology, Department of
Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Tokyo
183-8509, Japan
| |
Collapse
|
|
50
|
Shao T, Yu Q, Zhu T, Liu A, Gao X, Long X, Liu Z. Inulin from Jerusalem artichoke tubers alleviates hyperglycaemia in high-fat-diet-induced diabetes mice through the intestinal microflora improvement. Br J Nutr 2020; 123:308-318. [PMID: 31915077 PMCID: PMC7015883 DOI: 10.1017/s0007114519002332] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 01/01/2023]
Abstract
The rate of hyperglycaemia in people around the world is increasing at an alarming rate at present, and innovative methods of alleviating hyperglycaemia are needed. The effects of Jerusalem artichoke inulin on hyperglycaemia, liver-related genes and the intestinal microbiota in mice fed a high-fat diet (HFD) and treated with streptozotocin (STZ) to induce hyperglycaemia were investigated. Inulin-treated hyperglycaemic mice had decreased average daily food consumption, body weight, average daily water consumption and relative liver weight and blood concentrations of TAG, total cholesterol, HDL-cholesterol and fasting blood glucose. Liver-related gene expressions in hyperglycaemic (HFD-fed and STZ-treated) compared with control mice showed eighty-four differentially expressed genes (forty-nine up-regulated and thirty-five down-regulated). In contrast, hyperglycaemic mice treated with inulin had twenty-two differentially expressed genes compared with control ones. Using Illumina high-throughput sequencing technology, the rarefaction and the rank abundance curves as well as the α diversity indices showed the treatment-induced differences in bacterial diversity in intestine. The linear discriminant analysis of effect size showed that the inulin treatment improved intestinal microbiota; in particular, it significantly increased the number of Bacteroides in the intestine of mice. In conclusion, inulin is potentially an effective functional food for the prevention and/or treatment of hyperglycaemia.
Collapse
Affiliation(s)
- Tianyun Shao
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People’s Republic of China
| | - Qiuhong Yu
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People’s Republic of China
| | - Tingshuo Zhu
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People’s Republic of China
| | - Anhong Liu
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People’s Republic of China
| | - Xiumei Gao
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People’s Republic of China
| | - Xiaohua Long
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People’s Republic of China
| | - Zhaopu Liu
- College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People’s Republic of China
| |
Collapse
|