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Fu Y, Francés R, Monge C, Desterke C, Marchio A, Pineau P, Chang-Marchand Y, Mata-Garrido J. Metabolic and Epigenetic Mechanisms in Hepatoblastoma: Insights into Tumor Biology and Therapeutic Targets. Genes (Basel) 2024; 15:1358. [PMID: 39596558 PMCID: PMC11593527 DOI: 10.3390/genes15111358] [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: 10/01/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Hepatoblastoma, the most common pediatric liver malignancy, is characterized by significant molecular heterogeneity and poor prognosis in advanced stages. Recent studies highlight the importance of metabolic reprogramming and epigenetic dysregulation in hepatoblastoma pathogenesis. This review aims to explore the metabolic alterations and epigenetic mechanisms involved in hepatoblastoma and how these processes contribute to tumor progression and survival. METHODS Relevant literature on metabolic reprogramming, including enhanced glycolysis, mitochondrial dysfunction, and shifts in lipid and amino acid metabolism, as well as epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs, was reviewed. The interplay between these pathways and their potential as therapeutic targets were examined. RESULTS Hepatoblastoma exhibits metabolic shifts that support tumor growth and survival, alongside epigenetic changes that regulate gene expression and promote tumor progression. These pathways are interconnected, with metabolic changes influencing the epigenetic landscape and vice versa. CONCLUSIONS The dynamic interplay between metabolism and epigenetics in hepatoblastoma offers promising avenues for therapeutic intervention. Future research should focus on integrating metabolic and epigenetic therapies to improve patient outcomes, addressing current gaps in knowledge to develop more effective treatments.
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Affiliation(s)
- Yuanji Fu
- CNRS, INSERM, Institut Necker Enfants Malades, Université Paris Cité, 75015 Paris, France; (Y.F.); (Y.C.-M.)
| | - Raquel Francés
- Energy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, 75006 Paris, France;
| | - Claudia Monge
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75006 Paris, France; (C.M.); (A.M.); (P.P.)
| | - Christophe Desterke
- Faculté de Médecine du Kremlin Bicêtre, Université Paris-Sud, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France;
| | - Agnès Marchio
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75006 Paris, France; (C.M.); (A.M.); (P.P.)
| | - Pascal Pineau
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75006 Paris, France; (C.M.); (A.M.); (P.P.)
| | - Yunhua Chang-Marchand
- CNRS, INSERM, Institut Necker Enfants Malades, Université Paris Cité, 75015 Paris, France; (Y.F.); (Y.C.-M.)
| | - Jorge Mata-Garrido
- INSERM U993, Unité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, 75006 Paris, France; (C.M.); (A.M.); (P.P.)
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Suda T, Yokoo T, Kanefuji T, Kamimura K, Zhang G, Liu D. Hydrodynamic Delivery: Characteristics, Applications, and Technological Advances. Pharmaceutics 2023; 15:1111. [PMID: 37111597 PMCID: PMC10141091 DOI: 10.3390/pharmaceutics15041111] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/20/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023] Open
Abstract
The principle of hydrodynamic delivery was initially used to develop a method for the delivery of plasmids into mouse hepatocytes through tail vein injection and has been expanded for use in the delivery of various biologically active materials to cells in various organs in a variety of animal species through systemic or local injection, resulting in significant advances in new applications and technological development. The development of regional hydrodynamic delivery directly supports successful gene delivery in large animals, including humans. This review summarizes the fundamentals of hydrodynamic delivery and the progress that has been made in its application. Recent progress in this field offers tantalizing prospects for the development of a new generation of technologies for broader application of hydrodynamic delivery.
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Affiliation(s)
- Takeshi Suda
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma 949-7302, Niigata, Japan
| | - Takeshi Yokoo
- Department of Preemptive Medicine for Digestive Diseases and Healthy Active Life, School of Medicine, Niigata University, Niigata 951-8510, Niigata, Japan
| | - Tsutomu Kanefuji
- Department of Gastroenterology and Hepatology, Tsubame Rosai Hospital, Tsubame 959-1228, Niigata, Japan
| | - Kenya Kamimura
- Department of General Medicine, School of Medicine, Niigata University, Niigata 951-8510, Niigata, Japan
| | - Guisheng Zhang
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Dexi Liu
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
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3
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Banerjee A, Singh J. Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies. Bioeng Transl Med 2020; 5:e10150. [PMID: 32440558 PMCID: PMC7237149 DOI: 10.1002/btm2.10150] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/07/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
Obesity-associated type 2 diabetes mellitus (T2DM) is characterized by low-grade chronic systemic inflammation that arises primarily from the white adipose tissue. The interplay between various adipose tissue-derived chemokines drives insulin resistance in T2DM and has therefore become a subject of rigorous investigation. The adipocytokines strongly associated with glucose homeostasis include tumor necrosis factor-α, various interleukins, monocyte chemoattractant protein-1, adiponectin, and leptin, among others. Remodeling the adipose tissue inflammasome in obesity-associated T2DM is likely to treat the underlying cause of the disease and bring significant therapeutic benefit. Various strategies have been adopted or are being investigated to modulate the serum/tissue levels of pro- and anti-inflammatory adipocytokines to improve glucose homeostasis in T2DM. These include use of small molecule agonists/inhibitors, mimetics, antibodies, gene therapy, and other novel formulations. Here, we discuss adipocytokines that are strongly associated with insulin activity and therapies that are under investigation for modulation of their levels in the treatment of T2DM.
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Affiliation(s)
- Amrita Banerjee
- Department of Pharmaceutical SciencesNorth Dakota State UniversityFargoNorth Dakota
| | - Jagdish Singh
- Department of Pharmaceutical SciencesNorth Dakota State UniversityFargoNorth Dakota
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Dai C, Wang M, Zhao L, Xu C, Huang J, Fan Z. Liver gene transfection by retrograde intrabiliary infusion facilitated by temporary biliary obstruction. J Gene Med 2019; 22:e3144. [PMID: 31742830 DOI: 10.1002/jgm.3144] [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: 06/22/2019] [Revised: 11/13/2019] [Accepted: 11/14/2019] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The hepatobiliary tract may be a valuable administration site for gene delivery. We demonstrated the role of temporary biliary obstruction for gene transfection by retrograde intrabiliary infusion. METHODS Male Sprague-Dawley rats received intrabiliary infusion of luciferase plasmid via an artificial common bile duct, with temporary biliary obstruction for 0 minutes (NO group), 30 minutes (30 min group) and 24 hours (24 h group), respectively (n = 4 for each group). Gene expression levels were evaluated by luciferase bioluminescence on postoperative days (POD) 1, 2 and 7. Serum and livers were collected on POD 1 and 14 for liver biochemistry, hematoxylin and eosin staining, and immunohistochemistry. RESULTS On POD 1, luciferase chemoluminescence was significantly higher in the 24 h group than in the NO group (p = 0.002) and the 30 min group (p = 0.002). However, it decreased rapidly after reversal of the obstruction in the 24 h group (POD 1 versus POD 2, p = 0.002; POD 1 versus POD 7, p = 0.002). Liver biochemistry was changed on POD 1, but no significant differences were detected after 14 days of recovery (p > 0.05). Similar histological changes were found in the three groups, with no unwanted proliferation of biliary epithelial cells. The obstruction did not cause serious liver damage. CONCLUSIONS Temporary biliary obstruction for 24 hours facilitated the safe, feasible and effective transfection of plasmid DNA into the liver via the hepatobiliary tract. In the future, endoscopic retrograde cholangiopancreatography and its dilation balloon could be used to create biliary obstruction and allow the direct gene delivery into the liver. More research is necessary for achieving stable gene expression, as well as in terms of weighing its benefits against potential complications.
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Affiliation(s)
- Chenguang Dai
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Min Wang
- Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Lili Zhao
- Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jin Huang
- Department of Gastroenterology, The Changzhou Second People's Hospital, Changzhou, China.,Division of Digestive Diseases, the People's Hospital of Ma Anshan, Ma Anshan, China
| | - Zhining Fan
- Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Corbin KD, Driscoll KA, Pratley RE, Smith SR, Maahs DM, Mayer-Davis EJ. Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact, and Mechanisms. Endocr Rev 2018; 39:629-663. [PMID: 30060120 DOI: 10.1210/er.2017-00191] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 06/21/2018] [Indexed: 02/07/2023]
Abstract
There has been an alarming increase in the prevalence of obesity in people with type 1 diabetes in recent years. Although obesity has long been recognized as a major risk factor for the development of type 2 diabetes and a catalyst for complications, much less is known about the role of obesity in the initiation and pathogenesis of type 1 diabetes. Emerging evidence suggests that obesity contributes to insulin resistance, dyslipidemia, and cardiometabolic complications in type 1 diabetes. Unique therapeutic strategies may be required to address these comorbidities within the context of intensive insulin therapy, which promotes weight gain. There is an urgent need for clinical guidelines for the prevention and management of obesity in type 1 diabetes. The development of these recommendations will require a transdisciplinary research strategy addressing metabolism, molecular mechanisms, lifestyle, neuropsychology, and novel therapeutics. In this review, the prevalence, clinical impact, energy balance physiology, and potential mechanisms of obesity in type 1 diabetes are described, with a special focus on the substantial gaps in knowledge in this field. Our goal is to provide a framework for the evidence base needed to develop type 1 diabetes-specific weight management recommendations that account for the competing outcomes of glycemic control and weight management.
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Affiliation(s)
- Karen D Corbin
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, Florida
| | - Kimberly A Driscoll
- Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, Colorado.,Barbara Davis Center for Diabetes, Aurora, Colorado
| | - Richard E Pratley
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, Florida
| | - Steven R Smith
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, Florida
| | - David M Maahs
- Division of Pediatric Endocrinology, Department of Pediatrics, Stanford University, Stanford, California
| | - Elizabeth J Mayer-Davis
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.,Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Patel VJ, Joharapurkar AA, Kshirsagar SG, Sutariya BK, Patel MS, Patel HM, Pandey DK, Bahekar RH, Jain MR. Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus. World J Diabetes 2018; 9:80-91. [PMID: 29988851 PMCID: PMC6033704 DOI: 10.4239/wjd.v9.i6.80] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 05/10/2018] [Accepted: 05/15/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes (SREBP-1C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation (CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-α. Coagonist treatment reduced expression of inflammatory (TNF-α, MCP-1, and MMP-9) and pro-fibrotic (TGF-β, COL1A1, and α-SMA) genes and also improved histological derangement in renal tissue. CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.
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Affiliation(s)
- Vishal J Patel
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Amit A Joharapurkar
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Samadhan G Kshirsagar
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Brijesh K Sutariya
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Maulik S Patel
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Hiren M Patel
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Dheerendra K Pandey
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Rajesh H Bahekar
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
| | - Mukul R Jain
- Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
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Translational Advances of Hydrofection by Hydrodynamic Injection. Genes (Basel) 2018; 9:genes9030136. [PMID: 29494564 PMCID: PMC5867857 DOI: 10.3390/genes9030136] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/20/2018] [Accepted: 02/21/2018] [Indexed: 12/11/2022] Open
Abstract
Hydrodynamic gene delivery has proven to be a safe and efficient procedure for gene transfer, able to mediate, in murine model, therapeutic levels of proteins encoded by the transfected gene. In different disease models and targeting distinct organs, it has been demonstrated to revert the pathologic symptoms and signs. The therapeutic potential of hydrofection led different groups to work on the clinical translation of the procedure. In order to prevent the hemodynamic side effects derived from the rapid injection of a large volume, the conditions had to be moderated to make them compatible with its use in mid-size animal models such as rat, hamster and rabbit and large animals as dog, pig and primates. Despite the different approaches performed to adapt the conditions of gene delivery, the results obtained in any of these mid-size and large animals have been poorer than those obtained in murine model. Among these different strategies to reduce the volume employed, the most effective one has been to exclude the vasculature of the target organ and inject the solution directly. This procedure has permitted, by catheterization and surgical procedures in large animals, achieving protein expression levels in tissue close to those achieved in gold standard models. These promising results and the possibility of employing these strategies to transfer gene constructs able to edit genes, such as CRISPR, have renewed the clinical interest of this procedure of gene transfer. In order to translate the hydrodynamic gene delivery to human use, it is demanding the standardization of the procedure conditions and the molecular parameters of evaluation in order to be able to compare the results and establish a homogeneous manner of expressing the data obtained, as ‘classic’ drugs.
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Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis. Sci Rep 2017; 7:8436. [PMID: 28814745 PMCID: PMC5559446 DOI: 10.1038/s41598-017-08998-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 07/20/2017] [Indexed: 01/04/2023] Open
Abstract
Despite the associations between diabetic complications and vascular endothelial dysfunction, a direct therapeutic method targeting endothelial dysfunction remains poorly characterized. We have previously shown that chemical inhibition of G-protein-coupled receptor kinase 2 (GRK2) slightly enhances insulin sensitivity and reduces endothelial dysfunction in type 2 diabetic mice. In this study, we identified GRK2 as a novel therapeutic target of diabetic endothelial dysfunction and investigated the effect on diabetic endothelial dysfunction through the systemic administration of GRK2 siRNA using a hydrodynamic-based procedure, resulting in suppression of increased GRK2 protein levels in the liver. Suppressed GRK2 levels in the liver markedly improved glucose homeostasis, as well as improved the impaired endothelial Akt/eNOS-dependent signal activation (insulin-stimulated phosphorylation of Akt and eNOS) and vascular responses (clonidine-induced and insulin-induced endothelial-dependent relaxation response and phenylephrine-induced contractile response) in type 2 diabetic aortas. Interestingly, insulin-stimulated Akt/eNOS signaling was increased only by normalizing the glucose concentration in human umbilical vein endothelial cells (HUVECs) with GRK2 overexpression, suggesting of an important role of hepatic GRK2. Our results clarified the relationship among hepatic GRK2, glucose homeostasis, and vascular endothelial function. Liver-targeting GRK2 siRNA delivery represents a novel therapeutic tool to restore glucose homeostasis and reduce endothelial dysfunction.
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Huang CW, Hong TW, Wang YJ, Chen KC, Pei JC, Chuang TY, Lai WS, Tsai SH, Chu R, Chen WC, Sheen LY, Takahashi S, Ding ST, Shen TL. Ophiocordyceps formosana improves hyperglycemia and depression-like behavior in an STZ-induced diabetic mouse model. Altern Ther Health Med 2016; 16:310. [PMID: 27553852 PMCID: PMC4995616 DOI: 10.1186/s12906-016-1278-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 08/11/2016] [Indexed: 12/27/2022]
Abstract
Background A newly defined Cordyceps species, Ophiocordyceps formosana (O. formosana) has been implicated in multitudinous bioactivities, including lowering glucose and cholesterol levels and modulating the immune system. However, few literatures demonstrate sufficient evidence to support these proposed functions. Although the use of Cordyceps spp. has been previously addressed to improve insulin insensitivity and improve the detrimental symptoms of depression; its mechanistic nature remains unsettled. Herein, we reveal the effects of O. formosana in ameliorating hyperglycemia accompanied with depression. Methods Diabetes was induced in mice by employing streptozotocin(STZ), a chemical that is toxic to insulin-producing β cells of the pancreas. These streptozotocin (STZ)-induced diabetic mice showed combined symptoms of hyperglycemia and depressive behaviors. Twenty-four STZ-induced mice were randomly divided into 3 groups subjected to oral gavage with 100 μL solution of either PBS or 25 mg/mL Ophiocordyceps formosana extract (OFE) or 2 mg/mL rosiglitazone (Rosi, positive control group). Treatments were administered once per day for 28 days. An additional 6 mice without STZ induction were treated with PBS to serve as the control group. Insulin sensitivity was measured by a glucose tolerance test and levels of adiponectin in plasma and adipose tissue were also quantified. Behavioral tests were conducted and levels of monoamines in various brain regions relating to depression were evaluated. Results HPLC analysis uncovered three major constituents, adenosine, D-mannitol and cordycepin, within O. formosana similar to other prestigious medicinal Cordyceps spp.. STZ-induced diabetic mice demonstrated decreased body weight and subcutaneous adipose tissue, while these symptoms were recovered in mice receiving OFE treatment. Moreover, the OFE group displayed improved insulin sensitivity and elevated adiponectin within the plasma and adipose tissue. The anti-depressive effect of OFE was observed in various depression-related behavior tests. Concurrently, neurotransmitters, like 5-HT and dopamine in the frontal cortex, striatum and hippocampus were found to be up-regulated in OFE-treated mice. Conclusions Our findings illustrated, for the first time, the medicinal merits of O. formosana on Type I diabetes and hyperglycemia-induced depression. OFE were found to promote the expression of adiponectin, which is an adipokine involved in insulin sensitivity and hold anti-depressive effects. In addition, OFE administration also displayed altered levels of neurotransmitters in certain brain regions that may have contributed to its anti-depressive effect. Collectively, this current study provided insights to the potential therapeutic effects of O. formosana extracts in regards to hyperglycemia and its depressive complications.
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Kamimura K, Suda T, Kanefuji T, Yokoo T, Abe H, Kobayashi Y, Aoyagi Y, Liu D. Image-Guided Hydrodynamic Gene Delivery to the Liver: Toward Clinical Applications. GENE THERAPY AND CELL THERAPY THROUGH THE LIVER 2016:85-92. [DOI: 10.1007/978-4-431-55666-4_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kamimura K, Yokoo T, Abe H, Kobayashi Y, Ogawa K, Shinagawa Y, Inoue R, Terai S. Image-Guided Hydrodynamic Gene Delivery: Current Status and Future Directions. Pharmaceutics 2015; 7:213-223. [PMID: 26308044 PMCID: PMC4588196 DOI: 10.3390/pharmaceutics7030213] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/13/2015] [Accepted: 08/18/2015] [Indexed: 12/13/2022] Open
Abstract
Hydrodynamics-based delivery has been used as an experimental tool to express transgene in small animals. This in vivo gene transfer method is useful for functional analysis of genetic elements, therapeutic effect of oligonucleotides, and cancer cells to establish the metastatic cancer animal model for experimental research. Recent progress in the development of image-guided procedure for hydrodynamics-based gene delivery in large animals directly supports the clinical applicability of this technique. This review summarizes the current status and recent progress in the development of hydrodynamics-based gene delivery and discusses the future directions for its clinical application.
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Affiliation(s)
- Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Yuji Kobayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Kohei Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Yoko Shinagawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Ryosuke Inoue
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
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Combs TP, Snell-Bergeon JK, Maahs DM, Bergman BC, Lamarche M, Iberkleid L, AbdelBaky O, Tisch R, Scherer PE, Marliss EB. Adiponectin-SOGA Dissociation in Type 1 Diabetes. J Clin Endocrinol Metab 2015; 100:E1065-73. [PMID: 26052615 PMCID: PMC4524989 DOI: 10.1210/jc.2015-1275] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
CONTEXT Circulating adiponectin is elevated in human type 1 diabetes (T1D) and nonobese diabetic (NOD) mice without the expected indications of adiponectin action, consistent with tissue resistance. OBJECTIVE Adiponectin stimulates hepatocyte production of the suppressor of glucose from autophagy (SOGA), a protein that inhibits glucose production. We postulated that due to tissue resistance, the elevation of adiponectin in T1D should fail to increase the levels of a surrogate marker for liver SOGA, the circulating C-terminal SOGA fragment. MAIN OUTCOME MEASURES Liver and plasma SOGA were measured in NOD mice (n = 12) by Western blot. Serum adiponectin and SOGA were measured in T1D and control (Ctrl) participants undergoing a three-stage insulin clamp for the Coronary Artery Calcification in T1D study (n = 20). Glucose turnover was measured using 6,6[(2)H2]glucose (n = 12). RESULTS In diabetic NOD mice, the 13%-29% decrease of liver SOGA (P = .003) and the 30%-37% reduction of circulating SOGA (P < .001) were correlated (r = 0.826; P = .001). In T1D serum, adiponectin was 50%-60% higher than Ctrl, SOGA was 30%-50% lower and insulin was 3-fold higher (P < .05). At the low insulin infusion rate (4 mU/m(2)·min), the resulting glucose appearance correlated negatively with adiponectin in T1D (r = -0.985, P = .002) and SOGA in Ctrl and T1D (r = -0.837, P = .001). Glucose disappearance correlated with adiponectin in Ctrl (r = -0.757, P = .049) and SOGA in Ctrl and T1D (r = -0.709, P = .010). At 40 mU/m(2)·min, the lowered glucose appearance was similar in Ctrl and T1D. Glucose disappearance increased only in Ctrl (P = .005), requiring greater glucose infusion to maintain euglycemia (8.58 ± 1.29 vs 3.09 ± 0.87 mg/kg·min; P = .009). CONCLUSIONS The correlation between liver and plasma SOGA in NOD mice supports the use of the latter as surrogate marker for liver concentration. Reduced SOGA in diabetic NOD mice suggests resistance to adiponectin. The dissociation between adiponectin and SOGA in T1D raises the possibility that restoring adiponectin signaling and SOGA might improve the metabolic response to insulin therapy.
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Affiliation(s)
- Terry P Combs
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Janet K Snell-Bergeon
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - David M Maahs
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Bryan C Bergman
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Marie Lamarche
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Laura Iberkleid
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Omar AbdelBaky
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Roland Tisch
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Philipp E Scherer
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
| | - Errol B Marliss
- Department of Medicine (T.P.C., L.I., O.A.), Department of Microbiology and Immunology (R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Crabtree Nutrition Laboratories (T.P.C., M.L., E.B.M.), Department of Medicine, McGill University, Montréal, Québec, Canada H4A 3J1; Barbara Davis Center for Childhood Diabetes (J.K.S.-B., D.M.M., B.C.B.), Department of Medicine, University of Colorado, Anschutz Medical Campus, Denver, Colorado 80045; and Touchstone Diabetes Center (P.E.S.), Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
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Gunawardana SC, Piston DW. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab 2015; 308:E1043-55. [PMID: 25898954 PMCID: PMC4469812 DOI: 10.1152/ajpendo.00570.2014] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 04/11/2015] [Indexed: 02/07/2023]
Abstract
Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and long-lasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulin-like growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium.
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Affiliation(s)
- Subhadra C Gunawardana
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - David W Piston
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
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14
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Abstract
Hydrodynamic delivery (HD) is a broadly used procedure for DNA and RNA delivery in rodents, serving as a powerful tool for gene/protein drug discovery, gene function analysis, target validation, and identification of elements in regulating gene expression in vivo. HD involves a pressurized injection of a large volume of solution into a vasculature. New procedures are being developed to satisfy the need for a safe and efficient gene delivery in clinic. Here, we summarize the fundamentals of HD, its applications, and future perspectives for clinical use.
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Affiliation(s)
- Takeshi Suda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Dexi Liu
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, School of Pharmacy, Athens, GA, USA
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15
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Orally and Topically AdministeredSparassis crispa(Hanabiratake) Improved Healing of Skin Wounds in Mice with Streptozotocin-Induced Diabetes. Biosci Biotechnol Biochem 2014; 77:1303-5. [DOI: 10.1271/bbb.121016] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Stanford KI, Goodyear LJ. The therapeutic potential of brown adipose tissue. Hepatobiliary Surg Nutr 2014; 2:286-7. [PMID: 24570961 DOI: 10.3978/j.issn.2304-3881.2013.09.02] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Accepted: 09/11/2013] [Indexed: 01/13/2023]
Affiliation(s)
- Kristin I Stanford
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
| | - Laurie J Goodyear
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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17
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Gao M, Tong Y, Gao X, Yao W. PEGylation-aided refolding of globular adiponectin. World J Microbiol Biotechnol 2013; 29:1525-30. [PMID: 23512209 DOI: 10.1007/s11274-013-1312-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 03/07/2013] [Indexed: 11/25/2022]
Abstract
Globular adiponectin (GAD) as the active domain of adiponectin is a promising candidate for anti-diabetic drug development. The recombinant production of GAD in Escherichia coli, however, is difficult because it is mainly expressed as inclusion bodies which need to be refolded to regain function. In this study we developed a novel method for refolding of GAD with a high efficiency by using polyethylene glycol (PEG) conjugation. An artificially designed DNA sequence encoding for GAD was synthesized and inserted into the pET28a vector to construct an expression plasmid which was thereafter transformed into E. coli BL21 (DE3) host cells for heterologous expression. After bacterial cell culture employing auto-induction medium, the inclusion bodies were collected, washed and dissolved in guanidine hydrochloride before PEG conjugation. Then the PEG-conjugated GAD was refolded by dialysis and purified by two steps of chromatography. The refolded conjugate showed a marked glucose-lowering activity in mice, demonstrating that it had been successfully refolded. As a convenient method, PEGylation-aided refolding could also be tested on other proteins to explore its suitability.
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Affiliation(s)
- Mingming Gao
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China
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Du WH, Peng SM, Liu ZH, Shi L, Tan LF, Zou XQ. Hypoglycemic effect of the water extract of Pu-erh tea. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:10126-10132. [PMID: 22957968 DOI: 10.1021/jf302426w] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The water extraction and composition of pu-erh tea, as well as the hypoglycemic effect of the water extract of pu-erh tea (WEPT) in vivo and in vitro, are reported to investigate its hypoglycemic effect on diabetes. High-performance liquid chromatography and colorimetric methods are used to analyze the tea catechins, caffeine, polyphenols, amino acids, and polysaccharides of the WEPT. The effect of the WEPT on glucose uptake by cultured HepG2 cells and the inhibition effect of rat intestinal sucrase, maltase, and porcine pancreatic amylase are determined in vitro. Then, the blood glucose and insulin levels of intragastrically administered WEPT on fasting and oral glucose tolerance test (OGTT) using type 2 diabetic db/db (BKS.Cg-m +/+ Lepr(db)/J) mice are determined in vivo. The results showed that the WEPT dose-dependently and significantly increased glucose uptake by HepG2 cells and inhibited rat intestinal sucrase, maltase, and porcine pancreatic amylase activity. The WEPT intragastrically given for 4 weeks suppressed the increase in blood insulin and glucose levels of db/db mice fasted overnight. In OGTT, the WEPT improved impaired glucose tolerance and ameliorated retarded insulin response at 60 and 120 min in db/db mice. These results suggest that the WEPT has beneficial effects on glucose homeostasis in type 2 diabetes and in amendment of insulin resistance.
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Affiliation(s)
- Wan-hong Du
- Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University , Xiangtan 411105, Hunan, People's Republic of China
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Gunawardana SC. Therapeutic value of brown adipose tissue: Correcting metabolic disease through generating healthy fat. Adipocyte 2012; 1:250-255. [PMID: 23700541 PMCID: PMC3609108 DOI: 10.4161/adip.21042] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Brown adipose tissue (BAT), an important endocrine organ long known for thermogenesis and energy consumption, has received much attention in recent years for its potential to combat obesity. In general, BAT can enhance metabolism and improve overall health. Our recent work demonstrates the ability of embryonic BAT transplants to correct type 1 diabetes (T1D) without insulin, via mechanisms somewhat different from those involved in BAT-associated weight loss. BAT transplants seem to reverse T1D by decreasing inflammation and increasing functionality in the surrounding white adipose tissue (WAT), thereby enabling it to secrete hypoglycemic adipokines, which compensate for the function of insulin. Thus BAT can transform unhealthy WAT to a healthy status, sufficient to replace the function of endocrine pancreas and establish insulin-independent glycemic regulation. Several studies, including ours, demonstrate the remarkable ability of BAT to correct metabolic disorders and hint at its beneficial effects on inflammation. Hence, addition of more BAT to the body, through transplantation or stimulating regeneration, may well be the therapy of the future for the simple correction of numerous diseases.
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Abstract
Type 1 diabetes (T1D) is a serious disease with increasing incidence worldwide, with fatal consequences if untreated. Traditional therapies require direct or indirect insulin replacement, which involves numerous limitations and complications. While insulin is the major regulator of blood glucose, recent reports demonstrate the ability of several extra-pancreatic hormones to decrease blood glucose and improve metabolic homeostasis. Such hormones mainly include adipokines originating from adipose tissue (AT), while specific factors from the gut and liver also contribute to glucose homeostasis. Correction of T1D with adipokines is progressively becoming a realistic option, with the potential to overcome many problems associated with insulin replacement. Several recent studies demonstrate insulin-independent reversal or amelioration of T1D through administration of specific adipokines. Our recent work demonstrates the ability of healthy AT to compensate for the function of endocrine pancreas in long-term correction of T1D. This review discusses the potential of AT-related therapies for T1D as viable alternatives to insulin replacement.
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Affiliation(s)
- Subhadra C Gunawardana
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Abstract
BACKGROUND AND DESIGN Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance. METHODS AND RESULTS The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high-molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins. CONCLUSION Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity.
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Abstract
Current therapies for type 1 diabetes (T1D) involve insulin replacement or transplantation of insulin-secreting tissue, both of which suffer from numerous limitations and complications. Here, we show that subcutaneous transplants of embryonic brown adipose tissue (BAT) can correct T1D in streptozotocin-treated mice (both immune competent and immune deficient) with severely impaired glucose tolerance and significant loss of adipose tissue. BAT transplants result in euglycemia, normalized glucose tolerance, reduced tissue inflammation, and reversal of clinical diabetes markers such as polyuria, polydipsia, and polyphagia. These effects are independent of insulin but correlate with recovery of the animals' white adipose tissue. BAT transplants lead to significant increases in adiponectin and leptin, but with levels that are static and not responsive to glucose. Pharmacological blockade of the insulin receptor in BAT transplant mice leads to impaired glucose tolerance, similar to what is seen in nondiabetic animals, indicating that insulin receptor activity plays a role in the reversal of diabetes. One possible candidate for activating the insulin receptor is IGF-1, whose levels are also significantly elevated in BAT transplant mice. Thus, we propose that the combined action of multiple adipokines establishes a new equilibrium in the animal that allows for chronic glycemic control without insulin.
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Affiliation(s)
- Subhadra C Gunawardana
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
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Lee WH, Lin RJ, Lin SY, Chen YC, Lin HM, Liang YC. Osthole enhances glucose uptake through activation of AMP-activated protein kinase in skeletal muscle cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2011; 59:12874-12881. [PMID: 22098542 DOI: 10.1021/jf2036559] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. Activation of AMPK in skeletal muscles, the liver, and adipose tissues results in a favorable metabolic milieu for preventing and treating type 2 diabetes, i.e., decreased levels of circulating glucose, plasma lipids, and ectopic fat accumulation and enhanced insulin sensitivity. Osthole was extracted from a Chinese herbal medicine, and we found that it had glucose lowering activity in our previous study. However, the detailed glucose lowering mechanisms of osthole are still unclear. In this study, we used skeletal muscle cells to examine the underlying molecular mechanisms of osthole's glucose lowering activity. A Western blot analysis revealed that osthole significantly induced phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). Next, we found that osthole significantly increased the level of translocation of glucose transporter 4 (GLUT4) to plasma membranes and glucose uptake in a dose-dependent manner. Osthole-induced glucose uptake was reversed by treatment with Compound C, an AMPK inhibitor, suggesting that osthole-induced glucose uptake was mediated in an AMPK-dependent manner. The increase in the AMP:ATP ratio was involved in osthole's activation of AMPK. Finally, we found that osthole counteracted hyperglycemia in mice with streptozotocin-induced diabetes. These results suggest that the increase in the AMP:ATP ratio by osthole triggered activation of the AMPK signaling pathway and led to increases in plasma membrane GLUT4 content and glucose uptake level. Therefore, osthole might have potential as an antidiabetic agent for treating diabetes.
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Affiliation(s)
- Wei-Hwa Lee
- Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
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Garekani ET, Mohebbi H, Kraemer RR, Fathi R. Exercise training intensity/volume affects plasma and tissue adiponectin concentrations in the male rat. Peptides 2011; 32:1008-12. [PMID: 21291933 DOI: 10.1016/j.peptides.2011.01.027] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Revised: 01/20/2011] [Accepted: 01/21/2011] [Indexed: 01/05/2023]
Abstract
The objective of the study was to determine the effects of exercise training intensity/volume on plasma total and high molecular weight (HMW) adiponectin and tissue total adiponectin concentrations. Thirty-two, eight week-old male Wistar rats (185 ± 5g) were randomly assigned to one of four groups: high intensity (HI: 34 m/min ∼%80-%85 VO(2)max), moderate intensity (MI: 28 m/min ∼%70-%75 VO(2)max), low intensity (LI: 20 m/min ∼ %50-%55 VO(2)max), and sedentary control (SED). Experimental groups completed a 12-week exercise program of treadmill running at 0° slope, 1h/day, 5 days/week. Since frequency and duration of exercise were identical among training groups, the volume of training was highest in the HI group followed by the MI and LI groups. Compared with SED animals, fasting plasma total and HMW adiponectin and adipose tissue total adiponectin concentrations were significantly higher in the HI and MI groups, but total adiponectin concentrations in liver and soleus muscle were not significantly lower than the SED rats. There were significantly lower plasma total testosterone levels in the HI group vs. SED group. Plasma total and HMW adiponectin were negatively correlated with HOMA-IR and insulin whereas total adiponectin was inversely related to TNF-α and HMW adiponectin was negatively correlated with total testosterone. Thus, data suggest there is a dose effect for exercise training intensity and accompanying volume for the adaptation of adipose tissue and circulating total and HMW adiponectin concentrations, whereas the changes of adiponectin concentrations in skeletal muscle and liver tissue may depend on the body's energy balance in the recovery period.
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Affiliation(s)
- Elahe Talebi Garekani
- Department of Physical Education and Sport Sciences, University of Mazandaran, Babolsar, Iran
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Henein HY, Younan SM, Rashed LA, Fakhry A. Effect of adrenomedullin gene delivery on insulin resistance in type 2 diabetic rats. J Adv Res 2011. [DOI: 10.1016/j.jare.2010.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Nan MH, Park JS, Myung CS. Construction of adiponectin-encoding plasmid DNA and gene therapy of non-obese type 2 diabetes mellitus. J Drug Target 2010; 18:67-77. [PMID: 19708766 DOI: 10.3109/10611860903225719] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Adiponectin (ADN), an insulin-sensitizing adipokine, stimulates glucose uptake, inhibits gluconeogenesis, and plays an important role in improving insulin sensitivity. Since blood levels of ADN are low in type 2 diabetes mellitus (DM), this study was designed to investigate the therapeutic effectiveness of increasing the ADN level through injection of plasmid DNA encoding ADN in type 2 DM. A non-obese type 2 DM mouse model was established via combined administration of streptozotocin with nicotinamide and exhibited significantly higher plasma glucose concentration and insulin resistance compared with normal controls according to oral glucose tolerance and insulin challenge tests. Plasmid DNA encoding mouse ADN from differentiated NIH3T3 adipocytes was constructed in pVAX1 (pVAX/ADN). Transfection of pVAX/ADN into various cell lines including HeLa, HT22, HEK293, HepG2, and SK-Hep1 cells, increased ADN mRNA expression levels in a dose-dependent manner. The administration of pVAX/ADN into non-obese type 2 DM mice via tail vein significantly increased the blood level of ADN and decreased the plasma glucose concentration. Moreover, the parameters related to insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) were significantly improved. These results suggest that ADN gene therapy could be a clinically effective tool for the treatment of type 2 DM.
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Affiliation(s)
- Mei Hua Nan
- Department of Pharmacology, Chungnam National University College of Pharmacy, Yuseong-gu, Daejeon 305-764, Republic of Korea
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Beige J, Heipmann K, Stumvoll M, Körner A, Kratzsch J. Paradoxical role for adiponectin in chronic renal diseases? An example of reverse epidemiology. Expert Opin Ther Targets 2008; 13:163-73. [DOI: 10.1517/14728220802658481] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Niu L, Xu YC, Xie HY, Dai Z, Tang HQ. Expression of human insulin gene wrapped with chitosan nanoparticles in NIH3T3 cells and diabetic rats. Acta Pharmacol Sin 2008; 29:1342-9. [PMID: 18954529 DOI: 10.1111/j.1745-7254.2008.00888.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AIM To study the expression of human insulin gene wrapped with chitosan nanoparticles in NIH3T3 cells and diabetic rats. METHODS pCMV.Ins, an expression plasmid of the human insulin gene, was constructed. In total, 100 microg pCMV.Ins wrapped with chitosan nanoparticles (chitosan-pCMV.Ins) was transfected to NIH3T3 cells and diabetes rats through lavage and coloclysis, respectively. The transfected cells were grown in Dulbecco's modified Eagle's medium, containing G418, for 72 h after transfection. The clones were selected and continued to grow in G418 medium for 24 d. The expression of human insulin was detected by immunohistochemistry. Human insulin in the culture medium of transfected cells was measured. Fasting blood glucose and plasma human insulin of diabetic rats were measured for 5 d after transfection. RT-PCR and Western blotting were performed to confirm the expression of the human insulin gene in diabetic rats. RESULTS Approximately 10% of NIH3T3 cells transfected by chitosan-pCMV.Ins expressed human insulin. Human insulin in the culture medium of NIH3T3 cells transfected by chitosan-pCMV.Ins significantly increased compared with that of the control group (P<0.01). Fasting blood glucose levels of the lavage group and the coloclysis group decreased significantly in 5 d (P<0.01) in comparison, while plasma insulin levels were much higher (P<0.01). The human insulin gene mRNA and human insulin were only detected in the lavage and the coloclysis groups. CONCLUSION The human insulin gene can be transfected and expressed successfully by chitosan- pCMV.Ins in NIH3T3 cells and diabetes rats, which indicates that chitosan is a promising, non-viral vector for gene expression.
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Affiliation(s)
- Li Niu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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Niu L, Xu YC, Dai Z, Tang HQ. Gene therapy for type 1 diabetes mellitus in rats by gastrointestinal administration of chitosan nanoparticles containing human insulin gene. World J Gastroenterol 2008; 14:4209-15. [PMID: 18636668 PMCID: PMC2725384 DOI: 10.3748/wjg.14.4209] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression of human insulin gene in gastrointestinal tracts of diabetic rats.
METHODS: pCMV.Ins, an expression plasmid of the human insulin gene, wrapped with chitosan nanoparticles, was transfected to the diabetic rats through lavage and coloclysis, respectively. Fasting blood glucose and plasma insulin levels were measured for 7 d. Reverse transcription polymerase chain reaction (RT-PCR) analysis and Western blot analysis were performed to confirm the expression of human insulin gene.
RESULTS: Compared with the control group, the fasting blood glucose levels in the lavage and coloclysis groups were decreased significantly in 4 d (5.63 ± 0.48 mmol/L and 5.07 ± 0.37 mmol/L vs 22.12 ± 1.31 mmol/L, respectively, P < 0.01), while the plasma insulin levels were much higher (32.26 ± 1.81 &mgr;IU/mL and 32.79 ± 1.84 &mgr;IU/mL vs 14.23 ± 1.38 &mgr;IU/mL, respectively, P < 0.01). The human insulin gene mRNA and human insulin were only detected in the lavage and coloclysis groups.
CONCLUSION: Human insulin gene wrapped with chitosan nanoparticles can be successfully transfected to rats through gastrointestinal tract, indicating that chitosan is a promising non-viral vector.
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Bisht B, Srinivasan K, Dey CS. In vivo inhibition of focal adhesion kinase causes insulin resistance. J Physiol 2008; 586:3825-37. [PMID: 18587052 DOI: 10.1113/jphysiol.2008.157107] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has recently been implicated in the regulation of insulin resistance in vitro. However, its in vivo validation has not been attempted due to lethality of FAK knockout. Hence, to ascertain the role of FAK in the development of insulin resistance in vivo, we have down-regulated FAK expression by delivering FAK-specific small interfering RNA (siRNA) in mice using hydrodynamic tail vein injection. Here, we show for the first time that FAK silencing (57 +/- 0.05% in muscle and 80 +/- 0.08% in liver) exacerbates insulin signalling and causes hyperglycaemia (251.68 +/- 8.1 mg dl(-1)) and hyperinsulinaemia (3.48 +/- 0.06 ng ml(-1)) in vivo. FAK-silenced animals are less glucose tolerant and have physiological and biochemical parameters similar to that of high fat diet (HFD)-fed insulin-resistant animals. Phosphorylation and expression of insulin receptor substrate 1 (IRS-1) was attenuated by 40.2 +/- 0.03% and 35.2 +/- 0.6% in muscle and 52.3 +/- 0.04% and 40.2 +/- 0.03% in liver in FAK-silenced mice. Akt-Ser473-phosphorylation decreased in muscle and liver (50.3 +/- 0.03% and 70.2 +/- 0.02%, respectively) in FAK-silenced mice. This, in part, explains the mechanism of development of insulin resistance in FAK-silenced mice. The present study provides direct evidence that FAK is a crucial mediator of insulin resistance in vivo. Considering the lethality of FAK gene knockout the approach of this study will provide a new strategy for in vivo inhibition of FAK. Furthermore, the study should certainly motivate chemists to synthesize new chemical entities for FAK activation. This may shed light on new drug development against insulin resistance.
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Affiliation(s)
- Bharti Bisht
- Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India
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