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Li C, Yuan X, Huang L, Bai Z, Zheng L, Tan Y, Liu X. The Genetic Polymorphisms of rs161620 and rs2229611 in G6PC 3'UTR Are Associated With Metformin Efficacy in Chinese Type 2 Diabetes Mellitus. Pharmacol Res Perspect 2025; 13:e70090. [PMID: 40211429 PMCID: PMC11985355 DOI: 10.1002/prp2.70090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 03/07/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Metformin is a classical oral hypoglycemic drug, often recommended as the first-line therapy for type 2 diabetes mellitus (T2DM). Previous research has shown that the efficacy of metformin is associated with the genetic polymorphisms of patients. Considering the role of G6PC in gluconeogenesis and glycogenolysis, this study aims to investigate the association of G6PC rs161620 and rs2229611 with metformin efficacy in T2DM patients who take metformin only. According to the decrease of HbA1c, 116 T2DM patients receiving metformin monotherapy were divided into two groups: response group (the decrease of HbA1c by at least 1.5% after 3 months) and non-response group (the decrease of HbA1c < 1.5%). SNPscan technology was used to genotype. There were significant differences in rs161620 and rs2229611 presented in genotype frequency (p = 0.027 both) between the response group and the non-response group. According to the results of logistic analysis, the genetic polymorphisms of G6PC rs161620 or rs2229611 could influence the hypoglycemic effect of metformin in T2DM patients. We found that the decreasing values of PBG and HbA1c in G6PC rs161620 (C > A) or rs2229611 (T > C) mutants were significantly more than those in wild-type individuals, which means the more effective genotypes of metformin are CA/AA of rs161620 and TC/CC of rs2229611. This study suggested that the G6PC rs161620 and rs2229611 genetic polymorphisms were significantly associated with metformin efficacy in Chinese T2DM patients.
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Affiliation(s)
- Cuilin Li
- Department of Pharmacy, Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South UniversityZhuzhouChina
| | - Xiangmin Yuan
- Department of Pharmacy, Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South UniversityZhuzhouChina
| | - Li Huang
- Department of Pharmacy, Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South UniversityZhuzhouChina
| | - Zhuojun Bai
- Health Management Center, Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South UniversityZhuzhouChina
| | - Lian Zheng
- Department of Pharmacy, Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South UniversityZhuzhouChina
| | - Yani Tan
- Department of Pharmacy, Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South UniversityZhuzhouChina
| | - Xin Liu
- Department of Pharmacy, Zhuzhou Hospital Affiliated to Xiangya School of MedicineCentral South UniversityZhuzhouChina
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Leow SS, Khoo JS, Lee WK, Hoh CC, Fairus S, Sambanthamurthi R, Hayes KC. RNA-Seq transcriptome profiling of Nile rat livers reveals novel insights on the anti-diabetic mechanisms of Water-Soluble Palm Fruit Extract. J Appl Genet 2024; 65:867-895. [PMID: 38890243 DOI: 10.1007/s13353-024-00880-1] [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: 09/11/2023] [Revised: 04/08/2024] [Accepted: 05/15/2024] [Indexed: 06/20/2024]
Abstract
Water-Soluble Palm Fruit Extract (WSPFE) has been shown to confer anti-diabetic effects in the Nile rat (NR) (Arvicanthis niloticus). Liquid and powder WSPFE both deterred diabetes onset in NRs fed a high-carbohydrate (hiCHO) diet, but the liquid form provided better protection. In this study, NRs were fed either a hiCHO diet or the same diet added with liquid or powder WSPFE. Following feeding of the diets for 8 weeks, random blood glucose levels were measured to categorize NRs as either diabetes-resistant or diabetes-susceptible, based on a cut-off value of 75 mg/dL. Livers were then obtained for Illumina HiSeq 4000 paired end RNA-sequencing (RNA-Seq) and the data were mapped to the reference genome. Consistent with physiological and biochemical parameters, the gene expression data obtained indicated that WSPFE was associated with protection against diabetes. Among hepatic genes upregulated by WSPFE versus controls, were genes related to insulin-like growth factor binding protein, leptin receptor, and processes of hepatic metabolism maintenance, while those downregulated were related to antigen binding, immunoglobulin receptor, inflammation- and cancer-related processes. WSPFE supplementation thus helped inhibit diabetes progression in NRs by increasing insulin sensitivity and reducing both the inflammatory effects of a hiCHO diet and the related DNA-damage compensatory mechanisms contributing to liver disease progression. In addition, the genetic permissiveness of susceptible NRs to develop diabetes was potentially associated with dysregulated compensatory mechanisms involving insulin signaling and oxidative stress over time. Further studies on other NR organs associated with diabetes and its complications are warranted.
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Affiliation(s)
- Soon-Sen Leow
- Malaysian Palm Oil Board, No. 6, Persiaran Institusi, Bandar Baru Bangi, 43000, Kajang, Selangor, Malaysia.
| | - Jia-Shiun Khoo
- Codon Genomics Sdn Bhd, No. 26, Jalan Dutamas 7, Taman Dutamas Balakong, 43200, Seri Kembangan, Selangor, Malaysia
| | - Wei-Kang Lee
- Codon Genomics Sdn Bhd, No. 26, Jalan Dutamas 7, Taman Dutamas Balakong, 43200, Seri Kembangan, Selangor, Malaysia
| | - Chee-Choong Hoh
- Codon Genomics Sdn Bhd, No. 26, Jalan Dutamas 7, Taman Dutamas Balakong, 43200, Seri Kembangan, Selangor, Malaysia
| | - Syed Fairus
- Malaysian Palm Oil Board, No. 6, Persiaran Institusi, Bandar Baru Bangi, 43000, Kajang, Selangor, Malaysia
| | - Ravigadevi Sambanthamurthi
- Malaysian Palm Oil Board, No. 6, Persiaran Institusi, Bandar Baru Bangi, 43000, Kajang, Selangor, Malaysia
- Academy of Sciences Malaysia, Level 20, West Wing, MATRADE Tower, Jalan Sultan Haji Ahmad Shah, Off Jalan Tuanku Abdul Halim, 50480, Kuala Lumpur, Malaysia
| | - K C Hayes
- Brandeis University, 415 South Street, Waltham, MA, 02454, USA
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Vitale F, Ghelardoni M, Chiesa S, Carta S, Losacco S, Orengo AM, Bruno S, Ravera S, Bauckneht M, Riondato M, Donegani I, Dighero E, Martinelli J, Marini C, Sambuceti G. The pivotal role of endoplasmic reticulum in FDG uptake in cancer cells. EJNMMI Res 2024; 14:64. [PMID: 38995321 PMCID: PMC11245458 DOI: 10.1186/s13550-024-01124-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 06/26/2024] [Indexed: 07/13/2024] Open
Affiliation(s)
- Francesca Vitale
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy.
| | - Maddalena Ghelardoni
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
| | - Sabrina Chiesa
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
| | - Sonia Carta
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
| | - Serena Losacco
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
| | - Anna Maria Orengo
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
| | - Silvia Bruno
- Department of Experimental Medicine, Human Anatomy, University of Genoa, Genoa, Italy
| | - Silvia Ravera
- Department of Experimental Medicine, Human Anatomy, University of Genoa, Genoa, Italy
| | - Matteo Bauckneht
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
- Nuclear Medicine, Department of Health Science, University of Genoa, Genoa, Italy
| | - Mattia Riondato
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
- Nuclear Medicine, Department of Health Science, University of Genoa, Genoa, Italy
| | - Isabella Donegani
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
| | - Edoardo Dighero
- Nuclear Medicine, Department of Health Science, University of Genoa, Genoa, Italy
| | - Jonathan Martinelli
- Nuclear Medicine, Department of Health Science, University of Genoa, Genoa, Italy
| | - Cecilia Marini
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
- CNR Institute of Bioimages and Molecular Physiology, Milan, Italy
| | - Gianmario Sambuceti
- Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16133, Genoa, Italy
- Nuclear Medicine, Department of Health Science, University of Genoa, Genoa, Italy
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Miyamoto T, Hedjazi S, Miyamoto C, Amrein H. Drosophila Neuronal Glucose 6 Phosphatase is a Modulator of Neuropeptide Release that Regulates Muscle Glycogen Stores via FMRFamide Signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.11.28.568950. [PMID: 38077084 PMCID: PMC10705280 DOI: 10.1101/2023.11.28.568950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2024]
Abstract
Neuropeptides (NPs) and their cognate receptors are critical effectors of diverse physiological processes and behaviors. We recently reported of a non-canonical function of the Drosophila Glucose-6-Phosphatase ( G6P ) gene in a subset of neurosecretory cells in the CNS that governs systemic glucose homeostasis in food deprived flies. Here, we show that G6P expressing neurons define 6 groups of neuropeptide secreting cells, 4 in the brain and 2 in the thoracic ganglion. Using the glucose homeostasis phenotype as a screening tool, we find that neurons located in the thoracic ganglion expressing FMRFamide neuropeptides ( FMRFa G6P neurons) are necessary and sufficient to maintain systemic glucose homeostasis in starved flies. We further show that G6P is essential in FMRFa G6P neurons for attaining a prominent Golgi apparatus and secreting neuropeptides efficiently. Finally, we establish that G6P dependent FMRFa signaling is essential for the build-up of glycogen stores in the jump muscle which expresses the receptor for FMRFamides. We propose a general model in which the main role of G6P is to counteract glycolysis in peptidergic neurons for the purpose of optimizing the intracellular environment best suited for the expansion of the Golgi apparatus, boosting release of neuropeptides and enhancing signaling to respective target tissues expressing cognate receptors. SIGNIFICANCE STATEMENT Glucose-6-phosphtase (G6P) is a critical enzyme in sugar synthesis and catalyzes the final step in glucose production. In Drosophila - and insects in general - where trehalose is the circulating sugar and Trehalose phosphate synthase, and not G6P, is used for sugar production, G6P has adopted a novel and unique role in peptidergic neurons in the CNS. Interestingly, flies lacking G6P show diminished Neuropeptide secretions and have a smaller Golgi apparatus in peptidergic neurons. It is hypothesized that the role of G6P is to counteract glycolysis, thereby creating a cellular environment that is more amenable to efficient neuropeptide secretion.
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Coate KC, Ramnanan CJ, Smith M, Winnick JJ, Kraft G, Irimia-Dominguez J, Farmer B, Donahue EP, Roach PJ, Cherrington AD, Edgerton DS. Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog. Am J Physiol Endocrinol Metab 2024; 326:E428-E442. [PMID: 38324258 PMCID: PMC11193521 DOI: 10.1152/ajpendo.00316.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/08/2024]
Abstract
Glucagon rapidly and profoundly stimulates hepatic glucose production (HGP), but for reasons that are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course of glucagon-mediated molecular events and their relevance to metabolic flux in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a sixfold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group, glucose remained at basal, whereas in the other, glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) and largely sustained increase in hepatic cAMP over 4 h, a continued elevation in glucose-6-phosphate (G6P), and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis increased rapidly, peaking at 15 min due to activation of the cAMP/PKA pathway, then slowly returned to baseline over the next 3 h in line with allosteric inhibition by glucose and G6P. Glucagon's stimulatory effect on HGP was sustained relative to the hyperglycemic control group due to continued PKA activation. Hepatic gluconeogenic flux did not increase due to the lack of glucagon's effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, as well as downregulation of genes involved in extracellular matrix assembly and development.NEW & NOTEWORTHY Glucagon rapidly stimulates hepatic glucose production, but these effects are transient. This study links the molecular and metabolic flux changes that occur in the liver over time in response to a rise in glucagon, demonstrating the strength of the dog as a translational model to couple findings in small animals and humans. In addition, this study clarifies why the rapid effects of glucagon on liver glycogen metabolism are not sustained.
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Affiliation(s)
- Katie C Coate
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Christopher J Ramnanan
- Department of Innovation in Medical Education, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
| | - Marta Smith
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
| | - Jason J Winnick
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Guillaume Kraft
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
| | - Jose Irimia-Dominguez
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute, Duarte, California, United States
| | - Ben Farmer
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
| | - E Patrick Donahue
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Peter J Roach
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
| | - Dale S Edgerton
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
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Yanko R, Levashov M, Chaka OG, Nosar V, Khasabov SG, Khasabova I. Tryptophan Prevents the Development of Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes 2023; 16:4195-4204. [PMID: 38152280 PMCID: PMC10752026 DOI: 10.2147/dmso.s444278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 12/18/2023] [Indexed: 12/29/2023] Open
Abstract
Purpose The main aim of this research is to study the protective effects of tryptophan on the histomorphological and biochemical abnormalities in the liver caused by a high-calorie diet (HCD), as well as its ability to normalize mitochondrial functions in order to prevent the development of non-alcoholic fatty liver disease (NAFLD). Methods The study was conducted in male Wistar rats aged 3 months at the start of the experiment. Control animals (group I) were fed a standard diet. Group II experimental animals were fed a diet with an excess of fat (45%) and carbohydrates (31%) for 12 weeks. Group III experimental animals also received L-tryptophan at a dose of 80 mg/kg body weight in addition to the HCD. The presence of NAFLD, functional activity, physiological regeneration, and the state of the liver parenchyma and connective tissue were assessed using physiological, morphological, histo-morphometric, biochemical, and biophysical research methods. Results HCD induced the development of NAFLD, which is characterized by an increase in liver weight, hypertrophy of hepatocytes and an increase in the concentration of lipids, cholesterol and triglycerides in liver tissue. Increased alanine aminotransferase activity in the liver of obese rats also confirm hepatocytes damage. Tryptophan added to the diet lowered the severity of NAFLD by reducing fat accumulation and violations of bioelectric properties, and prevented a decrease in mitochondrial ATP synthesis. Conclusion The addition of tryptophan can have a potential positive effect on the liver, reducing the severity of structural, biochemical, mitochondrial and bioelectric damage caused by HCD.
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Affiliation(s)
- Roman Yanko
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Mikhail Levashov
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Olena Georgievna Chaka
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Valentina Nosar
- Department of Clinical Physiology of Connective Tissue, Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
| | - Sergey G Khasabov
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
| | - Iryna Khasabova
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA
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Wang Z, Zhao R, Jia X, Li X, Ma L, Fu H. Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review. J Int Med Res 2023; 51:3000605231216633. [PMID: 38087503 PMCID: PMC10718061 DOI: 10.1177/03000605231216633] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 11/08/2023] [Indexed: 12/18/2023] Open
Abstract
Glycogen storage disease type 1b (GSD1b) is a rare genetic disorder, resulting from mutations in the SLC37A4 gene located on chromosome 11q23.3. Although the SLC37A4 gene has been identified as the pathogenic gene for GSD1b, the complete variant spectrum of this gene remains to be fully elucidated. In this study, we present three patients diagnosed with GSD1b through genetic testing. We detected five variants of the SLC37A4 gene in these three patients, with three of these mutations (p. L382Pfs*15, p. G117fs*28, and p. T312Sfs*13) being novel variants not previously reported in the literature. We also present a literature review and general overview of the currently reported SLC37A4 gene variants. Our study expands the mutation spectrum of SLC37A4, which may help enable genetic testing to facilitate prompt diagnosis, appropriate intervention, and genetic counseling for affected families.
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Affiliation(s)
- Zhuolin Wang
- Department of Gastroenterology, Hebei Children's Hospital, 133 Jianhua South Street, Shijiazhuang 050031, Hebei Province, China
| | - Ruiqin Zhao
- Department of Gastroenterology, Hebei Children's Hospital, 133 Jianhua South Street, Shijiazhuang 050031, Hebei Province, China
| | - Xiaoyun Jia
- Department of Gastroenterology, Hebei Children's Hospital, 133 Jianhua South Street, Shijiazhuang 050031, Hebei Province, China
| | - Xiaolei Li
- Department of Gastroenterology, Hebei Children's Hospital, 133 Jianhua South Street, Shijiazhuang 050031, Hebei Province, China
| | - Li Ma
- Department of Neonatology, Hebei Children's Hospital, 133 Jianhua South Street, Shijiazhuang 050031, Hebei Province, China
| | - Haiyan Fu
- Department of Gastroenterology, Hebei Children's Hospital, 133 Jianhua South Street, Shijiazhuang 050031, Hebei Province, China
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Torabidastgerdooei S, Roy ME, Annabi B. A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype. Front Endocrinol (Lausanne) 2023; 14:1265698. [PMID: 38034009 PMCID: PMC10687460 DOI: 10.3389/fendo.2023.1265698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Glycogen plays an important role in glucose homeostasis and contributes to key functions related to brain cancer cell survival in glioblastoma multiforme (GBM) disease progression. Such adaptive molecular mechanism is dependent on the glycogenolytic pathway and intracellular glucose-6-phosphate (G6P) sensing by brain cancer cells residing within those highly hypoxic tumors. The involvement of components of the glucose-6-phosphatase (G6Pase) system remains however elusive. OBJECTIVE We questioned the gene expression levels of components of the G6Pase system in GBM tissues and their functional impact in the control of the invasive and brain cancer stem cells (CSC) phenotypes. METHODS In silico analysis of transcript levels in GBM tumor tissues was done by GEPIA. Total RNA was extracted and gene expression of G6PC1-3 as well as of SLC37A1-4 members analyzed by qPCR in four human brain cancer cell lines and from clinically annotated brain tumor cDNA arrays. Transient siRNA-mediated gene silencing was used to assess the impact of TGF-β-induced epithelial-to-mesenchymal transition (EMT) and cell chemotaxis. Three-dimensional (3D) neurosphere cultures were generated to recapitulate the brain CSC phenotype. RESULTS Higher expression in G6PC3, SLC37A2, and SLC37A4 was found in GBM tumor tissues in comparison to low-grade glioma and healthy tissue. The expression of these genes was also found elevated in established human U87, U251, U118, and U138 GBM cell models compared to human HepG2 hepatoma cells. SLC37A4/G6PC3, but not SLC37A2, levels were induced in 3D CD133/SOX2-positive U87 neurospheres when compared to 2D monolayers. Silencing of SLC37A4/G6PC3 altered TGF-β-induced EMT biomarker SNAIL and cell chemotaxis. CONCLUSION Two members of the G6Pase system, G6PC3 and SLC37A4, associate with GBM disease progression and regulate the metabolic reprogramming of an invasive and CSC phenotype. Such molecular signature may support their role in cancer cell survival and chemoresistance and become future therapeutic targets.
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Affiliation(s)
| | | | - Borhane Annabi
- Laboratoire d’Oncologie Moléculaire, Centre de recherche CERMO-FC, Département de Chimie, Université du Québec à Montréal, Montreal, QC, Canada
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Kmita H, Pinna G, Lushchak VI. Potential oxidative stress related targets of mitochondria-focused therapy of PTSD. Front Physiol 2023; 14:1266575. [PMID: 38028782 PMCID: PMC10679466 DOI: 10.3389/fphys.2023.1266575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) remains a highly prevalent, under-diagnosed, and under-treated psychiatric disorder that often deteriorates over time, and is highly comorbid with major depressive disorder, suicidality, and substance use disorder. Several biomarkers have been proposed but have yet to be implemented into clinical practice. Treatments, including selective serotonin reuptake inhibitors, are efficacious in only a small number of patients, which underscores the need to develop novel, efficient treatments. Mitochondrial dysfunction resulting from chronic oxidative stress has been linked with both altered neurotransmitter signaling and the inflammatory response. Hereinafter, we discuss mechanisms by which mitochondrial dysfunction may contribute to the development of PTSD symptoms, and how these may even increase PTSD susceptibility. We also highlight possible therapeutic targets to reduce oxidative stress to prevent or treat PTSD symptoms.
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Affiliation(s)
- Hanna Kmita
- Department of Bioenergetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Graziano Pinna
- Psychiatric Institute (SPHPI), Chicago, IL, United States
- UI Center on Depression and Resilience (UICDR), Chicago, IL, United States
- Center for Alcohol Research in Epigenetics (CARE), Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Volodymyr I. Lushchak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine
- Research and Development University, Ivano-Frankivsk, Ukraine
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Gümüş E, Özen H. Glycogen storage diseases: An update. World J Gastroenterol 2023; 29:3932-3963. [PMID: 37476587 PMCID: PMC10354582 DOI: 10.3748/wjg.v29.i25.3932] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/15/2023] [Accepted: 04/30/2023] [Indexed: 06/28/2023] Open
Abstract
Glycogen storage diseases (GSDs), also referred to as glycogenoses, are inherited metabolic disorders of glycogen metabolism caused by deficiency of enzymes or transporters involved in the synthesis or degradation of glycogen leading to aberrant storage and/or utilization. The overall estimated GSD incidence is 1 case per 20000-43000 live births. There are over 20 types of GSD including the subtypes. This heterogeneous group of rare diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. However, besides liver and skeletal muscle, depending on the affected enzyme and its expression in various tissues, multiorgan involvement including heart, kidney and/or brain may be seen. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. Currently, the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch. In addition to nutritional interventions, pharmacological treatment, physical and supportive therapies, enzyme replacement therapy (ERT) and organ transplantation are other treatment approaches for both disease manifestations and long-term complications. The lack of a specific therapy for GSDs has prompted efforts to develop new treatment strategies like gene therapy. Since early diagnosis and aggressive treatment are related to better prognosis, physicians should be aware of these conditions and include GSDs in the differential diagnosis of patients with relevant manifestations including fasting hypoglycemia, hepatomegaly, hypertransaminasemia, hyperlipidemia, exercise intolerance, muscle cramps/pain, rhabdomyolysis, and muscle weakness. Here, we aim to provide a comprehensive review of GSDs. This review provides general characteristics of all types of GSDs with a focus on those with liver involvement.
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Affiliation(s)
- Ersin Gümüş
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Ankara 06230, Turkey
| | - Hasan Özen
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Ankara 06230, Turkey
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Pan S, Worker CJ, Feng Earley Y. The hypothalamus as a key regulator of glucose homeostasis: emerging roles of the brain renin-angiotensin system. Am J Physiol Cell Physiol 2023; 325:C141-C154. [PMID: 37273237 PMCID: PMC10312332 DOI: 10.1152/ajpcell.00533.2022] [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: 11/29/2022] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/06/2023]
Abstract
The regulation of plasma glucose levels is a complex and multifactorial process involving a network of receptors and signaling pathways across numerous organs that act in concert to ensure homeostasis. However, much about the mechanisms and pathways by which the brain regulates glycemic homeostasis remains poorly understood. Understanding the precise mechanisms and circuits employed by the central nervous system to control glucose is critical to resolving the diabetes epidemic. The hypothalamus, a key integrative center within the central nervous system, has recently emerged as a critical site in the regulation of glucose homeostasis. Here, we review the current understanding of the role of the hypothalamus in regulating glucose homeostasis, with an emphasis on the paraventricular nucleus, the arcuate nucleus, the ventromedial hypothalamus, and lateral hypothalamus. In particular, we highlight the emerging role of the brain renin-angiotensin system in the hypothalamus in regulating energy expenditure and metabolic rate, as well as its potential importance in the regulation of glucose homeostasis.
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Affiliation(s)
- Shiyue Pan
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Department of Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, United States
| | - Caleb J Worker
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Department of Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, United States
| | - Yumei Feng Earley
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Department of Physiology & Cell Biology, School of Medicine, University of Nevada, Reno, Reno, Nevada, United States
- Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, Nevada, United States
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12
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Si HR, Sun SS, Liu YK, Qiu LY, Tang B, Liu F, Fu Q, Xu CD, Wan PJ. Roles of GFAT and PFK genes in energy metabolism of brown planthopper, Nilaparvata lugens. Front Physiol 2023; 14:1213654. [PMID: 37415905 PMCID: PMC10320585 DOI: 10.3389/fphys.2023.1213654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/13/2023] [Indexed: 07/08/2023] Open
Abstract
Glutamine:fructose-6-phosphate aminotransferases (GFATs) and phosphofructokinase (PFKs) are the principal rate-limiting enzymes involved in hexosamine biosynthesis pathway (HBP) and glycolysis pathway, respectively. In this study, the NlGFAT and NlPFK were knocked down through RNA interference (RNAi) in Nilaparvata lugens, the notorious brown planthopper (BPH), and the changes in energy metabolism were determined. Knockdown of either NlGFAT or NlPFK substantially reduced gene expression related to trehalose, glucose, and glycogen metabolism pathways. Moreover, trehalose content rose significantly at 72 h after dsGFAT injection, and glycogen content increased significantly at 48 h after injection. Glucose content remained unchanged throughout the experiment. Conversely, dsPFK injection did not significantly alter trehalose, but caused an extreme increase in glucose and glycogen content at 72 h after injection. The Knockdown of NlGFAT or NlPFK significantly downregulated the genes in the glycolytic pathway, as well as caused a considerable and significant decrease in pyruvate kinase (PK) activity after 48 h and 72 h of inhibition. After dsGFAT injection, most of genes in TCA cycle pathway were upregulated, but after dsNlPFK injection, they were downregulated. Correspondingly, ATP content substantially increased at 48 h after NlGFAT knockdown but decreased to an extreme extent by 72 h. In contrast, ATP content decreased significantly after NlPFK was knocked down and returned. The results have suggested the knockdown of either NlGFAT or NlPFK resulted in metabolism disorders in BPHs, highlighting the difference in the impact of those two enzyme genes on energy metabolism. Given their influence on BPHs energy metabolism, developing enzyme inhibitors or activators may provide a biological control for BPHs.
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Affiliation(s)
- Hui-Ru Si
- State Key Laboratory of Rice Biology and Breeding, China National Rice Research Institute, Hangzhou, Zhejiang, China
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Si-Si Sun
- Guizhou Institute of Mountainous Environment and Climate, Guiyang, China
| | - Yong-Kang Liu
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Ling-Yu Qiu
- State Key Laboratory of Rice Biology and Breeding, China National Rice Research Institute, Hangzhou, Zhejiang, China
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Bin Tang
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Fang Liu
- State Key Laboratory of Rice Biology and Breeding, China National Rice Research Institute, Hangzhou, Zhejiang, China
| | - Qiang Fu
- State Key Laboratory of Rice Biology and Breeding, China National Rice Research Institute, Hangzhou, Zhejiang, China
| | - Cai-Di Xu
- Jing Hengyi School of Education, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Pin-Jun Wan
- State Key Laboratory of Rice Biology and Breeding, China National Rice Research Institute, Hangzhou, Zhejiang, China
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13
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Cao J, Markel A, Hanahoe E, Ketova T, Mihai C, Zalinger Z, Marquardt D, Amato NJ, Cheng YM, Reid DW, Dousis A, Giangrande PH, Schultz JR, Martini PGV, Finn PF. Amnio acid substitution at position 298 of human glucose-6 phosphatase-α significantly impacts its stability in mammalian cells. Amino Acids 2023:10.1007/s00726-023-03263-8. [PMID: 36944899 DOI: 10.1007/s00726-023-03263-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/09/2023] [Indexed: 03/23/2023]
Abstract
Glucose-6-phosphatase-α (G6Pase-α) catalyzes the hydrolysis of glucose-6-phosphate to glucose and functions as a key regulator in maintaining blood glucose homeostasis. Deficiency in G6Pase-α causes glycogen storage disease 1a (GSD1a), an inherited disorder characterized by life-threatening hypoglycemia and other long-term complications. We have developed a potential mRNA-based therapy for GSD1a and demonstrated that a human G6Pase-α (hG6Pase-α) variant harboring a single serine (S) to cysteine (C) substitution at the amino acid site 298 (S298C) had > twofold increase in protein expression, resulting in improved in vivo efficacy. Here, we sought to investigate the mechanisms contributing to the increased expression of the S298C variant. Mutagenesis of hG6Pase-α identified distinct protein variants at the 298 amino acid position with substantial reduction in protein expression in cultured cells. Kinetic analysis of expression and subcellular localization in mammalian cells, combined with cell-free in vitro translation assays, revealed that altered protein expression stemmed from differences in cellular protein stability rather than biosynthetic rates. Site-specific mutagenesis studies targeting other cysteines of the hG6Pase-α S298C variant suggest the observed improvements in stability are not due to additional disulfide bond formation. The glycosylation at Asparagine (N)-96 is critical in maintaining enzymatic activity and mutations at position 298 mainly affected glycosylated forms of hG6Pase-α. Finally, proteasome inhibition by lactacystin improved expression levels of unstable hG6Pase-α variants. Taken together, these data uncover a critical role for a single amino acid substitution impacting the stability of G6Pase-α and provide insights into the molecular genetics of GSD1a and protein engineering for therapeutic development.
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Affiliation(s)
- Jingsong Cao
- Rare Diseases, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Arianna Markel
- Rare Diseases, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Erin Hanahoe
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Tatiana Ketova
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Cosmin Mihai
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Zach Zalinger
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - David Marquardt
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Nicholas J Amato
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Yi Min Cheng
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - David W Reid
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Athanasios Dousis
- Platform, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
- Current Address: Tessera Therapeutics, Somerville, MA, USA
| | - Paloma H Giangrande
- Rare Diseases, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
- Current Address: Wave Life Sciences, Cambridge, MA, USA
| | - Joshua R Schultz
- Rare Diseases, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
| | - Paolo G V Martini
- Rare Diseases, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA.
| | - Patrick F Finn
- Rare Diseases, Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA.
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14
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Kaunitz JD, Mandelkern M, Fowler JS. It's Not What You Take Up, It's What You Keep: How Discoveries from Diverse Disciplines Directed the Development of the FDG PET/CT Scan. Dig Dis Sci 2022; 67:4620-4632. [PMID: 35908123 DOI: 10.1007/s10620-022-07615-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2022] [Indexed: 12/14/2022]
Abstract
Although imaging glucose metabolism with positron emission tomography combined with X-ray CT (FDG-PET/CT) has become a standard diagnostic modality for the discovery and surveillance of malignant tumors and inflammatory processes, its origins extend back to more than a century of notable discoveries in the fields of inorganic and organic chemistry, nuclear physics, mathematics, biochemistry, solute transport physiology, metabolism, and imaging, accomplished by pioneering and driven investigators, of whom at least ten were recipients of the Nobel Prize. These tangled and diverse roots eventually coalesced into the FDG-PET/CT method, that through its many favorable characteristics inherent in the isotope used (18F), the accurate imaging derived from coincidence detection of positron annihilation radiation combined with computed tomography, and the metabolic trapping of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) in tissues, provides safety, sensitivity, and specificity for tumor and inflammation detection. The authors hope that this article will increase the appreciation among its readers of the insight, creativity, persistence, and drive of the many investigators who made this technique possible. This article is followed by a review of the many applications of FDG-PET/CT to the gastrointestinal tract and hepatobiliary system (Mandelkern in Dig Dis Sci 2022).
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Affiliation(s)
- Jonathan D Kaunitz
- Medical Service, Greater Los Angeles VAMC, Los Angeles, CA, USA. .,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| | - Mark Mandelkern
- Nuclear Medicine Service, Greater Los Angeles VAMC, Los Angeles, CA, USA.,Department of Physics, University of California, Irvine, Irvine, CA, USA
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15
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Zhang X, Wu Q, Zheng W, Liu C, Huang L, Zuo X, Xiao W, Han X, Ye H, Wang W, Zhu Y, Yang L. Exogenous Linoleic Acid Intervention Alters Hepatic Glucose Metabolism in an Avian Embryo Model. Front Physiol 2022; 13:844148. [PMID: 35264980 PMCID: PMC8899105 DOI: 10.3389/fphys.2022.844148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/31/2022] [Indexed: 11/28/2022] Open
Abstract
In the present study, developmental changes of gluconeogenesis and glycolysis in an avian model were measured, and then the intervention effects of in ovo feeding (IOF) linoleic acid (LA) on hepatic glucose metabolism were evaluated. In Experiment 1, thirty fertilized eggs were sampled on embryonic days (E) of 16, 19, 22, 25, 28, 31, and thirty newly-hatched ducklings at hatch (E34 and E35). In Experiment 2, a total of 120 fertilized eggs (60 eggs for each group) were injected into the yolk sac with PBS as the control group and LA as the IOF LA group on E25. Twelve eggs were selected for sample collection on E28 and E31. Serum contents of glucose, pyruvate, and lactate increased ( p < 0.05) linearly or quadratically from E16 to hatch, as well as hepatic glycogen and pyruvate contents. Hepatic mRNA expression related to energy homeostasis, gluconeogenesis, and glycolysis increased ( p < 0.05) in embryogenesis, and the plateau period was presented on E25–E31. IOF LA decreased ( p < 0.05) serum contents of glucose, triacylglycerol, cholesterol, and hepatic oleic acid, unsaturated fatty acids on E28, as well as the gene expression relative to gluconeogenesis. IOF LA increased ( p < 0.05) pyruvate content in serum and liver, and hepatic gene expression relative to glycolysis on E31. In summary, hepatic gluconeogenesis and glycolysis were enhanced to meet the increasing energy demands of embryonic development during E25 – hatch. Exogenous LA intervention on E25 could inhibit hepatic gluconeogenesis and enhance glycolysis during the later developmental period, disrupting glucose embryonic homeostasis and energy status.
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Affiliation(s)
- Xiufen Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qilin Wu
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Wenxuan Zheng
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Chuang Liu
- Wen’s Food Group Co., Ltd., Yunfu, China
| | - Liang Huang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xin Zuo
- Wen’s Food Group Co., Ltd., Yunfu, China
| | | | | | - Hui Ye
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Wence Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yongwen Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
- Yongwen Zhu,
| | - Lin Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
- *Correspondence: Lin Yang,
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16
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Histidine Promotes the Glucose Synthesis through Activation of the Gluconeogenic Pathway in Bovine Hepatocytes. Animals (Basel) 2021; 11:ani11113295. [PMID: 34828026 PMCID: PMC8614563 DOI: 10.3390/ani11113295] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/13/2021] [Accepted: 11/15/2021] [Indexed: 12/05/2022] Open
Abstract
Simple Summary This study evaluated the effect of histidine (His) on hepatic glucose output and the expression of genes related to the gluconeogenic pathway in vitro. The results demonstrate that the supplementation of HIS can significantly improve the mRNA expression of phosphoenolpyruvate carboxykinase 1 (PCK1), phosphoenolpyruvate carboxykinase 2 (PCK2), fructose-1,6-bisphosphatase 1 (FBP1), and glucose-6-phosphatase (G6PC). Moreover, the addition of His ameliorated bovine hepatocytes glucose output. This study demonstrated that bovine hepatocytes can efficiently convert His into glucose to provide the energy required. Abstract Histidine (His) is considered to be the first-limiting amino acid (AA) on grass silage-based diets in lactation cows, which correlate positively with lactose yield. The higher glucose requirements of lactating cows can be met through a combination of increased capacity for gluconeogenesis and increased supply of gluconeogenic precursors. However, the effect of His on the expression of gluconeogenic genes in the bovine hepatocytes is less known. Therefore, this study aimed to investigate the regulatory effect of His on the key gluconeogenic genes and glucose output in bovine hepatocytes. The addition of 0.15, 0.6, and 1.2 mM His in a medium significantly enhanced (p < 0.05) the viability of bovine hepatocytes. Remarkably, 1.2 mM His induced profound changes (p < 0.05) in the mRNA level of key genes involved in gluconeogenesis, including PCK1, PCK2, FBP1, and G6PC in vitro. Furthermore, the mRNA expression of PCK1 was significantly elevated (p < 0.05) by the addition of 1.2 mM His at 3, 6, 12, and 24 h of incubation. The hepatic glucose output increased (p < 0.05) linearly with increasing His concentration. These findings indicate that the addition of His may be efficiently converted into glucose via the upregulation of genes related to the gluconeogenic pathway.
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17
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Fungal Depsides-Naturally Inspiring Molecules: Biosynthesis, Structural Characterization, and Biological Activities. Metabolites 2021; 11:metabo11100683. [PMID: 34677398 PMCID: PMC8540757 DOI: 10.3390/metabo11100683] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/05/2021] [Accepted: 10/02/2021] [Indexed: 11/23/2022] Open
Abstract
Fungi represent a huge reservoir of structurally diverse bio-metabolites. Although there has been a marked increase in the number of isolated fungal metabolites over the past years, many hidden metabolites still need to be discovered. Depsides are a group of polyketides consisting of two or more ester-linked hydroxybenzoic acid moieties. They possess valuable bioactive properties, such as anticancer, antidiabetic, antibacterial, antiviral, anti-inflammatory, antifungal, antifouling, and antioxidant qualities, as well as various human enzyme-inhibitory activities. This review provides an overview of the reported data on fungal depsides, including their sources, biosynthesis, physical and spectral data, and bioactivities in the period from 1975 to 2020. Overall, 110 metabolites and more than 122 references are confirmed. This is the first review of these multi-faceted metabolites from fungi.
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18
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Sarikaya I, Schierz JH, Sarikaya A. Liver: glucose metabolism and 18F-fluorodeoxyglucose PET findings in normal parenchyma and diseases. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2021; 11:233-249. [PMID: 34513277 PMCID: PMC8414405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/14/2021] [Indexed: 06/13/2023]
Abstract
Liver has a complex and unique energy metabolism and plays a major role in glucose homeostasis. Liver is the main control center for glycogenesis, glycogenolysis, glycolysis and gluconeogenesis which are essential to provide energy for other tissues. Liver meets its own energy need from various sources which is mainly glucose in the fed state and fatty acids in the fasting state. In this review article, we will mainly describe the glucose metabolism of the liver, effect of various factors on 18F-fluorodeoxyglucose (FDG) activity/uptake in the normal liver and 18F- FDG positron emission tomography (PET) uptake patterns in various malignant and benign liver pathologies. Brief information on metabolomics profiling analyses in liver disorders will also be provided.
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Affiliation(s)
- Ismet Sarikaya
- Department of Nuclear Medicine, Kuwait University Faculty of MedicineSafat, Kuwait
| | | | - Ali Sarikaya
- Department of Nuclear Medicine, Trakya University Faculty of MedicineTurkey
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19
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Flynn BP, Birnie MT, Kershaw YM, Pauza AG, Kim S, Baek S, Rogers MF, Paterson AR, Stavreva DA, Murphy D, Hager GL, Lightman SL, Conway-Campbell BL. Corticosterone pattern-dependent glucocorticoid receptor binding and transcriptional regulation within the liver. PLoS Genet 2021; 17:e1009737. [PMID: 34375333 PMCID: PMC8378686 DOI: 10.1371/journal.pgen.1009737] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/20/2021] [Accepted: 07/23/2021] [Indexed: 12/21/2022] Open
Abstract
Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction. Adrenal glucocorticoid hormones are released in a characteristic ultradian rhythm that becomes dysregulated during chronic stress, disease, or synthetic corticosteroid treatment. Metabolic dysfunction is a comorbidity associated with all these conditions, but the role that altered glucocorticoid dynamics play is unknown. As the liver is a major site of glucocorticoid action on metabolic homeostasis regulated by the glucocorticoid receptor, we have assessed how different patterns of hormone replacement in adrenalectomised rats differentially regulate gene pathways involved in type II diabetes, cirrhosis, and fatty liver development, via altering the pattern of glucocorticoid receptor binding to regulatory sites. We believe our findings have important implications for therapies that can reproduce the endogenous glucocorticoid rhythm and thus minimize adverse metabolic side-effects in patients.
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Affiliation(s)
- Benjamin P. Flynn
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
- * E-mail:
| | - Matthew T. Birnie
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | - Yvonne M. Kershaw
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | - Audrys G. Pauza
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | - Sohyoung Kim
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America
| | - Songjoon Baek
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America
| | - Mark F. Rogers
- Intelligent Systems Laboratory, University of Bristol, Bristol, United Kingdom
| | - Alex R. Paterson
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | - Diana A. Stavreva
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America
| | - David Murphy
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | - Gordon L. Hager
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institute of Health, Bethesda, Maryland, United States of America
| | - Stafford L. Lightman
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | - Becky L. Conway-Campbell
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
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20
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Tunyasuvunakool K, Adler J, Wu Z, Green T, Zielinski M, Žídek A, Bridgland A, Cowie A, Meyer C, Laydon A, Velankar S, Kleywegt GJ, Bateman A, Evans R, Pritzel A, Figurnov M, Ronneberger O, Bates R, Kohl SAA, Potapenko A, Ballard AJ, Romera-Paredes B, Nikolov S, Jain R, Clancy E, Reiman D, Petersen S, Senior AW, Kavukcuoglu K, Birney E, Kohli P, Jumper J, Hassabis D. Highly accurate protein structure prediction for the human proteome. Nature 2021; 596:590-596. [PMID: 34293799 PMCID: PMC8387240 DOI: 10.1038/s41586-021-03828-1] [Citation(s) in RCA: 1754] [Impact Index Per Article: 438.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/16/2021] [Indexed: 02/07/2023]
Abstract
Protein structures can provide invaluable information, both for reasoning about biological processes and for enabling interventions such as structure-based drug development or targeted mutagenesis. After decades of effort, 17% of the total residues in human protein sequences are covered by an experimentally determined structure1. Here we markedly expand the structural coverage of the proteome by applying the state-of-the-art machine learning method, AlphaFold2, at a scale that covers almost the entire human proteome (98.5% of human proteins). The resulting dataset covers 58% of residues with a confident prediction, of which a subset (36% of all residues) have very high confidence. We introduce several metrics developed by building on the AlphaFold model and use them to interpret the dataset, identifying strong multi-domain predictions as well as regions that are likely to be disordered. Finally, we provide some case studies to illustrate how high-quality predictions could be used to generate biological hypotheses. We are making our predictions freely available to the community and anticipate that routine large-scale and high-accuracy structure prediction will become an important tool that will allow new questions to be addressed from a structural perspective.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Sameer Velankar
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
| | - Gerard J Kleywegt
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
| | - Alex Bateman
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Ewan Birney
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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21
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Yang P, Fan Q, Cai H, Tian R, Su M. The effect of hypothyroidism on referential background metabolic activity on 18F-FDG PET/CT. Quant Imaging Med Surg 2021; 11:3666-3676. [PMID: 34341740 DOI: 10.21037/qims-20-1310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 04/01/2021] [Indexed: 02/05/2023]
Abstract
Background Background uptake activity is used as a reference to assess treatment response by positron emission tomography-computed tomography (PET/CT) with 2-deoxy-2-[F-18]fluoro- D-glucose (18F-FDG). Prior studies have reported decreased liver and increased muscle 18F-FDG uptake in patients with hyperthyroidism. We hypothesized that hyperthyroidism and hypothyroidism might have inverse effects on 18F-FDG uptake on PET/CT. Methods We recruited 36 patients with hypothyroidism and 36 age and gender-matched euthyroid participants. We recorded patient factors and background mean standardized uptake values normalized by lean body mass from the aortic blood pool, liver, and muscle. We compared the patient factors and background standardized uptake values normalized by lean body mass between hypothyroidism patients and the controls. We performed a multivariate analysis to determine the best predictors of the 3 different background standardized uptake values normalized by lean body mass. Results Patients with hypothyroidism had higher liver standardized uptake values normalized by lean body mass (1.77±0.33 vs. 1.58±0.26, P=0.009) and aortic blood-pool standardized uptake values normalized by lean body mass (1.21±0.22 vs. 1.11±0.20, P=0.040) than the controls. In contrast, the muscle standardized uptake value normalized by lean body mass (0.50±0.09 vs. 0.54±0.09, P=0.044) of the patients with hypothyroidism was lower than that of the controls. The serum level of thyroid-stimulating hormone was an independent predictor of liver standardized uptake values normalized by lean body mass (β=0.356, P<0.001) and blood-pool standardized uptake values normalized by lean body mass (β=0.288, P=0.001). The serum level of free triiodothyronine was an independent predictor of muscle standardized uptake values normalized by lean body mass (β=0.310, P=0.002). Conclusions PET/CT scans showed that hypothyroidism patients had increased liver and blood-pool 18F-FDG uptake and decreased skeletal muscle 18F-FDG uptake compared with euthyroid individuals. These alterations should be noted when a metabolic response to cancer treatment on PET/CT is determined.
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Affiliation(s)
- Pei Yang
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuping Fan
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Huawei Cai
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Rong Tian
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Minggang Su
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
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22
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Sommariva S, Scussolini M, Cossu V, Marini C, Sambuceti G, Caviglia G, Piana M. The role of endoplasmic reticulum in in vivo cancer FDG kinetics. PLoS One 2021; 16:e0252422. [PMID: 34061902 PMCID: PMC8168898 DOI: 10.1371/journal.pone.0252422] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 05/17/2021] [Indexed: 11/18/2022] Open
Abstract
A recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that the reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper is to confirm in vivo the result obtained in vitro concerning the crucial role played by the endoplasmic reticulum in FDG cancer metabolism. This study utilizes data acquired by means of a Positron Emission Tomography scanner for small animals in the case of CT26 models of cancer tissues. The recorded concentration images are interpreted within the framework of a three-compartment model for FDG kinetics, which explicitly assumes that the endoplasmic reticulum is the dephosphorylation site for FDG in cancer cells. The numerical reduction of the compartmental model is performed by means of a regularized Gauss-Newton algorithm for numerical optimization. This analysis shows that the proposed three-compartment model equals the performance of a standard Sokoloff’s two-compartment system in fitting the data. However, it provides estimates of some of the parameters, such as the phosphorylation rate of FDG, more consistent with prior biochemical information. These results are made more solid from a computational viewpoint by proving the identifiability and by performing a sensitivity analysis of the proposed compartment model.
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Affiliation(s)
- Sara Sommariva
- Dipartimento di Matematica, Università di Genova, Genova, Italy
| | - Mara Scussolini
- Dipartimento di Matematica, Università di Genova, Genova, Italy
| | - Vanessa Cossu
- Dipartimento di Medicina Nucleare, Policlinico San Martino IRCCS, Genova, Italy
| | | | - Gianmario Sambuceti
- Dipartimento di Medicina Nucleare, Policlinico San Martino IRCCS, Genova, Italy
- Dipartimento di Scienze della Salute, Università di Genova, Genova, Italy
| | | | - Michele Piana
- Dipartimento di Matematica, Università di Genova, Genova, Italy
- CNR - SPIN, Genova, Italy
- * E-mail:
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23
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Hernández-Aguirre LE, Cota-Ruiz K, Peregrino-Uriarte AB, Gómez-Jiménez S, Yepiz-Plascencia G. The gluconeogenic glucose-6-phosphatase gene is expressed during oxygen-limited conditions in the white shrimp Penaeus (Litopenaeus) vannamei: Molecular cloning, membrane protein modeling and transcript modulation in gills and hepatopancreas. J Bioenerg Biomembr 2021; 53:449-461. [PMID: 34043143 DOI: 10.1007/s10863-021-09903-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 05/14/2021] [Indexed: 11/28/2022]
Abstract
The white shrimp Penaeus (Litopenaeus) vannamei is the most economically important crustacean species cultivated in the Western Hemisphere. This crustacean shifts its metabolism to survive under extreme environmental conditions such as hypoxia, although for a limited time. Glucose-6-phosphatase (G6Pase) is a key enzyme contributing to maintain blood glucose homeostasis through gluconeogenesis and glycogenolysis. To our knowledge, there are no current detailed studies about cDNA or gene sequences of G6Pase from any crustacean reported. Herein we report the shrimp P. (L.) vannamei cDNA and gene sequences. The gene contains seven exons interrupted by six introns. The deduced amino acid sequence has 35% identity to other homolog proteins, with the catalytic amino acids conserved and phylogenetically close to the corresponding invertebrate homologs. Protein molecular modeling predicted eight transmembrane helices with the catalytic site oriented towards the lumen of the endoplasmic reticulum. G6Pase expression under normoxic conditions was evaluated in hepatopancreas, gills, and muscle and the highest transcript abundance was detected in hepatopancreas. In response to different times of hypoxia, G6Pase mRNA expression did not change in hepatopancreas and became undetectable in muscle; however, in gills, its expression increased after 3 h and 24 h of oxygen limitation, indicating its essential role to maintain glycemic control in these conditions.
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Affiliation(s)
- Laura E Hernández-Aguirre
- Biología de Organismos Acuáticos, Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera Gustavo Enrique Astiazarán Rosas, No. 46, Colonia La Victoria, Sonora, 83304, Hermosillo, Mexico
| | - Keni Cota-Ruiz
- DOE-Plant Research Laboratory, Michigan State University, East Lansing, MI, 48824, USA
| | - Alma B Peregrino-Uriarte
- Biología de Organismos Acuáticos, Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera Gustavo Enrique Astiazarán Rosas, No. 46, Colonia La Victoria, Sonora, 83304, Hermosillo, Mexico
| | - Silvia Gómez-Jiménez
- Biología de Organismos Acuáticos, Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera Gustavo Enrique Astiazarán Rosas, No. 46, Colonia La Victoria, Sonora, 83304, Hermosillo, Mexico
| | - Gloria Yepiz-Plascencia
- Biología de Organismos Acuáticos, Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera Gustavo Enrique Astiazarán Rosas, No. 46, Colonia La Victoria, Sonora, 83304, Hermosillo, Mexico.
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24
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Palombo V, Alharthi A, Batistel F, Parys C, Guyader J, Trevisi E, D'Andrea M, Loor JJ. Unique adaptations in neonatal hepatic transcriptome, nutrient signaling, and one-carbon metabolism in response to feeding ethyl cellulose rumen-protected methionine during late-gestation in Holstein cows. BMC Genomics 2021; 22:280. [PMID: 33865335 PMCID: PMC8053294 DOI: 10.1186/s12864-021-07538-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/11/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Methionine (Met) supply during late-pregnancy enhances fetal development in utero and leads to greater rates of growth during the neonatal period. Due to its central role in coordinating nutrient and one-carbon metabolism along with immune responses of the newborn, the liver could be a key target of the programming effects induced by dietary methyl donors such as Met. To address this hypothesis, liver biopsies from 4-day old calves (n = 6/group) born to Holstein cows fed a control or the control plus ethyl-cellulose rumen-protected Met for the last 28 days prepartum were used for DNA methylation, transcriptome, metabolome, proteome, and one-carbon metabolism enzyme activities. RESULTS Although greater withers and hip height at birth in Met calves indicated better development in utero, there were no differences in plasma systemic physiological indicators. RNA-seq along with bioinformatics and transcription factor regulator analyses revealed broad alterations in 'Glucose metabolism', 'Lipid metabolism, 'Glutathione', and 'Immune System' metabolism due to enhanced maternal Met supply. Greater insulin sensitivity assessed via proteomics, and efficiency of transsulfuration pathway activity suggested beneficial effects on nutrient metabolism and metabolic-related stress. Maternal Met supply contributed to greater phosphatidylcholine synthesis in calf liver, with a role in very low density lipoprotein secretion as a mechanism to balance metabolic fates of fatty acids arising from the diet or adipose-depot lipolysis. Despite a lack of effect on hepatic amino acid (AA) transport, a reduction in metabolism of essential AA within the liver indicated an AA 'sparing effect' induced by maternal Met. CONCLUSIONS Despite greater global DNA methylation, maternal Met supply resulted in distinct alterations of hepatic transcriptome, proteome, and metabolome profiles after birth. Data underscored an effect on maintenance of calf hepatic Met homeostasis, glutathione, phosphatidylcholine and taurine synthesis along with greater efficiency of nutrient metabolism and immune responses. Transcription regulators such as FOXO1, PPARG, E2F1, and CREB1 appeared central in the coordination of effects induced by maternal Met. Overall, maternal Met supply induced better immunometabolic status of the newborn liver, conferring the calf a physiologic advantage during a period of metabolic stress and suboptimal immunocompetence.
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Affiliation(s)
- Valentino Palombo
- Dipartimento Agricoltura, Ambiente e Alimenti, Università degli Studi del Molise, via De Sanctis snc, 86100, Campobasso, Italy
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, 61801, USA
| | - Abdulrahman Alharthi
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, 61801, USA
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Fernanda Batistel
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, 84322, USA
| | - Claudia Parys
- Evonik Operations GmbH, Hanau-Wolfgang, 63457, Essen, Germany
| | - Jessie Guyader
- Evonik Operations GmbH, Hanau-Wolfgang, 63457, Essen, Germany
| | - Erminio Trevisi
- Department of Animal Sciences, Food and Nutrition (DIANA), Università Cattolica del Sacro Cuore, 29122, Piacenza, Italy
| | - Mariasilvia D'Andrea
- Dipartimento Agricoltura, Ambiente e Alimenti, Università degli Studi del Molise, via De Sanctis snc, 86100, Campobasso, Italy
| | - Juan J Loor
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, 61801, USA.
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25
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Mang Q, Hou J, Han T, Wang G, Wang Y, Liu Y, Ren Y, Zhao Y, He Z, Zhang X. The Effect of Infertility on the Liver Structure, Endocrinology, and Gene Network in Japanese Flounder. Animals (Basel) 2021; 11:936. [PMID: 33806167 PMCID: PMC8066618 DOI: 10.3390/ani11040936] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/20/2021] [Accepted: 03/23/2021] [Indexed: 12/19/2022] Open
Abstract
The liver can synthesize vitellogenin, the precursor of vitellin, which is needed for oocyte development and maturation. Here, we investigated the effects of infertility on liver structure, hormone regulation, and gene and protein networks in Japanese flounder (Paralichthys olivaceus). Results showed that the liver of infertile fish had fewer vacuoles and significantly lower serum vitellogenin (VTG) level than in liver of fertile fish. Whole transcriptomics analysis between infertile and fertile groups identified 2076 significantly differentially expressed (DE) mRNAs, 431 DE lncRNAs, 265 DE circRNAs, and 53 DE miRNAs. Proteomics analysis identified 838 DE proteins. Integrated analysis of whole transcriptomics and proteomics revealed 60 significantly DE genes and proteins associated with metabolism, immunity, signal transduction, and steroid biosynthesis. Moreover, non-coding RNA (miRNAs, circRNA, and lncRNA) transcripts involved in metabolism, immunity, and signal transduction in infertile liver were identified. In conclusion, this study shows that gonadal infertility is associated with not only changes in histological structure and hormone secretion but also changes in metabolism, immunity, and signal transduction networks in the liver. These results provide valuable information concerning the mechanism underlying infertility in fish.
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Affiliation(s)
- Qi Mang
- Key Laboratory of Aquatic Genomics, Ministry of Agriculture, Beijing 100141, China; (Q.M.); (J.H.)
- Chinese Academy of Fishery Sciences, Beijing 100141, China
| | - Jilun Hou
- Key Laboratory of Aquatic Genomics, Ministry of Agriculture, Beijing 100141, China; (Q.M.); (J.H.)
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Tian Han
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Guixing Wang
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Yufen Wang
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Yufeng Liu
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Yuqin Ren
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Yaxian Zhao
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Zhongwei He
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
| | - Xiaoyan Zhang
- Key Laboratory of Aquatic Genomics, Ministry of Agriculture, Beijing 100141, China; (Q.M.); (J.H.)
- Beidaihe Central Experiment Station, Chinese Academy of Fishery Sciences, Qinhuangdao 066100, China; (T.H.); (G.W.); (Y.W.); (Y.L.); (Y.R.); (Y.Z.); (Z.H.)
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26
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Egami R, Kokaji T, Hatano A, Yugi K, Eto M, Morita K, Ohno S, Fujii M, Hironaka KI, Uematsu S, Terakawa A, Bai Y, Pan Y, Tsuchiya T, Ozaki H, Inoue H, Uda S, Kubota H, Suzuki Y, Matsumoto M, Nakayama KI, Hirayama A, Soga T, Kuroda S. Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle. iScience 2021; 24:102217. [PMID: 33748705 PMCID: PMC7961104 DOI: 10.1016/j.isci.2021.102217] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/01/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Systemic metabolic homeostasis is regulated by inter-organ metabolic cycles involving multiple organs. Obesity impairs inter-organ metabolic cycles, resulting in metabolic diseases. The systemic landscape of dysregulated inter-organ metabolic cycles in obesity has yet to be explored. Here, we measured the transcriptome, proteome, and metabolome in the liver and skeletal muscle and the metabolome in blood of fasted wild-type and leptin-deficient obese (ob/ob) mice, identifying components with differential abundance and differential regulation in ob/ob mice. By constructing and evaluating the trans-omic network controlling the differences in metabolic reactions between fasted wild-type and ob/ob mice, we provided potential mechanisms of the obesity-associated dysfunctions of metabolic cycles between liver and skeletal muscle involving glucose-alanine, glucose-lactate, and ketone bodies. Our study revealed obesity-associated systemic pathological mechanisms of dysfunction of inter-organ metabolic cycles.
Multi-omic data in liver and skeletal muscle of WT and ob/ob mice were measured We developed the trans-omic network of differentially regulated metabolic reactions Dysregulation of inter-organ metabolic cycles associated with obesity was revealed
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Affiliation(s)
- Riku Egami
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Toshiya Kokaji
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Atsushi Hatano
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.,Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Katsuyuki Yugi
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.,Institute for Advanced Biosciences, Keio University, Fujisawa, 252-8520, Japan.,PRESTO, Japan Science and Technology Agency, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Miki Eto
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Keigo Morita
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Satoshi Ohno
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Molecular Genetics Research Laboratory, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Masashi Fujii
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Molecular Genetics Research Laboratory, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Department of Mathematical and Life Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-hiroshima City, Hiroshima, 739-8526, Japan
| | - Ken-Ichi Hironaka
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Saori Uematsu
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Akira Terakawa
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yunfan Bai
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Yifei Pan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Takaho Tsuchiya
- Bioinformatics Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.,Center for Artificial Intelligence Research, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan
| | - Haruka Ozaki
- Bioinformatics Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.,Center for Artificial Intelligence Research, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Shinsuke Uda
- Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hiroyuki Kubota
- Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Masaki Matsumoto
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Keiichi I Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan
| | - Shinya Kuroda
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.,Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan
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27
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Wilson MP, Quelhas D, Leão‐Teles E, Sturiale L, Rymen D, Keldermans L, Race V, Souche E, Rodrigues E, Campos T, Van Schaftingen E, Foulquier F, Garozzo D, Matthijs G, Jaeken J. SLC37A4-CDG: Second patient. JIMD Rep 2021; 58:122-128. [PMID: 33728255 PMCID: PMC7932867 DOI: 10.1002/jmd2.12195] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/01/2020] [Accepted: 12/16/2020] [Indexed: 12/19/2022] Open
Abstract
Recently, a disorder caused by the heterozygous de novo c.1267C>T (p.R423*) substitution in SLC37A4 has been described. This causes mislocalization of the glucose-6-phosphate transporter to the Golgi leading to a congenital disorder of glycosylation type II (SLC37A4-CDG). Only one patient has been reported showing liver disease that improved with age and mild dysmorphism. Here we report the second patient with a type II CDG caused by the same heterozygous de novo c.1267C>T (p.R423*) mutation thereby confirming the pathogenicity of this variant and expanding the clinical picture with type 1 diabetes, severe scoliosis, and membranoproliferative glomerulonephritis. Additional clinical and biochemical data provide further insight into the mechanism and prognosis of SLC37A4-CDG.
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Affiliation(s)
- Matthew P. Wilson
- Laboratory for Molecular DiagnosisCenter for Human Genetics, KU LeuvenLeuvenBelgium
| | - Dulce Quelhas
- Centro de Genetica Medica Jacinto de Magalhaes, Centro Hospitalar Universitário de São JoãoPortoPortugal
| | - Elisa Leão‐Teles
- Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de São JoãoPortoPortugal
| | - Luisa Sturiale
- CNR, Institute for Polymers, Composites and Biomaterials (IPCB)CataniaItaly
| | - Daisy Rymen
- Department of PediatricsCenter for Metabolic Diseases, University Hospitals LeuvenLeuvenBelgium
| | - Liesbeth Keldermans
- Laboratory for Molecular DiagnosisCenter for Human Genetics, KU LeuvenLeuvenBelgium
| | - Valérie Race
- Laboratory for Molecular DiagnosisCenter for Human Genetics, KU LeuvenLeuvenBelgium
| | - Erika Souche
- Laboratory for Molecular DiagnosisCenter for Human Genetics, KU LeuvenLeuvenBelgium
| | - Esmeralda Rodrigues
- Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de São JoãoPortoPortugal
| | - Teresa Campos
- Centro de Referência de Doenças Hereditárias do Metabolismo, Centro Hospitalar Universitário de São JoãoPortoPortugal
| | | | - François Foulquier
- Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et FonctionnelleLilleFrance
| | - Domenico Garozzo
- CNR, Institute for Polymers, Composites and Biomaterials (IPCB)CataniaItaly
| | - Gert Matthijs
- Laboratory for Molecular DiagnosisCenter for Human Genetics, KU LeuvenLeuvenBelgium
| | - Jaak Jaeken
- Department of PediatricsCenter for Metabolic Diseases, University Hospitals LeuvenLeuvenBelgium
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Lu Y, Wang E, Chen Y, Zhou B, Zhao J, Xiang L, Qian Y, Jiang J, Zhao L, Xiong X, Lu Z, Wu D, Liu B, Yan J, Zhang R, Zhang H, Hu C, Li X. Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor. J Clin Invest 2021; 130:3791-3804. [PMID: 32510471 DOI: 10.1172/jci134485] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 04/08/2020] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.
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Affiliation(s)
- Yan Lu
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - E Wang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Ying Chen
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Bing Zhou
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Jiejie Zhao
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Liping Xiang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Yiling Qian
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Jingjing Jiang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Lin Zhao
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Xuelian Xiong
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Zhiqiang Lu
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
| | - Duojiao Wu
- Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bin Liu
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and.,Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China
| | - Jing Yan
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, and
| | - Rong Zhang
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, and.,Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai, China
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Cheng Hu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, and.,Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai, China.,Institute for Metabolic Disease, Fengxian Central Hospital, Southern Medical University, Shanghai, China
| | - Xiaoying Li
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Endocrinology and Metabolism, and
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29
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Chung SI, Kang MY. Oral Administration of Germinated, Pigmented, Giant Embryo Rice ( Oryza sativa L. cv. Keunnunjami) Extract Improves the Lipid and Glucose Metabolisms in High-Fat Diet-Fed Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8829778. [PMID: 33552386 PMCID: PMC7846407 DOI: 10.1155/2021/8829778] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 11/18/2022]
Abstract
Obesity is a significant risk factor for chronic diseases. The effect of ethanol extract from germinated Keunnunjami, blackish-purple rice with a giant embryo, compare to ordinary brown rice, on the body weight and lipid and glucose metabolism in high-fat diet-fed mice was analyzed. Mice were fed with a high-fat diet-fed for 3 weeks and then orally administered with either distilled water (HF) or extract (0.25%, w/w) from brown, germinated brown, Keunnunjami, and germinated Keunnunjami rice for 4 weeks. Control mice were fed with a normal diet and orally administered with distilled water. The HF group showed markedly higher body weight and triglyceride, cholesterol, fatty acid, glucose, and insulin levels than the control group. However, the oral administration of rice extracts ameliorated this high-fat diet-induced obesity, hyperlipidemia, and hypoglycemia through the modulation of adipokine production, lipogenic and glucose-regulating enzyme activities, and mRNA expression of genes associated with lipid and glucose metabolism. The germinated Keunnunjami extract exhibited greater hypolipidemic, hypoglycemic, and body weight-lowering effects than the other rice extracts. The results demonstrated that germination could further enhance the physiological properties of rice and that germinated Keunnunjami extract has a strong therapeutic potential against high-fat diet-induced obesity, hyperlipidemia, and hyperglycemia.
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Affiliation(s)
- Soo Im Chung
- International Agricultural Training Center, Kyungpook National University, Daegu 41566, Republic of Korea
- Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Mi Young Kang
- Department of Food Science and Nutrition, Kyungpook National University, Daegu 41566, Republic of Korea
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30
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Doerksen MJ, Jones RS, Coughtrie MWH, Collier AC. Parameterization of Microsomal and Cytosolic Scaling Factors: Methodological and Biological Considerations for Scalar Derivation and Validation. Eur J Drug Metab Pharmacokinet 2020; 46:173-183. [PMID: 33340340 DOI: 10.1007/s13318-020-00666-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2020] [Indexed: 12/22/2022]
Abstract
Mathematical models that can predict the kinetics of compounds have been increasingly adopted for drug development and risk assessment. Data for these models may be generated from in vitro experimental systems containing enzymes contributing to metabolic clearance, such as subcellular tissue fractions including microsomes and cytosol. Extrapolation from these systems is facilitated by common scaling factors, known as microsomal protein per gram (MPPG) and cytosolic protein per gram (CPPG). Historically, parameterization of MPPG and CPPG has employed the use of recovery factors, commonly benchmarked to cytochromes P450 which work well in some contexts, but could be problematic for other enzymes. Here, we propose absolute quantification of protein content and supplementary assays to evaluate microsomal/cytosolic purity that should be employed. Examples include calculation of microsomal latency by mannose-6-phosphatase activity and immunoblotting of subcellular fractions with fraction-specific markers. Further considerations include tissue source, as disease states can affect enzyme expression and activity, and the methodology used for scalar parameterization. Regional- and organ-specific expression of enzymes, in addition to differences in organ physiology, is another important consideration. Because most efforts have focused on the liver that is, for the most part, homogeneous, derived scalars may not capture the heterogeneity of other major tissues contributing to xenobiotic metabolism including the kidneys and small intestine. Better understanding of these scalars, and how to appropriately derive them from extrahepatic tissues can provide support to the inferences made with physiologically based pharmacokinetic modeling, increase its accuracy in characterizing in vivo drug pharmacokinetics, and improve confidence in go-no-go decisions for clinical trials.
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Affiliation(s)
- Michael J Doerksen
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Robert S Jones
- Genentech Inc, 1 DNA Way, South San Francisco, California, 94080, USA
| | - Michael W H Coughtrie
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Abby C Collier
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
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31
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Almodóvar-Payá A, Villarreal-Salazar M, de Luna N, Nogales-Gadea G, Real-Martínez A, Andreu AL, Martín MA, Arenas J, Lucia A, Vissing J, Krag T, Pinós T. Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models. Int J Mol Sci 2020; 21:ijms21249621. [PMID: 33348688 PMCID: PMC7766110 DOI: 10.3390/ijms21249621] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 12/19/2022] Open
Abstract
GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD.
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Affiliation(s)
- Aitana Almodóvar-Payá
- Mitochondrial and Neuromuscular Disorders Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (A.A.-P.); (M.V.-S.); (A.R.-M.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
| | - Mónica Villarreal-Salazar
- Mitochondrial and Neuromuscular Disorders Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (A.A.-P.); (M.V.-S.); (A.R.-M.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
| | - Noemí de Luna
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
- Laboratori de Malalties Neuromusculars, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain
| | - Gisela Nogales-Gadea
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
- Grup de Recerca en Malalties Neuromusculars i Neuropediàtriques, Department of Neurosciences, Institut d’Investigacio en Ciencies de la Salut Germans Trias i Pujol i Campus Can Ruti, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Alberto Real-Martínez
- Mitochondrial and Neuromuscular Disorders Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (A.A.-P.); (M.V.-S.); (A.R.-M.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
| | - Antoni L. Andreu
- EATRIS, European Infrastructure for Translational Medicine, 1081 HZ Amsterdam, The Netherlands;
| | - Miguel Angel Martín
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
- Mitochondrial and Neuromuscular Diseases Laboratory, 12 de Octubre Hospital Research Institute (i+12), 28041 Madrid, Spain
| | - Joaquin Arenas
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
- Mitochondrial and Neuromuscular Diseases Laboratory, 12 de Octubre Hospital Research Institute (i+12), 28041 Madrid, Spain
| | - Alejandro Lucia
- Faculty of Sport Sciences, European University, 28670 Madrid, Spain;
| | - John Vissing
- Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; (J.V.); (T.K.)
| | - Thomas Krag
- Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; (J.V.); (T.K.)
| | - Tomàs Pinós
- Mitochondrial and Neuromuscular Disorders Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (A.A.-P.); (M.V.-S.); (A.R.-M.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain; (N.d.L.); (G.N.-G.); (M.A.M.); (J.A.)
- Correspondence: ; Tel.: +34-934894057
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The role of histidine dipeptides on postmortem acidification of broiler muscles with different energy metabolism. Poult Sci 2020; 100:1299-1307. [PMID: 33518087 PMCID: PMC7858186 DOI: 10.1016/j.psj.2020.11.032] [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: 04/29/2020] [Revised: 11/10/2020] [Accepted: 11/22/2020] [Indexed: 11/24/2022] Open
Abstract
It is generally held that the content of several free amino acids and dipeptides is closely related to the energy-supplying metabolism of skeletal muscles. Metabolic characteristics of muscles are involved in the variability of meat quality due to their ability to influence the patterns of energy metabolism not only in living animal but also during postmortem time. Within this context, this study aimed at establishing whether the concentration of histidine dipeptides can affect muscle postmortem metabolism, examining the glycolytic pathway of 3 chicken muscles (pectoralis major, extensor iliotibialis lateralis, and gastrocnemius internus as glycolytic, intermediate, and oxidative-type, respectively) selected based on their histidine dipeptides content and ultimate pH. Thus, a total of 8 carcasses were obtained from the same flock of broiler chickens (Ross 308 strain, females, 49 d of age, 2.8 kg body weight at slaughter) and selected immediately after evisceration from the line of a commercial processing plant. Meat samples of about 1 cm3 were excised from bone-in muscles at 15, 60, 120, and 1,440 min postmortem, instantly frozen in liquid nitrogen and used for the determination of pH, glycolytic metabolites, buffering capacity as well as histidine dipeptides content through 1H-NMR. Overall results suggest that glycolysis in leg muscles ceased already after 2 h postmortem, whereas in breast muscle continued until 24 h, when it exhibited significantly lower pH values (P < 0.05). However, considering its remarkable glycolytic potential, pectoralis major muscle should have exhibited a greater and faster acidification, suggesting that its higher (P < 0.05) histidine dipeptides' content might have prevented a potentially stronger acidification process. Accordingly, breast muscle also showed greater (P < 0.05) buffering ability in the pH range 6.0–7.0. Therefore, anserine and carnosine, being highly positively correlated with muscle's buffering capacity (P < 0.001), might play a role in regulating postmortem pH decline, thus exerting an effect on muscle metabolism during prerigor phase and the quality of the forthcoming meat. Overall results also suggest that total histidine dipeptides content along with muscular ultimate pH represent good indicators for the energy-supplying metabolism of chicken muscles.
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Shah AM, Wondisford FE. Tracking the carbons supplying gluconeogenesis. J Biol Chem 2020; 295:14419-14429. [PMID: 32817317 PMCID: PMC7573258 DOI: 10.1074/jbc.rev120.012758] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 08/12/2020] [Indexed: 11/06/2022] Open
Abstract
As the burden of type 2 diabetes mellitus (T2DM) grows in the 21st century, the need to understand glucose metabolism heightens. Increased gluconeogenesis is a major contributor to the hyperglycemia seen in T2DM. Isotope tracer experiments in humans and animals over several decades have offered insights into gluconeogenesis under euglycemic and diabetic conditions. This review focuses on the current understanding of carbon flux in gluconeogenesis, including substrate contribution of various gluconeogenic precursors to glucose production. Alterations of gluconeogenic metabolites and fluxes in T2DM are discussed. We also highlight ongoing knowledge gaps in the literature that require further investigation. A comprehensive analysis of gluconeogenesis may enable a better understanding of T2DM pathophysiology and identification of novel targets for treating hyperglycemia.
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Affiliation(s)
- Ankit M Shah
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA
| | - Fredric E Wondisford
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA
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Biochemistry of mammalian ferritins in the regulation of cellular iron homeostasis and oxidative responses. SCIENCE CHINA. LIFE SCIENCES 2020; 64:352-362. [PMID: 32974854 DOI: 10.1007/s11427-020-1795-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/11/2020] [Indexed: 02/08/2023]
Abstract
Ferritin, an iron-storage protein, regulates cellular iron metabolism and oxidative stress. The ferritin structure is characterized as a spherical cage, inside which large amounts of iron are deposited in a safe, compact and bioavailable form. All ferritins readily catalyze Fe(II) oxidation by peroxides at the ferroxidase center to prevent free Fe(II) from participating in oxygen free radical formation via Fenton chemistry. Thus, ferritin is generally recognized as a cytoprotective stratagem against intracellular oxidative damage The expression of cytosolic ferritins is usually regulated by iron status and oxidative stress at both the transcriptional and post-transcriptional levels. The mechanism of ferritin-mediated iron recycling is far from clarified, though nuclear receptor co-activator 4 (NCOA4) was recently identified as a cargo receptor for ferritin-based lysosomal degradation. Cytosolic ferritins are heteropolymers assembled by H- and L-chains in different proportions. The mitochondrial ferritins are homopolymers and distributed in restricted tissues. They play protective roles in mitochondria where heme- and Fe/S-enzymes are synthesized and high levels of ROS are produced. Genetic ferritin disorders are mainly related to the L-chain mutations, which generally cause severe movement diseases. This review is focused on the biochemistry and function of mammalian intracellular ferritin as the major iron-storage and anti-oxidation protein.
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Choi BR, Kim HJ, Lee YJ, Ku SK. Anti-Diabetic Obesity Effects of Wasabia Japonica Matsum Leaf Extract on 45% Kcal High-Fat Diet-Fed Mice. Nutrients 2020; 12:nu12092837. [PMID: 32947952 PMCID: PMC7551095 DOI: 10.3390/nu12092837] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/14/2020] [Accepted: 09/14/2020] [Indexed: 12/11/2022] Open
Abstract
The present study examined the effects of Wasabi leaf (WL) on 45% Kcal high-fat diet (HFD)-fed mild diabetic obese mice. In particular, the hepatoprotective (i.e., liver weight, histopathology of liver, serum aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase) effects of 12 weeks of continuous oral administration of 250 mg/kg metformin, and 200, 100, or 50 mg/kg WL were investigated. In addition, the hypolipidemic (i.e., serum triglyceride, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein levels), hypoglycemic (i.e., glycated hemoglobin, blood glucose and insulin levels, pancreatic weight, and immunohistochemical-histopathological analysis of the pancreas), and anti-obesity effects (i.e., body weight, mean food consumption, total and abdominal body fat mass, periovarian fat weight, and histopathology of the periovarian and abdominal wall adipocytes) were monitored. The liver and general antioxidant defense systems were also assessed by lipid metabolism-related gene expression. All diabetes manifestations and related complications, including obesity and non-alcoholic fatty liver disease (NAFLD), were dose-dependently reduced after 84 days of oral treatment with metformin or each of the three dosages of WL. In particular, 50 mg/kg WL showed effective suppression effects against HFD-induced diabetes and related complications of obesity, NAFLD, and hyperlipidemia, comparable to the effects of metformin.
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Affiliation(s)
- Beom-Rak Choi
- Research Institute, Nutracore Co., Ltd., Gwanggyo SK Viewlake A-3206, Beobjo-Ro 25, Yeongtong-Gu, Suwon, Gyeonggi-Do 16514, Korea;
| | - Hyun-Jee Kim
- Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Korea;
| | - Young-Joon Lee
- Department of Preventive Medicine, College of Korean Medicine, Deagu Haany University, 1, Haanydaero, Gyeongsan, Gyeongsangbuk-Do 38610, Korea
- Correspondence: (Y.-J.L.); (S.-K.K.); Tel.: +82-53-819-1296 (Y.-J.L.); +82-53-819-1549 (S.-K.K.)
| | - Sae-Kwang Ku
- Department of Histology and Anatomy, College of Korean Medicine, Daegu Haany University, 1, Haanydaero, Gyeongsan, Gyeongsangbuk-Do 38610, Korea
- Correspondence: (Y.-J.L.); (S.-K.K.); Tel.: +82-53-819-1296 (Y.-J.L.); +82-53-819-1549 (S.-K.K.)
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NHERF1 Loss Upregulates Enzymes of the Pentose Phosphate Pathway in Kidney Cortex. Antioxidants (Basel) 2020; 9:antiox9090862. [PMID: 32937931 PMCID: PMC7554817 DOI: 10.3390/antiox9090862] [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: 08/07/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
(1) Background: We previously showed Na/H exchange regulatory factor 1 (NHERF1) loss resulted in increased susceptibility to cisplatin nephrotoxicity. NHERF1-deficient cultured proximal tubule cells and proximal tubules from NHERF1 knockout (KO) mice exhibit altered mitochondrial protein expression and poor survival. We hypothesized that NHERF1 loss results in changes in metabolic pathways and/or mitochondrial dysfunction, leading to increased sensitivity to cisplatin nephrotoxicity. (2) Methods: Two to 4-month-old male wildtype (WT) and KO mice were treated with vehicle or cisplatin (20 mg/kg dose IP). After 72 h, kidney cortex homogenates were utilized for metabolic enzyme activities. Non-treated kidneys were used to isolate mitochondria for mitochondrial respiration via the Seahorse XF24 analyzer. Non-treated kidneys were also used for LC-MS analysis to evaluate kidney ATP abundance, and electron microscopy (EM) was utilized to evaluate mitochondrial morphology and number. (3) Results: KO mouse kidneys exhibit significant increases in malic enzyme and glucose-6 phosphate dehydrogenase activity under baseline conditions but in no other gluconeogenic or glycolytic enzymes. NHERF1 loss does not decrease kidney ATP content. Mitochondrial morphology, number, and area appeared normal. Isolated mitochondria function was similar between WT and KO. Conclusions: KO kidneys experience a shift in metabolism to the pentose phosphate pathway, which may sensitize them to the oxidative stress imposed by cisplatin.
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Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci 2020; 21:ijms21176275. [PMID: 32872570 PMCID: PMC7503727 DOI: 10.3390/ijms21176275] [Citation(s) in RCA: 1311] [Impact Index Per Article: 262.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/26/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023] Open
Abstract
Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.
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Gluconeogenesis and PEPCK are critical components of healthy aging and dietary restriction life extension. PLoS Genet 2020; 16:e1008982. [PMID: 32841230 PMCID: PMC7473531 DOI: 10.1371/journal.pgen.1008982] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 09/04/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023] Open
Abstract
High glucose diets are unhealthy, although the mechanisms by which elevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metabolism on aging quality (maintained locomotory capacity and median lifespan) and found that, in addition to shortening lifespan, excess glucose negatively impacts locomotory healthspan. Conversely, disrupting glucose utilization by knockdown of glycolysis-specific genes results in large mid-age physical improvements via a mechanism that requires the FOXO transcription factor DAF-16. Adult locomotory capacity is extended by glycolysis disruption, but maximum lifespan is not, indicating that limiting glycolysis can increase the proportion of life spent in mobility health. We also considered the largely ignored role of glucose biosynthesis (gluconeogenesis) in adult health. Directed perturbations of gluconeogenic genes that specify single direction enzymatic reactions for glucose synthesis decrease locomotory healthspan, suggesting that gluconeogenesis is needed for healthy aging. Consistent with this idea, overexpression of the central gluconeogenic gene pck-2 (encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promote pck-2 expression in specific intestinal cells. Dietary restriction also features DAF-16-dependent pck-2 expression in the intestine, and the healthspan benefits conferred by dietary restriction require pck-2. Together, our results describe a new paradigm in which nutritional signals engage gluconeogenesis to influence aging quality via DAF-16. These data underscore the idea that promotion of gluconeogenesis might be an unappreciated goal for healthy aging and could constitute a novel target for pharmacological interventions that counter high glucose consequences, including diabetes. It is known that high levels of dietary sugar can negatively impact human health, but the mechanisms underlying this remain unclear. Here we use the facile Caenorhabditis elegans genetic model to extend understanding of the impact of glucose and glucose metabolism on health and aging. We show that the two opposing glucose metabolism pathways–glycolysis and gluconeogenesis–have dramatically opposite effects on health: glycolytic activity responsible for sugar catabolism is detrimental, but driving gluconeogenesis promotes healthy aging. The powerful longevity regulator DAF-16 is required for the healthspan effects of gluconeogenesis. Our data highlight the intriguing possibility that driving the biosynthetic gluconeogenesis pathway could be a novel strategy for healthspan promotion. Indeed, we find that increasing levels of the core gluconeogenic enzyme PEPCK (PCK-2) in just a few intestinal cells can increase overall health in a DAF-16-dependent manner. Dietary restriction, which can promote health and longevity across species, increases PCK-2 levels in the intestine via DAF-16, and PCK-2 is required for the health benefits seen when calories are limited. Our results define gluconeogenic metabolism as a key component of healthy aging, and suggest that interventions that promote gluconeogenesis may help combat the onset of age-related diseases, including diabetes.
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Altberg A, Hovav R, Chapnik N, Madar Z. Effect of dietary oils from various sources on carbohydrate and fat metabolism in mice. Food Nutr Res 2020; 64:4287. [PMID: 32952497 PMCID: PMC7478119 DOI: 10.29219/fnr.v64.4287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 06/04/2020] [Accepted: 06/10/2020] [Indexed: 12/11/2022] Open
Abstract
Background Dietary oils differ in their fatty acid composition and the presence of additional microcomponents (antioxidants, etc.). These differences are thought to invoke different biochemical pathways, thus affecting fats and carbohydrates metabolism differently. Olive oil (OO) and soybean oil (SO) are common vegetable oils in the local cuisine. Peanuts oils of local varieties are viewed as potential sources of dietary vegetable oils, especially in the food industry. Objective We examined the effect of four different dietary vegetable oils on carbohydrate and lipid metabolism in mice. The selected oils were OO, high in oleic acid, extracted from cultivated high oleic acid peanut (C-PO), regular peanut oil (PO), and SO. Design In this study, 32 male C57BL/6J mice were randomly divided into four groups (n = 8 in each group) and were fed with four different diets enriched with 4% (w/w) dietary vegetable oils (OO, C-PO, PO, or SO). After 10 weeks, the mice were sacrificed. Western blot was used to examine proteins such as phospho-AMP-activated protein kinase (p-AMPK), ace-tyl-CoA carboxylase (ACC), cluster of differentiation 36 (CD36), and Sirtuin 1 (SIRT1), whereas real-time polymerase chain reaction (PCR) was used to examine the expression of sterol regulatory element-binding protein-1c (SREBP-1C), fatty acid synthase (FAS), glucose-6-phosphatase (G6Pase), and CD36 transcripts. Results In mice-fed SO, lipid accumulation was predominately in adipose tissue, accompanied a tendency decrease in insulin sensitivity. Mice-fed OO had lower plasma triglycerides (TG) and increased hepatic CD36 gene expression. The C-PO group presented lower messenger RNA (mRNA) levels in the liver for all examined genes: SREBP-1c, FAS, G6Pase, and CD36. There were no significant differences in weight gain, plasma cholesterol and high-density lipoprotein (HDL) cholesterol levels, hepatic ACC, SIRT1, AMPK, and CD36 protein levels or in liver function among the diets. Discussion It seems that as long as fat is consumed in moderation, oil types may play a lesser role in the metabolism of healthy individuals. Conclusion This finding has the potential to increase flexibility in choosing oil types for consumption.
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Affiliation(s)
- Anna Altberg
- Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Ran Hovav
- Department of Field and Vegetable Crops, Plant Sciences Institute, ARO (Volcani Center), Bet Dagan, Israel
| | - Nava Chapnik
- Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Zecharia Madar
- Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
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Laskar A, Shklyaev OE, Balazs AC. Controlling the Spatiotemporal Transport of Particles in Fluid-Filled Microchambers. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2020; 36:7124-7132. [PMID: 32073864 DOI: 10.1021/acs.langmuir.9b03546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The development of microscale devices that autonomously perform multistep processes is vital to advancing the use of microfluidics in industrial applications. Such advances can potentially be achieved through the use of "chemical pumps" that transduce the energy from inherent catalytic reactions into fluid flow within microchambers, without the need for extraneous external equipment. Using computational modeling, we focus on arrangements of multiple chemical pumps that are formed by anchoring patches of different enzymes onto the floor of a fluid-filled chamber. With the addition of the appropriate reactants, only one of the enzymatic patches is activated and thereby generates fluid flow centered about that patch. These flows drive the self-assembly of microparticles in the solution and localize the particles onto the activated patches. By varying the spatial arrangement of the enzymatic patches, and the sequence in which the appropriate reactants are added to the solution, we realize spatiotemporal control over the fluid flow and the sequential transport of microparticles from one patch to another. The order in which the particles visit the different patches can be altered by varying the sequence in which the reactants are added to the solution. By harnessing catalytic cascade reactions, where the product of one reaction is the reactant for the next, we achieve directed transport between the patches with the addition of just one reactant, which initiates the catalytic cascade. Through these studies, we show how the trajectory of the particles' motion among different "stations" can be readily regulated through intrinsic catalytic reactions and thus, provide guidelines for creating fluidic devices that perform multistep reactions in an autonomous, self-sustained manner.
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Affiliation(s)
- Abhrajit Laskar
- Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Oleg E Shklyaev
- Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Anna C Balazs
- Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
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Wang X, Mick G, McCormick K. Pyridine nucleotide regulation of hepatic endoplasmic reticulum calcium uptake. Physiol Rep 2020; 7:e14151. [PMID: 31222964 PMCID: PMC6586769 DOI: 10.14814/phy2.14151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 05/31/2019] [Indexed: 01/03/2023] Open
Abstract
Pyridine nucleotides serve an array of intracellular metabolic functions such as, to name a few, shuttling electrons in enzymatic reactions, safeguarding the redox state against reactive oxygen species, cytochrome P450 (CYP) enzyme detoxification pathways and, relevant to this study, the regulation of ion fluxes. In particular, the maintenance of a steep calcium gradient between the cytosol and endoplasmic reticulum (ER), without which apoptosis ensues, is achieved by an elaborate combination of energy–requiring ER membrane pumps and efflux channels. In liver microsomes, net calcium uptake was inhibited by physiological concentrations of NADP. In the presence of 1 mmol/L NADP, calcium uptake was attenuated by nearly 80%, additionally, this inhibitory effect was blunted by concomitant addition of NADPH. No other nicotinamide containing compounds ‐save a slight inhibition by NAADP‐hindered calcium uptake; thus, only oxidized pyridine nucleotides, or related compounds with a phosphate moiety, had an imposing effect. Moreover, the NADP inhibition was evident even after selectively blocking ER calcium efflux channels. Given the fundamental role of endoplasmic calcium homeostasis, it is plausible that changes in cytosolic NADP concentration, for example, during anabolic processes, could regulate net ER calcium uptake.
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Affiliation(s)
- Xudong Wang
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Gail Mick
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Kenneth McCormick
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
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Nam SJ, Chung SI, Kang MY. Acidic-Treated Acorn Pollen as Health Functional Food Materials for Improvement of Post-Menopausal Glucose Metabolism. Prev Nutr Food Sci 2020; 25:50-57. [PMID: 32292755 PMCID: PMC7143018 DOI: 10.3746/pnf.2020.25.1.50] [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: 05/07/2019] [Accepted: 01/17/2020] [Indexed: 11/14/2022] Open
Abstract
Pollen has high physiological value because it contains protein, essential amino acids, and 16 vitamins. However, pollen is difficult to absorb because of its hard form. This study explores the use of the acid-treated acorn pollen (acorn pollen deposited in apple vinegar for 30 days). The health functions of acid-treated acorn pollen on post-menopausal metabolism was tested by analyzing in vitro and in vivo biomarkers for glucose metabolism, by using the acid-treated acorn pollen and its residues, respectively. In vitro experiments showed high activity after measuring the low potency of glucose-related enzymes. In vivo experiments showed reduced blood glucose and insulin levels after consuming pollen. Pollen also increased the concentration of glucokinase, a glucose-regulating enzyme in hepatic and nephritic tissue, and lowered the concentration of glucose-6-phosphatase. These results are encouraging in showing that acid pollen can be used as a functional health food for treatment of post-menopausal metabolism.
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Affiliation(s)
- Su Jin Nam
- Department of Food Sciences and Nutrition, Kyungpook National University, Daegu 41566, Korea
| | - Soo Im Chung
- International Agricultural Training Center, Kyungpook National University, Daegu 41566, Korea
| | - Mi Young Kang
- Department of Food Sciences and Nutrition, Kyungpook National University, Daegu 41566, Korea
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Mata-Torres G, Andrade-Cetto A, Espinoza-Hernández FA, Cárdenas-Vázquez R. Hepatic Glucose Output Inhibition by Mexican Plants Used in the Treatment of Type 2 Diabetes. Front Pharmacol 2020; 11:215. [PMID: 32194426 PMCID: PMC7065531 DOI: 10.3389/fphar.2020.00215] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 02/14/2020] [Indexed: 11/21/2022] Open
Abstract
De novo hepatic glucose production or hepatic gluconeogenesis is the main contributor to hyperglycemia in the fasting state in patients with type 2 diabetes (T2D) owing to insulin resistance, which leads to at least twice as much glucose synthesis compared to healthy subjects. Therefore, control of this pathway is a promising target to avoid the chronic complications associated with elevated glucose levels. Patients with T2D in the rural communities of Mexico use medicinal plants prepared as infusions that are consumed over the day between meals, thus following this rationale (consumption of the infusions in the fasting state), one approach to understanding the possible mechanism of action of medicinal plants is to assess their capacity to inhibit hepatic glucose production. Furthermore, in several of these plants, the presence of phenolic acids able to block the enzyme glucose-6-phosphatase (G6Pase) is reported. In the present work, extracts of Ageratina petiolaris, Bromelia karatas, Equisetum myriochaetum, Rhizophora mangle, and Smilax moranensis, which are Mexican plants that have been traditionally used to treat T2D, were assayed to evaluate their possible hepatic glucose output (HGO) inhibitory activity with a pyruvate tolerance test in 18-h fasted STZ-NA Wistar rats after oral administration of the extracts. In addition, the in vitro effects of the extracts on the last HGO rate-limiting enzyme G6Pase was analyzed. Our results showed that four of these plants had an effect on hepatic glucose production in the in vivo or in vitro assays. A. petiolaris and R. mangle extracts decreased glucose output, preventing an increase in the blood glucose levels and sustaining this prevented increase after pyruvate administration. Moreover, both extracts inhibited the catalytic activity of the G6Pase complex. On the other hand, even though S. moranensis and B. karatas did not exhibit a significant in vivo effect, S. moranensis had the most potent inhibitory effect on this enzymatic system, while the E. myriochaetum extract only inhibited hepatic glucose production in the pyruvate tolerance test. Because of the traditional method in which diabetic patients use plants, hepatic glucose production inhibition seems to be a mechanism that partially explains the common hypoglycemic effect. However, further studies must be carried out to characterize other mechanisms whereby these plants can decrease HGO.
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Affiliation(s)
- Gerardo Mata-Torres
- Laboratorio de Etnofarmacología, Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Adolfo Andrade-Cetto
- Laboratorio de Etnofarmacología, Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | - René Cárdenas-Vázquez
- Laboratorio de Biología Animal Experimental, Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Veiga‐da‐Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. J Inherit Metab Dis 2020; 43:14-24. [PMID: 31691304 PMCID: PMC7041631 DOI: 10.1002/jimd.12187] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/18/2019] [Accepted: 11/04/2019] [Indexed: 12/11/2022]
Abstract
It is traditionally assumed that enzymes of intermediary metabolism are extremely specific and that this is sufficient to prevent the production of useless and/or toxic side-products. Recent work indicates that this statement is not entirely correct. In reality, enzymes are not strictly specific, they often display weak side activities on intracellular metabolites (substrate promiscuity) that resemble their physiological substrate or slowly catalyse abnormal reactions on their physiological substrate (catalytic promiscuity). They thereby produce non-classical metabolites that are not efficiently metabolised by conventional enzymes. In an increasing number of cases, metabolite repair enzymes are being discovered that serve to eliminate these non-classical metabolites and prevent their accumulation. Metabolite repair enzymes also eliminate non-classical metabolites that are formed through spontaneous (ie, not enzyme-catalysed) reactions. Importantly, genetic deficiencies in several metabolite repair enzymes lead to 'inborn errors of metabolite repair', such as L-2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria, 'ubiquitous glucose-6-phosphatase' (G6PC3) deficiency, the neutropenia present in Glycogen Storage Disease type Ib or defects in the enzymes that repair the hydrated forms of NADH or NADPH. Metabolite repair defects may be difficult to identify as such, because the mutated enzymes are non-classical enzymes that act on non-classical metabolites, which in some cases accumulate only inside the cells, and at rather low, yet toxic, concentrations. It is therefore likely that many additional metabolite repair enzymes remain to be discovered and that many diseases of metabolite repair still await elucidation.
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Affiliation(s)
| | - Emile Van Schaftingen
- de Duve InstituteUniversité Catholique de Louvain (UCLouvain)BrusselsBelgium
- Walloon Excellence in Life Sciences and Biotechnology (WELBIO)UCLouvainBrusselsBelgium
| | - Guido T. Bommer
- de Duve InstituteUniversité Catholique de Louvain (UCLouvain)BrusselsBelgium
- Walloon Excellence in Life Sciences and Biotechnology (WELBIO)UCLouvainBrusselsBelgium
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The Effect of Vascular Endothelial Growth Factor on Bone Marrow Mesenchymal Stem Cell Engraftment in Rat Fibrotic Liver upon Transplantation. Stem Cells Int 2019; 2019:5310202. [PMID: 31885614 PMCID: PMC6915021 DOI: 10.1155/2019/5310202] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/17/2019] [Indexed: 12/17/2022] Open
Abstract
Background According to existing related experiments and research reports, stem cell transplantation therapy has been shown to have a positive effect on the recovery of liver fibrosis/cirrhosis, but for some reason, this therapy still cannot be widely used in clinical work. One of the reasons that cannot be ignored is the low quantity of exogenous stem cells transplanted into the liver in vivo. Thus, we investigated whether the use of the vascular endothelial growth factor (VEGF) can increase the number of stem cell transplants and improve the efficacy of stem cell transplantation therapy. Methods Using a Sprague-Dawley rat liver fibrosis model, we transplanted into fibrosis liver allograft bone marrow mesenchymal stem cells (BMSCs) which were labelled with chlormethylbenzamido-1,1-dioctadecyl-3,3,3′3′-tetramethylin-docarbocyamine (CM-DiI) or injected VEGF adenovirus solution through the tail vein or conducted the above two operations simultaneously. The cell surface receptor profile of BMSC was examined by flow cytometry and immunofluorescence staining. Hepatic sinusoidal vascular leakage was measured with Evan's blue dye assay. Paraffin section staining, immunofluorescent staining, RT-qPCR (quantitative reverse transcription polymerase chain reaction), and Western blot were used to evaluate hepatic pathological changes and physiology function. Result The in vivo study indicated that, comparing with other groups of rats, the rats with combined treatment of BMSC transplantation and VEGF injection exhibited obvious reduction in liver fibrosis. Evan's blue dye assay suggests that after injecting with VEGF adenovirus solution, the rat's hepatic sinusoidal permeability would be increased. We confirmed the expression of very late antigen-4 (VLA4, integrin α4β1) on rat BMSCs and the elevated expression of vascular adhesion molecule-1 (VCAM-1) in the hepatic sinusoidal endothelial cells. In addition, the analysis of CM-DiI-labeled BMSCs showed that the BMSC+VEGF group exhibited better cell engraftment and that the engrafted cells were mainly distributed in the hepatic parenchyma. Furthermore, compared with the other situation, it is best to reconstitute the liver secretion and regeneration function of rats after combined application of VEGF and BMSC. Conclusion We showed that VEGF promotes the engraftment of BMSCs in liver fibrosis, enhances liver regeneration, and improves liver function. These outcomes may be related to the increasing hepatic sinusoidal endothelium permeability and VCAM-1-increased expression.
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Camaforte NADP, Saldanha LL, Vareda PMP, Rezende-Neto JM, Senger MR, Delgado AQ, Morgan HJN, Violato NM, Pieroni LG, Dokkedal AL, Silva-Júnior FP, Bosqueiro JR. Hypoglycaemic activity of Bauhinia holophylla through GSK3-β inhibition and glycogenesis activation. PHARMACEUTICAL BIOLOGY 2019; 57:269-279. [PMID: 31007116 PMCID: PMC6493280 DOI: 10.1080/13880209.2019.1599962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 03/07/2019] [Accepted: 03/21/2019] [Indexed: 06/09/2023]
Abstract
CONTEXT Bauhinia L. species, including Bauhinia holophylla (Bong.) Steud. (Fabaceae), have traditionally been used to treat diabetes. Bauhinia is a complex botanical genus, and the indiscriminate use of the diverse Bauhinia species is reflected in the experimental divergence of their medicinal potential. OBJECTIVE The hypoglycaemic and hypolipidaemic effects, molecular mechanism of action and phytochemical properties of an authentic extract of B. holophylla leaves were evaluated. MATERIALS AND METHODS A phytochemical study of a 70% EtOH extract was performed using FIA-ESI-IT-MS/MSn and HPLC-PAD-ESI-IT-MS. The extract (200 or 400 mg/kg b.w.) was administered for 14 days to streptozotocin-induced diabetic Swiss mice. Glucose tolerance and insulin sensitivity, blood parameters, gene and protein expression, and the in vivo and in vitro inhibition of intestinal glucosidases were assessed. RESULTS HPLC-PAD-ESI-IT-MS analysis identified flavonoid derivatives of quercetin, myricetin, luteolin and kaempferol. Treatment with 400 mg/kg of the extract reduced blood glucose (269.0 ± 32.4 mg/dL vs. 468.0 ± 32.2 mg/dL for diabetic animals), improved glucose tolerance, decreased cholesterol and triglyceride levels, and increased the mRNA expression of proteins involved in glucogenesis in the liver and muscle, such as PI3-K/Akt, GS, GSK3-β (ser-9), AMPK and Glut4. The activity of intestinal maltase was inhibited in vitro (IC50: 43.0 µg/mL for the extract compared to 516.4 µg/mL for acarbose) and in vivo. DISCUSSION AND CONCLUSIONS Treatment with B. holophylla was associated with a marked hypoglycaemic effect through the stimulation of glycogenesis and inhibition of gluconeogenesis and intestinal glucose absorption, without increasing basal insulinaemia.
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Affiliation(s)
| | | | | | - João M. Rezende-Neto
- Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute (FIOCRUZ), Rio de Janeiro, Brazil
| | - Mario R. Senger
- Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute (FIOCRUZ), Rio de Janeiro, Brazil
| | - Aislan Q. Delgado
- Institute of Biosciences, São Paulo State University, Botucatu, São Paulo, Brazil
| | - Henrique J. N. Morgan
- Department of Biological Sciences, São Paulo State University, Bauru, São Paulo, Brazil
| | | | - Laís Goyos Pieroni
- Institute of Biosciences, São Paulo State University, Botucatu, São Paulo, Brazil
| | - Anne Lígia Dokkedal
- Department of Biological Sciences, São Paulo State University, Bauru, São Paulo, Brazil
| | - Floriano P. Silva-Júnior
- Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute (FIOCRUZ), Rio de Janeiro, Brazil
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Erukainure OL, Oyebode OA, Salau VF, Koorbanally NA, Islam MS. Flowers of Clerodendrum volubile modulates redox homeostasis and suppresses DNA fragmentation in Fe 2+ - induced oxidative hepatic and pancreatic injuries; and inhibits carbohydrate catabolic enzymes linked to type 2 diabetes. J Diabetes Metab Disord 2019; 18:513-524. [PMID: 31890677 PMCID: PMC6915180 DOI: 10.1007/s40200-019-00458-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 10/17/2019] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Medicinal plants have long been recognized for their roles in the treatment and management of diabetes and its complications. The antioxidative and antidiabetic properties of Clerodendrum volubile flowers were investigated in vitro and ex vivo. METHODS The flowers were sequentially extracted with solvents of increasing polarity (n-hexane, ethyl acetate, ethanol and water). The concentrated extracts were subjected to in vitro antioxidant assays using the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) scavenging and Ferric reducing antioxidant power (FRAP) protocols. Their inhibitory activities were investigated on α-glucosidase, pancreatic lipases, pancreatic ATPase and glucose-6-phosphatase activities. Their anti-oxidative and anti-apoptotic effects on Fe2+-induced oxidative injuries were also investigated in pancreatic and hepatic tissues ex vivo. RESULTS The extracts showed potent free radical scavenging activity and significantly (p < 0.05) inhibited all studied enzymes. The GSH level was significantly (p < 0.05) elevated in both tissues with concomitant increase in superoxide dismutase (SOD) and catalase activities as well as reduced levels of malondialdehyde (MDA). The extracts significantly (p < 0.05) suppressed DNA fragmentation in hepatic tissue. These activities were dose-dependent. The ethanol extract showed the best activity and can be attributed to the synergetic effect of its chemical constituents identified via gas chromatography-mass spectroscopy (GC-MS). CONCLUSION These results suggest the antioxidative, antidiabetic and anti-obesogenic potentials of C. volubile flowers.
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Affiliation(s)
- Ochuko L. Erukainure
- Department of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, (Westville Campus), Durban, 4000 South Africa
- Nutrition and Toxicology Division, Federal Institute of Industrial Research, Lagos, Nigeria
- Department of Pharmacology, School of Clinical Medicine, Faculty of Health Sciences, University of the Free State, Bloemfontein, 9300 South Africa
| | - Olajumoke A. Oyebode
- Department of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, (Westville Campus), Durban, 4000 South Africa
| | - Veronica F. Salau
- Department of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, (Westville Campus), Durban, 4000 South Africa
| | - Neil A. Koorbanally
- School of Chemistry and Physics, University of KwaZulu-Natal, (Westville Campus), Durban, 4000 South Africa
| | - Md. Shahidul Islam
- Department of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, (Westville Campus), Durban, 4000 South Africa
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Lizák B, Szarka A, Kim Y, Choi KS, Németh CE, Marcolongo P, Benedetti A, Bánhegyi G, Margittai É. Glucose Transport and Transporters in the Endomembranes. Int J Mol Sci 2019; 20:ijms20235898. [PMID: 31771288 PMCID: PMC6929180 DOI: 10.3390/ijms20235898] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/16/2019] [Accepted: 11/21/2019] [Indexed: 12/18/2022] Open
Abstract
Glucose is a basic nutrient in most of the creatures; its transport through biological membranes is an absolute requirement of life. This role is fulfilled by glucose transporters, mediating the transport of glucose by facilitated diffusion or by secondary active transport. GLUT (glucose transporter) or SLC2A (Solute carrier 2A) families represent the main glucose transporters in mammalian cells, originally described as plasma membrane transporters. Glucose transport through intracellular membranes has not been elucidated yet; however, glucose is formed in the lumen of various organelles. The glucose-6-phosphatase system catalyzing the last common step of gluconeogenesis and glycogenolysis generates glucose within the lumen of the endoplasmic reticulum. Posttranslational processing of the oligosaccharide moiety of glycoproteins also results in intraluminal glucose formation in the endoplasmic reticulum (ER) and Golgi. Autophagic degradation of polysaccharides, glycoproteins, and glycolipids leads to glucose accumulation in lysosomes. Despite the obvious necessity, the mechanism of glucose transport and the molecular nature of mediating proteins in the endomembranes have been hardly elucidated for the last few years. However, recent studies revealed the intracellular localization and functional features of some glucose transporters; the aim of the present paper was to summarize the collected knowledge.
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Affiliation(s)
- Beáta Lizák
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary; (B.L.); (C.E.N.); (G.B.)
| | - András Szarka
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, 1111 Budapest, Hungary;
| | - Yejin Kim
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (Y.K.); (K.-s.C.)
| | - Kyu-sung Choi
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (Y.K.); (K.-s.C.)
| | - Csilla E. Németh
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary; (B.L.); (C.E.N.); (G.B.)
| | - Paola Marcolongo
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy; (P.M.); (A.B.)
| | - Angelo Benedetti
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy; (P.M.); (A.B.)
| | - Gábor Bánhegyi
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary; (B.L.); (C.E.N.); (G.B.)
| | - Éva Margittai
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (Y.K.); (K.-s.C.)
- Correspondence: ; Tel.: +36-459-1500 (ext. 60311); Fax: +36-1-2662615
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Species-Specific Glucose-6-Phosphatase Activity in the Small Intestine-Studies in Three Different Mammalian Models. Int J Mol Sci 2019; 20:ijms20205039. [PMID: 31614497 PMCID: PMC6829527 DOI: 10.3390/ijms20205039] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/04/2019] [Accepted: 10/09/2019] [Indexed: 12/16/2022] Open
Abstract
Besides the liver, which has always been considered the major source of endogenous glucose production in all post-absorptive situations, kidneys and intestines can also produce glucose in blood, particularly during fasting and under protein feeding. However, observations gained in different experimental animals have given ambiguous results concerning the presence of the glucose-6-phosphatase system in the small intestine. The aim of this study was to better define the species-related differences of this putative gluconeogenic organ in glucose homeostasis. The components of the glucose-6-phosphatase system (i.e., glucose-6-phosphate transporter and glucose-6-phosphatase itself) were analyzed in homogenates or microsomal fractions prepared from the small intestine mucosae and liver of rats, guinea pigs, and humans. Protein and mRNA levels, as well as glucose-6-phosphatase activities, were detected. The results showed that the glucose-6-phosphatase system is poorly represented in the small intestine of rats; on the other hand, significant expressions of glucose-6-phosphate transporter and of the glucose-6-phosphatase were found in the small intestine of guinea pigs and homo sapiens. The activity of the recently described fructose-6-phosphate transporter–intraluminal hexose isomerase pathway was also present in intestinal microsomes from these two species. The results demonstrate that the gluconeogenic role of the small intestine is highly species-specific and presumably dependent on feeding behavior (e.g., fructose consumption) and the actual state of metabolism.
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Linked Hexokinase and Glucose-6-Phosphatase Activities Reflect Grade of Ovarian Malignancy. Mol Imaging Biol 2019; 21:375-381. [PMID: 29987620 DOI: 10.1007/s11307-018-1247-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE Malignant cells exhibit increased rates of aerobic glycolysis. Here, we tested whether the accumulation of fluoro-deoxyglucose-6-phosphate (FDG6P) in ovarian cancers of differential malignancy reflects inversely correlated elevations of hexokinase (HK) and glucose-6-phosphatase (G6Pase) activities. PROCEDURES Twenty-nine women with suspected ovarian cancer had positron emission tomography (PET) prior to surgery. From fresh-frozen tissue, we determined the activities of HK and G6Pase, and from the PET images, we determined the tumor maximum standardized uptake value (SUVmax) of 2-deoxy-2-[18F]fluoro-D-glucose. RESULTS The SUVmax of malignant lesions significantly exceeded the SUVmax of benign (p < 0.005) and borderline lesions (p < 0.0005) that did not differ significantly. We found no significant correlation between measured HK or G6Pase activities and histological tumor type or SUVmax except that G6Pase activities were higher in malignant than borderline lesions (p < 0.05). Measured HK and G6Pase activities correlated inversely (p < 0.05). The slopes from the regression lines of the three correlations yielded positively correlated abscissa and ordinate intercepts, designated HKmax and G6Pasemax, respectively (r = 0.67, p < 0.0001). The positive correlations between the abscissa and ordinate intercepts with SUVmax had regression coefficients of r = 0.44, p < 0.05; and r = 0.39, p < 0.05, respectively. CONCLUSIONS The results distinguished two ovarian cancer phenotypes, one with elevated HK activity and low G6Pase activity, and another with the opposite characteristics.
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