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1
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Jiang Q, Xu W, Ding Q, Cai X, Dong Q, Gao X, Zhang Y, Zhang X. Molecular characterization and function of sodium-dependent glucose transporter 1 in postprandial glucose homeostasis in Macrobrachium rosenbergii. Comp Biochem Physiol A Mol Integr Physiol 2025; 302:111822. [PMID: 39921081 DOI: 10.1016/j.cbpa.2025.111822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/04/2025] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
Aquatic animals often exhibit glucose intolerance following a glucose load, and understanding the mechanisms of glucose uptake is crucial for elucidating the underlying processes. Sodium-dependent glucose transporter 1 (SGLT1) plays a crucial role in the process of intestinal glucose absorption and transport in vertebrates, but there is limited information about its function in crustaceans. This study identified the SGLT1 gene (named MrSGLT1) from Macrobrachium rosenbergii. The full cDNA sequence is 3764 bp, encoding 903 amino acids. Unlike SGLT1 in most teleost fish, which have 14 transmembrane domains, MrSGLT1 protein has only 12. MrSGLT1 was predominantly expressed in the intestine, with its expression increasing after feeding. This was accompanied by elevated levels of glucose and trehalose in the hemolymph, and increased glycogen levels in the hepatopancreas. Silencing MrSGLT1 in vivo resulted in decreased glucose and trehalose levels in the hemolymph and reduced glycogen levels in the hepatopancreas, although muscle glycogen levels were unaffected. Moreover, knockdown of MrSGLT1 led to increased expression of genes involved in glycogenolysis and decreased expression of genes associated with glycogenesis, inhibiting postprandial glycogen accumulation in the hepatopancreas. Feeding-induced glycolysis was also inhibited following MrSGLT1 silencing, while no significant changes were observed in gluconeogenesis-related genes. These findings highlight the critical role of MrSGLT1 in regulating postprandial glucose homeostasis in crustaceans.
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Affiliation(s)
- Qun Jiang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Wenjing Xu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Qianqian Ding
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Xiaoyu Cai
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Qi Dong
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Xiaojian Gao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Yao Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Xiaojun Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
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2
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Ruan Z, Wang Y, Shi L, Yang XJ. Progress of research on glucose transporter proteins in hepatocellular carcinoma. World J Hepatol 2025; 17:104715. [DOI: 10.4254/wjh.v17.i3.104715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 02/02/2025] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs’ roles in HCC and to determine the most effective ways to translate these findings into clinical practice.
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Affiliation(s)
- Zheng Ruan
- The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yan Wang
- Division of Personnel, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
| | - Lei Shi
- Department of General Surgery, The Second people’s Hospital of Lanzhou, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jun Yang
- Department of General Surgery, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
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3
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Coca A, López S, Órdenes P, Sepúlveda V, Cuevas D, Villarroel A, Álvarez-Indo J, Burgos PV, Tarifeño E, Elizondo-Vega R, García-Robles MA. Knocking down the neuronal lactate transporter MCT2 in the arcuate nucleus of female rats increases food intake and body weight. Sci Rep 2025; 15:7497. [PMID: 40032881 DOI: 10.1038/s41598-025-90513-2] [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: 11/10/2024] [Accepted: 02/13/2025] [Indexed: 03/05/2025] Open
Abstract
In the arcuate nucleus of the hypothalamus, tanycyte-neuron interactions regulate glucose homeostasis and feeding behavior. Previously, we reported that monocarboxylate transporters (MCT) 1 and 4 are localized in tanycytes, whereas MCT2 is present in arcuate nucleus neurons, including orexigenic and anorexigenic neurons (POMC). MCT1 and MCT4 inhibition impacts feeding behavior, suggesting that monocarboxylate transfer between tanycytes and neurons influences food intake. Electrophysiological studies have shown that POMC neurons respond to lactate through transport and indirect signaling using astrocytic hydroxycarboxylic acid receptor 1. To investigate the role of MCT2 further, we generated MCT2 knockdown rats and analyzed their feeding behavior. Female Sprague-Dawley rats received bilateral injections in the arcuate nucleus with an adeno-associated virus (AAV) carrying a specific short hairpin RNA to inhibit MCT2 expression, thereby generating neuronal MCT2 knockdown rats. Knockdown efficiency in rat hypothalamic tissue was assessed using real-time PCR, Western Blot, and immunohistochemistry. The acute effect on feeding behavior was evaluated following 24 h of fasting, followed by 24 h of refeeding. In MCT2-knockdown rats, we observed additional inhibition of MCT1, suggesting a potential glial response to increased parenchymal lactate levels. Both macrostructure and microstructure of feeding were evaluated in MCT2-knockdown rats and compared to control AAV-injected rats. MCT2 knockdown led to a significant increase in macrostructural parameters, such as food intake and body weight. These findings underscore the importance of lactate transfer as a mechanism in tanycyte-neuron communication mediated by monocarboxylates.
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Affiliation(s)
- Alanis Coca
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Sergio López
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Patricio Órdenes
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción, Chile
| | - Vania Sepúlveda
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Diego Cuevas
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Andrés Villarroel
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Javiera Álvarez-Indo
- Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Patricia V Burgos
- Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Estefanía Tarifeño
- Laboratorio de Expresión y Regulación Génica, Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Roberto Elizondo-Vega
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - María A García-Robles
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
- Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile.
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4
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Deng M, Liao S, Deng J, Li C, Liu L, Han Q, Huo Y, Zhou X, Teng X, Lai M, Zhang H, Lai C. S100A2 promotes clear cell renal cell carcinoma tumor metastasis through regulating GLUT2 expression. Cell Death Dis 2025; 16:135. [PMID: 40011447 DOI: 10.1038/s41419-025-07418-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 12/20/2024] [Accepted: 01/31/2025] [Indexed: 02/28/2025]
Abstract
Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer and is highly malignant. Despite advances in diagnostics and treatment, the prognosis for ccRCC remains poor. The dual nature (promotion or inhibition) of S100A2 in different cancer types shows the complex involvement of its tumorigenesis, but its effect in ccRCC remains unclear. In this study, we first elucidate the tumor-promoting function of S100A2 in ccRCC by reprogramming glycolysis. Mechanistically, we demonstrate that S100A2 accelerates cancer progression through its interaction with the transcription factor HNF1A, leading to activating GLUT2 transcription. The upregulation of GLUT2 significantly enhances glucose uptake by cancer cells, thereby fueling augmented glucose metabolism and fostering the malignant progression of ccRCC. Collectively, our findings highlight the pivotal role of the S100A2-HNF1A-GLUT2 axis in promoting migration and invasion of ccRCC by amplifying glycolysis and suggest that targeting the S100A2-HNF1A-GLUT2 axis is clinically relevant for the treatment of metastatic ccRCC.
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Affiliation(s)
- Mengli Deng
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China
| | - Shaoxia Liao
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China
| | - Jingwen Deng
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
| | - Chen Li
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lu Liu
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China
| | - Qizheng Han
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China
| | - Yifeng Huo
- Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiao Zhou
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China
| | - Xiaodong Teng
- Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Maode Lai
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China.
- Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China.
| | - Honghe Zhang
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China.
| | - Chong Lai
- Department of Urology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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5
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Chaudhari BY, Pradhan AG, Joshi RS. Metabolic gatekeepers: Dynamic roles of sugar transporters in insect metabolism and physiology. INSECT MOLECULAR BIOLOGY 2025; 34:1-18. [PMID: 39394882 DOI: 10.1111/imb.12963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/25/2024] [Indexed: 10/14/2024]
Abstract
Sugars play multiple critical roles in insects, serving as energy sources, carbon skeletons, osmolytes and signalling molecules. The transport of sugars from source to sink via membrane proteins is essential for the uptake, distribution and utilization of sugars across various tissues. Sugar supply and distribution are crucial for insect development, flight, diapause and reproduction. Insect sugar transporters (STs) share significant structural and functional similarities with those in mammals and other higher eukaryotes. However, they exhibit unique characteristics, including differential regulation, substrate selectivity and kinetics. Here, we have discussed structural diversity, evolutionary trends, expression dynamics, mechanisms of action and functional significance of insect STs. The sequence and structural diversity of insect STs, highlighted by the analysis of conserved domains and evolutionary patterns, underpins their functional differentiation and divergence. The review emphasizes the importance of STs in insect metabolism, physiology and stress tolerance. It also discusses how variations in transporter regulation, expression, selectivity and activity contribute to functional differences. Furthermore, we have underlined the potential and necessity of studying these mechanisms and roles to gain a deeper understanding of insect glycobiology. Understanding the regulation and function of sugar transporters is vital for comprehending insect metabolism and physiological potential. This review provides valuable insights into the diverse functionalities of insect STs and their significant roles in metabolism and physiology.
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Affiliation(s)
- Bhagyashri Y Chaudhari
- Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Aditya G Pradhan
- Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India
| | - Rakesh S Joshi
- Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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6
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Wang Y, Sun Z, Zhao Z, Pang J, Chen J. Recent Progress in the Development of Glucose Transporter (GLUT) Inhibitors. J Med Chem 2025; 68:1033-1050. [PMID: 39746141 DOI: 10.1021/acs.jmedchem.4c02717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Cancer cells exhibit an accelerated glucose uptake and glycolysis. The transmembrane uptake of glucose requires specific carrier proteins, such as glucose transporters (GLUTs) and sodium-coupled glucose cotransporters (SGLTs). GLUTs transport glucose independently of the energy supply and have become promising targets for cancer therapy. This Perspective mainly focuses on the current research progress and design strategy of GLUT inhibitors, particularly those targeting class I (GLUT1-4). To the best of our knowledge, this is the first systematic interpretation of the research progress, opportunities, and challenges faced in the development of GLUT inhibitors from a medicinal chemistry perspective. We hope that this Perspective will provide insights into the development of GLUT inhibitors, offering a feasible approach to cancer therapy.
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Affiliation(s)
- Yuxuan Wang
- Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510280, China
| | - Zhiqiang Sun
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Zean Zhao
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jianxin Pang
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jianjun Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
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7
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Shafi S, Khan MA, Ahmad J, Rabbani SA, Singh S, Najmi AK. Envisioning Glucose Transporters (GLUTs and SGLTs) as Novel Intervention against Cancer: Drug Discovery Perspective and Targeting Approach. Curr Drug Targets 2025; 26:109-131. [PMID: 39377414 DOI: 10.2174/0113894501335877240926101134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 10/09/2024]
Abstract
Metabolic reprogramming and altered cellular energetics have been recently established as an important cancer hallmark. The modulation of glucose metabolism is one of the important characteristic features of metabolic reprogramming in cancer. It contributes to oncogenic progression by supporting the increased biosynthetic and bio-energetic demands of tumor cells. This oncogenic transformation consequently results in elevated expression of glucose transporters in these cells. Moreover, various cancers exhibit abnormal transporter expression patterns compared to normal tissues. Recent investigations have underlined the significance of glucose transporters in regulating cancer cell survival, proliferation, and metastasis. Abnormal regulation of these transporters, which exhibit varying affinities for hexoses, could enable cancer cells to efficiently manage their energy supply, offering a crucial edge for proliferation. Exploiting the upregulated expression of glucose transporters, GLUTs, and Sodium Linked Glucose Transporters (SGLTs), could serve as a novel therapeutic intervention for anti-cancer drug discovery as well as provide a unique targeting approach for drug delivery to specific tumor tissues. This review aims to discussthe previous and emerging research on the expression of various types of glucose transporters in tumor tissues, the role of glucose transport inhibitors as a cancer therapy intervention as well as emerging GLUT/SGLT-mediated drug delivery strategies that can be therapeutically employed to target various cancers.
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Affiliation(s)
- Sadat Shafi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Kingdom of Saudi Arabia (KSA)
| | - Syed Arman Rabbani
- Department of Clinical Pharmacy and Pharmacology, Ras Al Khaimah College of Pharmacy, Ras Al Khaimah Medical and Health Science University, Ras Al Khaimah, United Arab Emirates
| | - Shailja Singh
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
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Jun H, Mazigo E, Lee WJ, Park YK, Han JH, Cha SH. Functional characterization of glucose transporter 4 involved in glucose uptake in Clonorchis sinensis. PARASITES, HOSTS AND DISEASES 2024; 62:450-460. [PMID: 39622656 PMCID: PMC11614484 DOI: 10.3347/phd.24051] [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] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/13/2024] [Indexed: 12/06/2024]
Abstract
Clonorchis sinensis, which causes clonorchiasis, is prevalent in East Asian countries and poses notable health risks, including bile duct complications. Although praziquantel is the primary treatment for the disease, the emerging resistance among trematodes highlights the need for alternative strategies. Understanding the nutrient uptake mechanisms in trematodes, including C. sinensis, is crucial for developing future effective treatments. This study aimed to characterize the function of C. sinensis glucose transporter 4 (CsGTP4) and determine its role in nutrient uptake employing synthesized cDNA of adult C. sinensis worms. The functional characterization of CsGTP4 involved injecting its cRNA into Xenopus laevis oocytes and analyzing the deoxy-D-glucose uptake levels. The results demonstrated that deoxy-D-glucose uptake depended on the deoxy-D-glucose incubation and CsGTP4 expression time, but not sodium-dependent. The concentration-dependent uptake followed the Michaelis-Menten equation, with a Km value of 2.7 mM and a Vmax value of 476 pmol/oocyte/h based on the Lineweaver-Burk analysis. No uptake of radiolabeled α-ketoglutarate, p-aminohippurate, taurocholate, arginine, or carnitine was observed. The uptake of deoxy-D-glucose by CsGTP4 was significantly inhibited by unlabeled glucose and galactose in a concentration-dependent manner. It was significantly inhibited under strongly acidic and basic conditions. These insights into the glucose uptake kinetics and pH dependency of CsGTP4 provide a deeper understanding of nutrient acquisition in trematodes. This study contributes to the development of novel antiparasitic agents, addressing a considerable socioeconomic challenge in affected regions.
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Affiliation(s)
- Hojong Jun
- Department of Parasitology and Tropical Medicine, Inha University School of Medicine, Incheon 22212,
Korea
- Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon 24341,
Korea
| | - Ernest Mazigo
- Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon 24341,
Korea
| | - Wang-Jong Lee
- Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon 24341,
Korea
| | - Yun-Kyu Park
- Department of Parasitology and Tropical Medicine, Inha University School of Medicine, Incheon 22212,
Korea
| | - Jin-Hee Han
- Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon 24341,
Korea
| | - Seok Ho Cha
- Department of Parasitology and Tropical Medicine, Inha University School of Medicine, Incheon 22212,
Korea
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Santucci L, Bernardi S, Vivarelli R, Santorelli FM, Marchese M. Glucose metabolism impairment as a hallmark of progressive myoclonus epilepsies: a focus on neuronal ceroid lipofuscinoses. Front Cell Neurosci 2024; 18:1445003. [PMID: 39364042 PMCID: PMC11447523 DOI: 10.3389/fncel.2024.1445003] [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: 06/06/2024] [Accepted: 08/12/2024] [Indexed: 10/05/2024] Open
Abstract
Glucose is the brain's main fuel source, used in both energy and molecular production. Impaired glucose metabolism is associated with adult and pediatric neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), GLUT1 deficiency syndrome, and progressive myoclonus epilepsies (PMEs). PMEs, a group of neurological disorders typical of childhood and adolescence, account for 1% of all epileptic diseases in this population worldwide. Diffuse glucose hypometabolism is observed in the brains of patients affected by PMEs such as Lafora disease (LD), dentatorubral-pallidoluysian (DRPLA) atrophy, Unverricht-Lundborg disease (ULD), and myoclonus epilepsy with ragged red fibers (MERRFs). PMEs also include neuronal ceroid lipofuscinoses (NCLs), a subgroup in which lysosomal and autophagy dysfunction leads to progressive loss of vision, brain atrophy, and cognitive decline. We examine the role of impaired glucose metabolism in neurodegenerative diseases, particularly in the NCLs. Our literature review, which includes findings from case reports and animal studies, reveals that glucose hypometabolism is still poorly characterized both in vitro and in vivo in the different NCLs. Better identification of the glucose metabolism pathway impaired in the NCLs may open new avenues for evaluating the therapeutic potential of anti-diabetic agents in this population and thus raise the prospect of a therapeutic approach able to delay or even halt disease progression.
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Affiliation(s)
- Lorenzo Santucci
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Calambrone, Italy
| | - Sara Bernardi
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Calambrone, Italy
- Department of Biology, University of Pisa, Pisa, Italy
| | - Rachele Vivarelli
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Calambrone, Italy
| | | | - Maria Marchese
- Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Calambrone, Italy
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10
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Pu J, Han J, Yang J, Yu L, Wan H. Anaerobic Glycolysis and Ischemic Stroke: From Mechanisms and Signaling Pathways to Natural Product Therapy. ACS Chem Neurosci 2024; 15:3090-3105. [PMID: 39140296 DOI: 10.1021/acschemneuro.4c00371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024] Open
Abstract
Ischemic stroke is a serious condition that results in high rates of illness and death. Anaerobic glycolysis becomes the primary means of providing energy to the brain during periods of low oxygen levels, such as in the aftermath of an ischemic stroke. This process is essential for maintaining vital brain functions and has significant implications for recovery following a stroke. Energy supply by anaerobic glycolysis and acidosis caused by lactic acid accumulation are important pathological processes after ischemic stroke. Numerous natural products regulate glucose and lactate, which in turn modulate anaerobic glycolysis. This article focuses on the relationship between anaerobic glycolysis and ischemic stroke, as well as the associated signaling pathways and natural products that play a therapeutic role. These natural products, which can regulate anaerobic glycolysis, will provide new avenues and perspectives for the treatment of ischemic stroke in the future.
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Affiliation(s)
- Jia Pu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jin Han
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jiehong Yang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Li Yu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
- Center of Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, Zhejiang 310053, China
| | - Haitong Wan
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
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11
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Sobhy MH, Ismail A, Abdel-Hamid MS, Wagih M, Kamel M. 2-Methoxyestradiol ameliorates doxorubicin-induced cardiotoxicity by regulating the expression of GLUT4 and CPT-1B in female rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7129-7139. [PMID: 38652282 PMCID: PMC11422279 DOI: 10.1007/s00210-024-03073-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 03/27/2024] [Indexed: 04/25/2024]
Abstract
The clinical usage of doxorubicin (DOX) is hampered due to cardiomyopathy. Studies reveal that estrogen (E2) modulates DOX-induced cardiotoxicity. Yet, the exact mechanism is unclear. The objective of the current study is to evaluate the influence of E2 and more specifically its metabolite 2-methoxyestradiol (2ME) on cardiac remodeling and the reprogramming of cardiac metabolism in rats subjected to DOX cardiotoxicity. Seventy-two female rats were divided into groups. Cardiotoxicity was induced by administering DOX (2.5 mg/kg three times weekly for 2 weeks). In some groups, the effect of endogenous E2 was abolished by ovariectomy (OVX) or by using the estrogen receptor (ER) blocker Fulvestrant (FULV). The effect of administering exogenous E2 or 2ME in the OVX group was studied. Furthermore, the influence of entacapone (COMT inhibitor) on induced cardiotoxicity was investigated. The evaluated cardiac parameters included ECG, histopathology, cardiac-related enzymes (creatine kinase isoenzyme-MB (CK-MB) and lactate dehydrogenase (LDH)), and lipid profile markers (total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL)). The expression levels of key metabolic enzymes (glucose transporter-4 (GLUT4) and carnitine palmitoyltransferase-1B (CPT-1B)) were assessed. Our results displayed that co-treatment of E2 and/or 2ME with DOX significantly reduced DOX-induced cardiomyopathy and enhanced the metabolism of the heart through the maintenance of GLUT4 and CPT-1B enzymes. On the other hand, co-treatment of DOX with OVX, entacapone, or FULV increased the toxic effect of DOX by further reducing these important metabolic enzymes. E2 and 2ME abrogate DOX-induced cardiomyopathy partly through modulation of GLUT 4 and CPT-1B enzymes.
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Affiliation(s)
- Mohamed H Sobhy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, 6th of October City, Giza, Egypt
| | - Ahmed Ismail
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mohammed S Abdel-Hamid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt
| | - Mohamed Wagih
- Department of Pathology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Marwa Kamel
- Department of Cancer Biology, Unit of Pharmacology and Experimental Therapeutics, National Cancer Institute, Cairo University, Cairo, Egypt.
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12
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Daida T, Shin BC, Cepeda C, Devaskar SU. Neurodevelopment Is Dependent on Maternal Diet: Placenta and Brain Glucose Transporters GLUT1 and GLUT3. Nutrients 2024; 16:2363. [PMID: 39064806 PMCID: PMC11279700 DOI: 10.3390/nu16142363] [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: 06/12/2024] [Revised: 07/09/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.
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Affiliation(s)
- Tomoko Daida
- Department of Pediatrics, Division of Neonatology and Developmental Biology and Neonatal Research Center, at the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (T.D.); (B.-C.S.)
| | - Bo-Chul Shin
- Department of Pediatrics, Division of Neonatology and Developmental Biology and Neonatal Research Center, at the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (T.D.); (B.-C.S.)
| | - Carlos Cepeda
- Intellectual and Developmental Disabilities Research Center and Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Sherin U. Devaskar
- Department of Pediatrics, Division of Neonatology and Developmental Biology and Neonatal Research Center, at the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (T.D.); (B.-C.S.)
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13
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Yan J, Bhadane R, Ran M, Ma X, Li Y, Zheng D, Salo-Ahen OMH, Zhang H. Development of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy. Nat Commun 2024; 15:3684. [PMID: 38693181 PMCID: PMC11063048 DOI: 10.1038/s41467-024-48149-9] [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: 08/22/2023] [Accepted: 04/23/2024] [Indexed: 05/03/2024] Open
Abstract
The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca2+/(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application.
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Affiliation(s)
- Jiaqi Yan
- Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine 197 Ruijin 2nd Road, Shanghai, 200025, PR China
- Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Rajendra Bhadane
- Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
- Structural Bioinformatics Laboratory, Biochemistry, Åbo Akademi University, 20520, Turku, Finland
| | - Meixin Ran
- Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Xiaodong Ma
- Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Yuanqiang Li
- Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Dongdong Zheng
- Department of Ultrasound, Fudan University Shanghai Cancer Center, Shanghai, 200032, PR China
| | - Outi M H Salo-Ahen
- Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- Structural Bioinformatics Laboratory, Biochemistry, Åbo Akademi University, 20520, Turku, Finland
| | - Hongbo Zhang
- Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine 197 Ruijin 2nd Road, Shanghai, 200025, PR China.
- Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
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14
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Ben Ali F, Qmichou Z, Oukabli M, Dakka N, Bakri Y, Eddouks M, Ameziane El Hassani R. Alteration of glucose metabolism and expression of glucose transporters in ovarian cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:384-399. [PMID: 38745772 PMCID: PMC11090687 DOI: 10.37349/etat.2024.00224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/09/2024] [Indexed: 05/16/2024] Open
Abstract
Aerobic glycolysis also known as the Warburg effect, remains a hallmark of various cancers, including ovarian cancer. Cancer cells undergo metabolic changes to sustain their tumorigenic properties and adapt to environmental conditions, such as hypoxia and nutrient starvation. Altered metabolic pathways not only facilitate ovarian cancer cells' survival and proliferation but also endow them to metastasize, develop resistance to chemotherapy, maintain cancer stem cell phenotype, and escape anti-tumor immune responses. Glucose transporters (GLUTs), which play a pivotal role as the rate-limiting step in glycolysis, are frequently overexpressed in a variety of tumors, including ovarian cancer. Multiple oncoproteins can regulate GLUT proteins, promoting tumor proliferation, migration, and metastasis, either dependent or independent of glycolysis. This review examines the alteration of GLUT proteins, particularly GLUT1, in ovarian cancer and its impact on cancer initiation, progression, and resistance to treatment. Additionally, it highlights the role of these proteins as biomarkers for diagnosis and prognosis in ovarian cancer, and delves into novel therapeutic strategies currently under development that target GLUT isoforms.
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Affiliation(s)
- Fatima Ben Ali
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Zineb Qmichou
- Medical Biotechnology Center, Moroccan Foundation for Advanced Science, Innovation and Research (MAScIR), Rabat 10001, Morocco
| | - Mohamed Oukabli
- Department of Anatomical Pathology, Military Hospital of Instruction Mohammed V (HMIMV-R), Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Nadia Dakka
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Youssef Bakri
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Mohammed Eddouks
- Team of Ethnopharmacology and Pharmacognosy, Faculty of Sciences and Techniques Errachidia, Moulay Ismail University of Meknes, Errachidia BP 509, Morocco
| | - Rabii Ameziane El Hassani
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
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15
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De Biasi S, Gigan JP, Borella R, Santacroce E, Lo Tartaro D, Neroni A, Paschalidis N, Piwocka K, Argüello RJ, Gibellini L, Cossarizza A. Cell metabolism: Functional and phenotypic single cell approaches. Methods Cell Biol 2024; 186:151-187. [PMID: 38705598 DOI: 10.1016/bs.mcb.2024.02.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2024]
Abstract
Several metabolic pathways are essential for the physiological regulation of immune cells, but their dysregulation can cause immune dysfunction. Hypermetabolic and hypometabolic states represent deviations in the magnitude and flexibility of effector cells in different contexts, for example in autoimmunity, infections or cancer. To study immunometabolism, most methods focus on bulk populations and rely on in vitro activation assays. Nowadays, thanks to the development of single-cell technologies, including multiparameter flow cytometry, mass cytometry, RNA cytometry, among others, the metabolic state of individual immune cells can be measured in a variety of samples obtained in basic, translational and clinical studies. Here, we provide an overview of different single-cell approaches that are employed to investigate both mitochondrial functions and cell dependence from mitochondria metabolism. Moreover, besides the description of the appropriate experimental settings, we discuss the strengths and weaknesses of different approaches with the aim to suggest how to study cell metabolism in the settings of interest.
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Affiliation(s)
- Sara De Biasi
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.
| | - Julien Paul Gigan
- Aix Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Rebecca Borella
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Elena Santacroce
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Domenico Lo Tartaro
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Anita Neroni
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Katarzyna Piwocka
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Rafael José Argüello
- Aix Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Lara Gibellini
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
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16
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Walk CL, Mullenix GJ, Maynard CW, Greene ES, Maynard C, Ward N, Dridi S. Novel 4th-generation phytase improves broiler growth performance and reduces woody breast severity through modulation of muscle glucose uptake and metabolism. Front Physiol 2024; 15:1376628. [PMID: 38559573 PMCID: PMC10978611 DOI: 10.3389/fphys.2024.1376628] [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: 01/25/2024] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
The objective of the present study was to determine the effect of a novel (4th generation) phytase supplementation as well as its mode of action on growth, meat quality, and incidence of muscle myopathies. One-day old male broilers (n = 720) were weighed and randomly allocated to 30 floor pens (24 birds/pen) with 10 replicate pens per treatment. Three diets were fed from hatch to 56- days-old: a 3-phase corn-soy based diet as a positive control (PC); a negative control (NC) formulated to be isocaloric and isonitrogenous to the PC and with a reduction in Ca and available P, respectively; and the NC supplemented with 2,000 phytase units per kg of diet (NC + P). At the conclusion of the experiment, birds fed with NC + P diet were significantly heavier and had 2.1- and 4.2-points better feed conversion ratio (FCR) compared to birds offered NC and PC diets, respectively. Processing data showed that phytase supplementation increased live weight, hot carcass without giblets, wings, tender, and skin-on drum and thigh compared to both NC and PC diets. Macroscopic scoring showed that birds fed the NC + P diet had lower woody breast (WB) severity compared to those fed the PC and NC diets, however there was no effect on white striping (WS) incidence and meat quality parameters (pH, drip loss, meat color). To delineate its mode of action, iSTAT showed that blood glucose concentrations were significantly lower in birds fed NC + P diet compared to those offered PC and NC diets, suggesting a better glucose uptake. In support, molecular analyses demonstrated that the breast muscle expression (mRNA and protein) of glucose transporter 1 (GLUT1) and glucokinase (GK) was significantly upregulated in birds fed NC + P diet compared to those fed the NC and PC diets. The expression of mitochondrial ATP synthase F0 subunit 8 (MT-ATP8) was significantly upregulated in NC + P compared to other groups, indicating intracellular ATP abundance for anabolic pathways. This was confirmed by the reduced level of phosphorylated-AMP-activated protein kinase (AMPKα1/2) at Thr172 site, upregulation of glycogen synthase (GYS1) gene and activation of mechanistic target of rapamycin and ribosomal protein S6 kinase (mTOR-P70S6K) pathway. In conclusion, this is the first report showing that in-feed supplementation of the novel phytase improves growth performance and reduces WB severity in broilers potentially through enhancement of glucose uptake, glycolysis, and intracellular ATP production, which used for muscle glycogenesis and protein synthesis.
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Affiliation(s)
| | - Garrett J. Mullenix
- Department of Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Craig W. Maynard
- Department of Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Elisabeth S. Greene
- Department of Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Clay Maynard
- Department of Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Nelson Ward
- DSM Nutritional Products, Jerusalem, OH, United States
| | - Sami Dridi
- Department of Poultry Science, University of Arkansas, Fayetteville, AR, United States
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17
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Lukic N, Macvanin MT, Gluvic Z, Rizzo M, Radak D, Suri JS, Isenovic ER. SGLT-2 Inhibitors: The Next-generation Treatment for Type 2 Diabetes Mellitus. Curr Med Chem 2024; 31:4781-4806. [PMID: 37855338 DOI: 10.2174/0109298673251493231011192520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 06/19/2023] [Accepted: 08/17/2023] [Indexed: 10/20/2023]
Abstract
Type 2 diabetes mellitus (T2DM) has become a worldwide concern in recent years, primarily in highly developed Western societies. T2DM causes systemic complications, such as atherosclerotic heart disease, ischemic stroke, peripheral artery disease, kidney failure, and diabetes-related maculopathy and retinopathy. The growing number of T2DM patients and the treatment of long-term T2DM-related complications pressurize and exhaust public healthcare systems. As a result, strategies for combating T2DM and developing novel drugs are critical global public health requirements. Aside from preventive measures, which are still the most effective way to prevent T2DM, novel and highly effective therapies are emerging. In the spotlight of next-generation T2DM treatment, sodium-glucose co-transporter 2 (SGLT-2) inhibitors are promoted as the most efficient perspective therapy. SGLT-2 inhibitors (SGLT2i) include phlorizin derivatives, such as canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT-2, along with SGLT-1, is a member of the SGLT family of proteins that play a role in glucose absorption via active transport mediated by Na+/K+ ATPase. SGLT-2 is only found in the kidney, specifically the proximal tubule, and is responsible for more than 90% glucose absorption. Inhibition of SGLT-2 reduces glucose absorption, and consequently increases urinary glucose excretion, decreasing blood glucose levels. Thus, the inhibition of SGLT-2 activity ultimately alleviates T2DM-related symptoms and prevents or delays systemic T2DM-associated chronic complications. This review aimed to provide a more detailed understanding of the effects of SGLT2i responsible for the acute improvement in blood glucose regulation, a prerequisite for T2DM-associated cardiovascular complications control.
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Affiliation(s)
- Nikola Lukic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Faculty of Medicine, Zemun Clinical Hospital, University of Belgrade, Belgrade, Serbia
| | - Manfredi Rizzo
- Department of Internal Medicine and Medical Specialties (DIMIS), Università degli Studi di Palermo (UNIPA), 90128 Palermo, Italy
| | - Djordje Radak
- Department of Vascular Surgery, Serbian Academy of Art and Sciences, Euromedic Clinic, 11000, Belgrade, Serbia
| | | | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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18
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Morrice N, Vainio S, Mikkola K, van Aalten L, Gallagher JR, Ashford MLJ, McNeilly AD, McCrimmon RJ, Grosfeld A, Serradas P, Koffert J, Pearson ER, Nuutila P, Sutherland C. Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression. Mol Metab 2023; 77:101807. [PMID: 37717665 PMCID: PMC10550722 DOI: 10.1016/j.molmet.2023.101807] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/28/2023] [Accepted: 09/12/2023] [Indexed: 09/19/2023] Open
Abstract
OBJECTIVES Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice. METHODS We performed extensive metabolic phenotyping and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced Slc2a2 (Slc2a2+/-) and intestinal Slc2a2 KO, to assess the impact of metformin treatment. RESULTS Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2+/-) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2+/+) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2+/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2+/- animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells. CONCLUSIONS Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing.
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Affiliation(s)
- Nicola Morrice
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Susanne Vainio
- Turku PET Centre, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Kirsi Mikkola
- Turku PET Centre, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Lidy van Aalten
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Jennifer R Gallagher
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Michael L J Ashford
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Alison D McNeilly
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Rory J McCrimmon
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Alexandra Grosfeld
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012, Paris, France
| | - Patricia Serradas
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic approaches, NutriOmics, Research group, F-75013, Paris, France
| | - Jukka Koffert
- Turku PET Centre, University of Turku, Turku, Finland; Department of Gastroenterology, Turku University Hospital, Turku, Finland
| | - Ewan R Pearson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku, Turku, Finland; Department of Endocrinology, Turku University Hospital, Turku, Finland
| | - Calum Sutherland
- Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK.
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19
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Geiser A, Foylan S, Tinning PW, Bryant NJ, Gould GW. GLUT4 dispersal at the plasma membrane of adipocytes: a super-resolved journey. Biosci Rep 2023; 43:BSR20230946. [PMID: 37791639 PMCID: PMC10600063 DOI: 10.1042/bsr20230946] [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: 09/07/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/05/2023] Open
Abstract
In adipose tissue, insulin stimulates glucose uptake by mediating the translocation of GLUT4 from intracellular vesicles to the plasma membrane. In 2010, insulin was revealed to also have a fundamental impact on the spatial distribution of GLUT4 within the plasma membrane, with the existence of two GLUT4 populations at the plasma membrane being defined: (1) as stationary clusters and (2) as diffusible monomers. In this model, in the absence of insulin, plasma membrane-fused GLUT4 are found to behave as clusters. These clusters are thought to arise from exocytic events that retain GLUT4 at their fusion sites; this has been proposed to function as an intermediate hub between GLUT4 exocytosis and re-internalisation. By contrast, insulin stimulation induces the dispersal of GLUT4 clusters into monomers and favours a distinct type of GLUT4-vesicle fusion event, known as fusion-with-release exocytosis. Here, we review how super-resolution microscopy approaches have allowed investigation of the characteristics of plasma membrane-fused GLUT4 and further discuss regulatory step(s) involved in the GLUT4 dispersal machinery, introducing the scaffold protein EFR3 which facilitates localisation of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) to the cell surface. We consider how dispersal may be linked to the control of transporter activity, consider whether macro-organisation may be a widely used phenomenon to control proteins within the plasma membrane, and speculate on the origin of different forms of GLUT4-vesicle exocytosis.
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Affiliation(s)
- Angéline Geiser
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Shannan Foylan
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Peter W Tinning
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
| | - Nia J Bryant
- Department of Biology, University of York, Heslington, York, U.K
| | - Gwyn W Gould
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K
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20
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Song A, Mao Y, Wei H. GLUT5: structure, functions, diseases and potential applications. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1519-1538. [PMID: 37674366 PMCID: PMC10582729 DOI: 10.3724/abbs.2023158] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 05/19/2023] [Indexed: 09/08/2023] Open
Abstract
Glucose transporter 5 (GLUT5) is a membrane transporter that specifically transports fructose and plays a key role in dietary fructose uptake and metabolism. In recent years, a high fructose diet has occupied an important position in the daily intake of human beings, resulting in a significant increase in the incidence of obesity and metabolic diseases worldwide. Over the past few decades, GLUT5 has been well understood to play a significant role in the pathogenesis of human digestive diseases. Recently, the role of GLUT5 in human cancer has received widespread attention, and a large number of studies have focused on exploring the effects of changes in GLUT5 expression levels on cancer cell survival, metabolism and metastasis. However, due to various difficulties and shortcomings, the molecular structure and mechanism of GLUT5 have not been fully elucidated, which to some extent prevents us from revealing the relationship between GLUT5 expression and cell carcinogenesis at the protein molecular level. In this review, we summarize the current understanding of the structure and function of mammalian GLUT5 and its relationship to intestinal diseases and cancer and suggest that GLUT5 may be an important target for cancer therapy.
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Affiliation(s)
- Aqian Song
- Department of GastroenterologyBeijing Ditan HospitalCapital Medical UniversityBeijing100015China
| | - Yuanpeng Mao
- Department of GastroenterologyPeking University Ditan Teaching HospitalBeijing100015China
| | - Hongshan Wei
- Department of GastroenterologyBeijing Ditan HospitalCapital Medical UniversityBeijing100015China
- Department of GastroenterologyPeking University Ditan Teaching HospitalBeijing100015China
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21
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Mylvaganam S, Freeman SA. The resolution of phagosomes. Immunol Rev 2023; 319:45-64. [PMID: 37551912 DOI: 10.1111/imr.13260] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/18/2023] [Indexed: 08/09/2023]
Abstract
Phagocytosis is a fundamental immunobiological process responsible for the removal of harmful particulates. While the number of phagocytic events achieved by a single phagocyte can be remarkable, exceeding hundreds per day, the same phagocytic cells are relatively long-lived. It should therefore be obvious that phagocytic meals must be resolved in order to maintain the responsiveness of the phagocyte and to avoid storage defects. In this article, we discuss the mechanisms involved in the resolution process, including solute transport pathways and membrane traffic. We describe how products liberated in phagolysosomes support phagocyte metabolism and the immune response. We also speculate on mechanisms involved in the redistribution of phagosomal metabolites back to circulation. Finally, we highlight the pathologies owed to impaired phagosome resolution, which range from storage disorders to neurodegenerative diseases.
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Affiliation(s)
- Sivakami Mylvaganam
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Spencer A Freeman
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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22
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Zhu J, Zhou Y, Jin B, Shu J. Role of estrogen in the regulation of central and peripheral energy homeostasis: from a menopausal perspective. Ther Adv Endocrinol Metab 2023; 14:20420188231199359. [PMID: 37719789 PMCID: PMC10504839 DOI: 10.1177/20420188231199359] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 08/16/2023] [Indexed: 09/19/2023] Open
Abstract
Estrogen plays a prominent role in regulating and coordinating energy homeostasis throughout the growth, development, reproduction, and aging of women. Estrogen receptors (ERs) are widely expressed in the brain and nearly all tissues of the body. Within the brain, central estrogen via ER regulates appetite and energy expenditure and maintains cell glucose metabolism, including glucose transport, aerobic glycolysis, and mitochondrial function. In the whole body, estrogen has shown beneficial effects on weight control, fat distribution, glucose and insulin resistance, and adipokine secretion. As demonstrated by multiple in vitro and in vivo studies, menopause-related decline of circulating estrogen may induce the disturbance of metabolic signals and a significant decrease in bioenergetics, which could trigger an increased incidence of late-onset Alzheimer's disease, type 2 diabetes mellitus, hypertension, and cardiovascular diseases in postmenopausal women. In this article, we have systematically reviewed the role of estrogen and ERs in body composition and lipid/glucose profile variation occurring with menopause, which may provide a better insight into the efficacy of hormone therapy in maintaining energy metabolic homeostasis and hold a clue for development of novel therapeutic approaches for target tissue diseases.
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Affiliation(s)
- Jing Zhu
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yier Zhou
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Bihui Jin
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jing Shu
- Reproductive Medicine Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
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23
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Kokeza J, Strikic A, Ogorevc M, Kelam N, Vukoja M, Dilber I, Zekic Tomas S. The Effect of GLUT1 and HIF-1α Expressions on Glucose Uptake and Patient Survival in Non-Small-Cell Lung Carcinoma. Int J Mol Sci 2023; 24:10575. [PMID: 37445752 DOI: 10.3390/ijms241310575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/16/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Lung cancer is the second-most-common cancer while being the leading cause of cancer deaths worldwide. It has been found that glucose transporter 1 (GLUT1) and hypoxia-inducible factor 1α (HIF-1α) are overexpressed in various malignancies and that they correlate with the maximum standard uptake values (SUVmax) on 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) and poor prognosis. In this study, we aim to evaluate the relationship between the SUVmax, GLUT1, and HIF-1α expression with primary tumor size, histological type, lymph node metastases, and patient survival. Of the 48 patients with non-small-cell lung cancer, those with squamous cell carcinomas (SCCs) had significantly higher GLUT1 and HIF-1α immunohistochemical expressions in comparison to adenocarcinomas (ACs), while there was no statistically significant difference in FDG accumulation between them. No significant correlation was noted between either GLUT1 or HIF-1α protein expression and FDG uptake and overall survival. However, an analysis of tumor transcriptomics showed a significant difference in overall survival depending on mRNA expression; patients with SCC and high HIF-1α levels survived longer compared to those with low HIF-1α levels, while patients with AC and low GLUT1 levels had a higher average survival time than those with high GLUT1 levels. Further studies are needed to determine the prognostic value of the expression of these factors depending on the histologic type.
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Affiliation(s)
- Josipa Kokeza
- Department of Pulmonology, University Hospital of Split, Spinčićeva 1, 21000 Split, Croatia
| | - Ante Strikic
- Department of Oncology and Radiotherapy, University Hospital of Split, Spinčićeva 1, 21000 Split, Croatia
| | - Marin Ogorevc
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
| | - Martina Vukoja
- Laboratory of Morphology, Department of Histology and Embryology, School of Medicine, University of Mostar, 88 000 Mostar, Bosnia and Herzegovina
| | - Ivo Dilber
- Department of Oncology and Nuclear Medicine, General Hospital Zadar, Ul. Bože Peričića 5, 23000 Zadar, Croatia
| | - Sandra Zekic Tomas
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, Spinčićeva 1, 21000 Split, Croatia
- Department of Pathology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
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24
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Liu L, Zhao D, Wang G, He Q, Song Y, Jiang Y, Xia Q, Zhao P. Adaptive Changes in Detoxification Metabolism and Transmembrane Transport of Bombyx mori Malpighian Tubules to Artificial Diet. Int J Mol Sci 2023; 24:9949. [PMID: 37373097 DOI: 10.3390/ijms24129949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/30/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
The high adaptability of insects to food sources has contributed to their ranking among the most abundant and diverse species on Earth. However, the molecular mechanisms underlying the rapid adaptation of insects to different foods remain unclear. We explored the changes in gene expression and metabolic composition of the Malpighian tubules as an important metabolic excretion and detoxification organ in silkworms (Bombyx mori) fed mulberry leaf and artificial diets. A total of 2436 differentially expressed genes (DEGs) and 245 differential metabolites were identified between groups, with the majority of DEGs associated with metabolic detoxification, transmembrane transport, and mitochondrial function. Detoxification enzymes, such as cytochrome P450 (CYP), glutathione-S-transferase (GST), and UDP-glycosyltransferase, and ABC and SLC transporters of endogenous and exogenous solutes were more abundant in the artificial diet group. Enzyme activity assays confirmed increased CYP and GST activity in the Malpighian tubules of the artificial diet-fed group. Metabolome analysis showed increased contents of secondary metabolites, terpenoids, flavonoids, alkaloids, organic acids, lipids, and food additives in the artificial diet group. Our findings highlight the important role of the Malpighian tubules in adaptation to different foods and provide guidance for further optimization of artificial diets to improve silkworm breeding.
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Affiliation(s)
- Lijing Liu
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
| | - Dongchao Zhao
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
| | - Genhong Wang
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
| | - Qingxiu He
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
| | - Yuwei Song
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
| | - Yulu Jiang
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
| | - Qingyou Xia
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
| | - Ping Zhao
- Biological Science Research Center, Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City, Southwest University, Chongqing 400715, China
- Key Laboratory for Germplasm Creation in Upper Reaches of the Yangtze River, Ministry of Agriculture and Rural Affairs, Chongqing 400715, China
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25
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Valberg SJ, Velez-Irizarry D, Williams ZJ, Pagan JD, Mesquita V, Waldridge B, Maresca-Fichter H. Novel Expression of GLUT3, GLUT6 and GLUT10 in Equine Gluteal Muscle Following Glycogen-Depleting Exercise: Impact of Dietary Starch and Fat. Metabolites 2023; 13:718. [PMID: 37367876 DOI: 10.3390/metabo13060718] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 05/23/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
Horses have a slow rate of muscle glycogen repletion relative to other species for unknown reasons. Our aim was to determine the expression of glucose transporters (GLUT) and genes impacting GLUT4 expression and translocation in the gluteal muscle. Five fit Thoroughbred horses performed glycogen-depleting exercises on high-starch (HS, 2869 g starch/day) and low-starch, high-fat diets (LS-HF, 358 g starch/d) with gluteal muscle biopsies obtained before and after depletion and during repletion. Muscle glycogen declined by ≈30% on both diets with little increase during repletion on LS-HF. Transcriptomic analysis identified differential expression (DE) of only 2/12 genes impacting GLUT4 translocation (two subunits of AMP protein kinase) and only at depletion on LS-HF. Only 1/13 genes encoding proteins that promote GLUT4 transcription had increased DE (PPARGC1A at depletion LS-HF). GLUT4 comprised ≈30% of total GLUT mRNA expression at rest. Remarkably, by 72 h of repletion expression of GLUT3, GLUT6 and GLUT10 increased to ≈25% of total GLUT mRNA. Expression of GLUT6 and GLUT10 lagged from 24 h of repletion on HS to 72 h on LS-HF. Lacking an increase in GLUT4 gene expression in response to glycogen-depleting exercise, equine muscle increases GLUT3, GLUT6 and GLUT10 expression potentially to enhance glucose transport, resembling responses observed in resistance trained GLUT4-null mice.
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Affiliation(s)
- Stephanie J Valberg
- McPhail Equine Performance Center, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 736 Wilson RD, East Lansing, MI 48824, USA
| | - Deborah Velez-Irizarry
- McPhail Equine Performance Center, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 736 Wilson RD, East Lansing, MI 48824, USA
| | - Zoe J Williams
- McPhail Equine Performance Center, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 736 Wilson RD, East Lansing, MI 48824, USA
| | - Joe D Pagan
- Kentucky Equine Research, 3910 Delany Ferry Rd., Versailles, KY 40383, USA
| | - Vanesa Mesquita
- Kentucky Equine Research, 3910 Delany Ferry Rd., Versailles, KY 40383, USA
| | - Brian Waldridge
- Kentucky Equine Research, 3910 Delany Ferry Rd., Versailles, KY 40383, USA
| | - Hailey Maresca-Fichter
- McPhail Equine Performance Center, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 736 Wilson RD, East Lansing, MI 48824, USA
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26
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Liu L, Ma F, Liu Q, Yu X, Zeng X. Association Between the SLC2A2 Gene rs1499821 Polymorphism and Caries Susceptibility. Genet Test Mol Biomarkers 2023; 27:149-156. [PMID: 37257183 DOI: 10.1089/gtmb.2022.0201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023] Open
Abstract
Objectives: This study was designed to analyze the association between the SLC2A2 rs1499821 polymorphism and caries susceptibility in the Chinese Han, Zhuang, and Baikuyao populations. Materials and Methods: The present case-control study included 1067 12-year-old children: 481 with caries (142 Han, 166 Zhuang and 173 Baikuyao) and 586 who were caries-free (135 Han, 178 Zhuang and 273 Baikuyao). Questionnaires about diet and oral habits were obtained from all subjects. All of the children received dental examinations and DNA collection. The SLC2A2 rs1499821 SNP was genotyped using the SNPscan technique. Results: The rs1499821 T polymorphism was significantly associated with caries susceptibility in both the Han population and the combined populations of the three ethnic subgroups. SLC2A2 rs1499821 was associated with caries susceptibility in the dominant model in the Han (p = 0.045) population and the combined (p = 0.038) group. The CT+TT genotypes at rs1499821 were associated with a higher risk of caries in the Han (OR = 1.69, adjusted 95% CI: 1.01-2.81) and combined (OR = 1.33, adjusted 95% CI: 1.02-1.74) populations. In both Han (p = 0.009) and the combined populations (p = 0.004), there were statistically significant associations between the frequency of sweet food intake and dental caries. However, the rs1499821 polymorphisms did not associate with the frequency of sweet food intake in these ethnic subgroups. Conclusion: In the Han population, the SLC2A2 rs1499821 T allele and the frequency of sweet food intake may be regarded as risk factors for caries susceptibility. The SLC2A2 rs1499821 T allele had no association with the frequency of sweet food intake in any of the three ethnic groups.
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Affiliation(s)
- Li Liu
- Guangxi Medical University College of Stomatology, Nanning, China
| | - Fei Ma
- Guangxi Medical University College of Stomatology, Nanning, China
| | - Qiulin Liu
- Guangxi Medical University College of Stomatology, Nanning, China
| | - Xueting Yu
- Guangxi Medical University College of Stomatology, Nanning, China
| | - Xiaojuan Zeng
- Guangxi Medical University College of Stomatology, Nanning, China
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27
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Identification of Structural Determinants of the Transport of the Dehydroascorbic Acid Mediated by Glucose Transport GLUT1. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28020521. [PMID: 36677580 PMCID: PMC9867014 DOI: 10.3390/molecules28020521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/12/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023]
Abstract
GLUT1 is a facilitative glucose transporter that can transport oxidized vitamin C (i.e., dehydroascorbic acid) and complements the action of reduced vitamin C transporters. To identify the residues involved in human GLUT1's transport of dehydroascorbic acid, we performed docking studies in the 5 Å grid of the glucose-binding cavity of GLUT1. The interactions of the bicyclic hemiacetal form of dehydroascorbic acid with GLUT1 through hydrogen bonds with the -OH group of C3 and C5 were less favorable than the interactions with the sugars transported by GLUT1. The eight most relevant residues in such interactions (i.e., F26, Q161, I164, Q282, Y292, and W412) were mutated to alanine to perform functional studies for dehydroascorbic acid and the glucose analog, 2-deoxiglucose, in Xenopus laevis oocytes. All the mutants decreased the uptake of both substrates to less than 50%. The partial effect of the N317A mutant in transporting dehydroascorbic acid was associated with a 30% decrease in the Vmax compared to the wildtype GLUT1. The results show that both substrates share the eight residues studied in GLUT1, albeit with a differential contribution of N317. Our work, combining docking with functional studies, marks the first to identify structural determinants of oxidized vitamin C's transport via GLUT1.
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28
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Ahmad M, Abramovich I, Agranovich B, Nemirovski A, Gottlieb E, Hinden L, Tam J. Kidney Proximal Tubule GLUT2-More than Meets the Eye. Cells 2022; 12:cells12010094. [PMID: 36611887 PMCID: PMC9818791 DOI: 10.3390/cells12010094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/06/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.
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Affiliation(s)
- Majdoleen Ahmad
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Ifat Abramovich
- Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 3525422, Israel
| | - Bella Agranovich
- Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 3525422, Israel
| | - Alina Nemirovski
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Eyal Gottlieb
- Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 3525422, Israel
| | - Liad Hinden
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
- Correspondence: (L.H.); (J.T.); Tel.: +972-2-675-7650 (L.H.); +972-2-675-7645 (J.T.)
| | - Joseph Tam
- Obesity and Metabolism Laboratory, Faculty of Medicine, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
- Correspondence: (L.H.); (J.T.); Tel.: +972-2-675-7650 (L.H.); +972-2-675-7645 (J.T.)
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29
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Temporal Pattern of Neuroinflammation Associated with a Low Glycemic Index Diet in the 5xFAD Mouse Model of Alzheimer's Disease. Mol Neurobiol 2022; 59:7303-7322. [PMID: 36175825 PMCID: PMC9616770 DOI: 10.1007/s12035-022-03047-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 09/21/2022] [Indexed: 10/14/2022]
Abstract
Alzheimer's disease (AD) is associated with brain amyloid-β (Aβ) peptide accumulation and neuroinflammation. Currants, a low glycemic index dried fruit, and their components display pleiotropic neuroprotective effects in AD. We examined how diet containing 5% Corinthian currant paste (CurD) administered in 1-month-old 5xFAD mice for 1, 3, and 6 months affects Aβ levels and neuroinflammation in comparison to control diet (ConD) or sugar-matched diet containing 3.5% glucose/fructose (GFD). No change in serum glucose or insulin levels was observed among the three groups. CurD administered for 3 months reduced brain Aβ42 levels in male mice as compared to ConD and GFD, but after 6 months, Aβ42 levels were increased in mice both on CurD and GFD compared to ConD. CurD for 3 months also reduced TNFα and IL-1β levels in male and female mouse cortex homogenates compared to ConD and GFD. However, after 6 months, TNFα levels were increased in cortex homogenates of mice both on CurD and GFD as compared to ConD. A similar pattern was observed for TNFα-expressing cells, mostly co-expressing the microglial marker CD11b, in mouse hippocampus. IL-1β levels were similarly increased in the brain of all groups after 6 months. Furthermore, a time dependent decrease of secreted TNFα levels was found in BV2 microglial cells treated with currant phenolic extract as compared to glucose/fructose solution. Overall, our findings suggest that a short-term currant consumption reduces neuroinflammation in 5xFAD mice as compared to sugar-matched or control diet, but longer-term intake of currant or sugar-matched diet enhances neuroinflammation.
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30
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Arponen M, Jalava N, Widjaja N, Ivaska KK. Glucose transporters GLUT1, GLUT3, and GLUT4 have different effects on osteoblast proliferation and metabolism. Front Physiol 2022; 13:1035516. [PMID: 36523556 PMCID: PMC9744933 DOI: 10.3389/fphys.2022.1035516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/15/2022] [Indexed: 03/05/2024] Open
Abstract
Bone is an active tissue that undergoes constant remodeling. Bone formation requires energy and one of the energy sources of bone-forming osteoblasts is glucose, which is transported inside the cells via glucose transporters. However, the role of class I glucose transporters in the differentiation and metabolism of osteoblasts and their precursors, bone marrow mesenchymal stromal cells (BMSCs) remains inconclusive. Our aim was to characterize the expression and contribution of main class I glucose transporters, GLUT1, GLUT3, and GLUT4, during osteoblast proliferation and differentiation. To investigate the role of each GLUT, we downregulated GLUTs with siRNA technology in primary rat BMSCs. Live-cell imaging and RNA-seq analysis was used to evaluate downstream pathways in silenced osteoblasts. Glucose transporters GLUT1, GLUT3, and GLUT4 had distinct expression patterns in osteoblasts. GLUT1 was abundant in BMSCs, but rapidly and significantly downregulated during osteoblast differentiation by up to 80% (p < 0.001). Similar downregulation was observed for GLUT4 (p < 0.001). In contrast, expression levels of GLUT3 remained stable during differentiation. Osteoblasts lacked GLUT2. Silencing of GLUT4 resulted in a significant decrease in proliferation and differentiation of preosteoblasts (p < 0.001) and several pathways related to carbohydrate metabolism and cell signaling were suppressed. However, silencing of GLUT3 resulted in increased proliferation (p < 0.001), despite suppression of several pathways involved in cellular metabolism, biosynthesis and actin organization. Silencing of GLUT1 had no effect on proliferation and less changes in the transcriptome. RNA-seq dataset further revealed that osteoblasts express also class II and III glucose transporters, except for GLUT7. In conclusion, GLUT1, -3 and -4 may all contribute to glucose uptake in differentiating osteoblasts. GLUT4 expression was clearly required for osteoblast proliferation and differentiation. GLUT1 appears to be abundant in early precursors, but stable expression of GLUT3 suggest also a role for GLUT3 in osteoblasts. Presence of other GLUT members may further contribute to fine-tuning of glucose uptake. Together, glucose uptake in osteoblast lineage appears to rely on several glucose transporters to ensure sufficient energy for new bone formation.
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Affiliation(s)
| | | | | | - Kaisa K. Ivaska
- Institute of Biomedicine, University of Turku, Turku, Finland
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31
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Heo HJ, Park Y, Lee JH, Kim Y, Kim EK, Kim GH, Yu Y, Park SY, Seo HB, Pak K, Goh TS, Park S, Oh SO, Kwon W, Kim YH. Clinical big-data-based design of GLUT2-targeted carbon nanodots for accurate diagnosis of hepatocellular carcinoma. NANOSCALE 2022; 14:17053-17064. [PMID: 36367284 DOI: 10.1039/d2nr04238j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Despite advances in diagnostic and therapeutic methods, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor due to the delay in diagnosis. Herein, we aimed to discover a highly sensitive and specific biomarker for HCC based on genomic big data analysis and create an HCC-targeted imaging probe using carbon nanodots (CNDs) as contrast agents. In genomic analysis, we selected glucose transporter 2 (GLUT2) as a potential imaging target for HCC. We confirmed the target suitability by immunohisto-chemistry tests of 339 patient samples, where 81.1% of the patients exhibited underexpression of GLUT2, i.e., higher GLUT2 intensity in non-tumor tissues than in tumor tissues. To visualize GLUT2, we conjugated CNDs with glucosamine (GLN) as a targeting ligand to yield glucosamine-labeled CNDs (GLN-CNDs). A series of in vitro and in vivo experiments were conducted on GLUT2-modified HepG2 cells to confirm the specificity of the GLN-CNDs. Since the GLUT2 expression is higher in hepatocytes than in HCC cells, the GLUT2-targeted contrast agent is highly attached to normal cells. However, it is possible to produce images in the same form as the images obtained with a cancer cell-targeted contrast agent by inverting color scaling. Our results indicate that GLUT2 is a promising target for HCC and that GLN-CNDs may potentially be used as targeted imaging probes for diagnosing HCC.
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Affiliation(s)
- Hye Jin Heo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Yoonsang Park
- Institute of Advanced Materials and Systems, Sookmyung Women's University, Seoul 04310, Republic of Korea.
- Nano Convergence Technology Research Center, Korea Electronics Technology Institute (KETI), Seongnam 13509, Republic of Korea
| | - Jung Hee Lee
- Department of Pathology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yujin Kim
- Department of Chemical and Biological Engineering, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Eun Kyoung Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Ga Hyun Kim
- Interdisciplinary Program of Genomic Data Science, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yeuni Yu
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
| | - So Youn Park
- Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hie Bum Seo
- Department of Radiology, School of Medicine, Pusan National University, Pusan National University Hospital, Yangsan 50612, Republic of Korea
| | - Kyoungjune Pak
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
- Department of Nuclear Medicine, Pusan National University Hospital, Yangsan 50612, Republic of Korea
| | - Tae Sik Goh
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
- Department of Orthopaedic Surgery, Pusan National University Hospital, Yangsan 50612, Republic of Korea
| | - Sehyeon Park
- Department of Chemical and Biological Engineering, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Woosung Kwon
- Institute of Advanced Materials and Systems, Sookmyung Women's University, Seoul 04310, Republic of Korea.
- Department of Chemical and Biological Engineering, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Yun Hak Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
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Temre MK, Kumar A, Singh SM. An appraisal of the current status of inhibition of glucose transporters as an emerging antineoplastic approach: Promising potential of new pan-GLUT inhibitors. Front Pharmacol 2022; 13:1035510. [PMID: 36386187 PMCID: PMC9663470 DOI: 10.3389/fphar.2022.1035510] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/18/2022] [Indexed: 07/23/2023] Open
Abstract
Neoplastic cells displayed altered metabolism with accelerated glycolysis. Therefore, these cells need a mammoth supply of glucose for which they display an upregulated expression of various glucose transporters (GLUT). Thus, novel antineoplastic strategies focus on inhibiting GLUT to intersect the glycolytic lifeline of cancer cells. This review focuses on the current status of various GLUT inhibition scenarios. The GLUT inhibitors belong to both natural and synthetic small inhibitory molecules category. As neoplastic cells express multiple GLUT isoforms, it is necessary to use pan-GLUT inhibitors. Nevertheless, it is also necessary that such pan-GLUT inhibitors exert their action at a low concentration so that normal healthy cells are left unharmed and minimal injury is caused to the other vital organs and systems of the body. Moreover, approaches are also emerging from combining GLUT inhibitors with other chemotherapeutic agents to potentiate the antineoplastic action. A new pan-GLUT inhibitor named glutor, a piperazine-one derivative, has shown a potent antineoplastic action owing to its inhibitory action exerted at nanomolar concentrations. The review discusses the merits and limitations of the existing GLUT inhibitory approach with possible future outcomes.
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Affiliation(s)
- Mithlesh Kumar Temre
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ajay Kumar
- Deparment of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sukh Mahendra Singh
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
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Chang YS, Lin CY, Liu TY, Huang CM, Chung CC, Chen YC, Tsai FJ, Chang JG, Chang SJ. Polygenic risk score trend and new variants on chromosome 1 are associated with male gout in genome-wide association study. Arthritis Res Ther 2022; 24:229. [PMID: 36221101 PMCID: PMC9552457 DOI: 10.1186/s13075-022-02917-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 09/24/2022] [Indexed: 11/30/2022] Open
Abstract
Background Gout is a highly hereditary disease, but not all those carrying well-known risk variants have developing gout attack even in hyperuricemia status. We performed a genome-wide association study (GWAS) and polygenic risk score (PRS) analysis to illustrate the new genetic architectures of gout and asymptomatic hyperuricemia (AH). Methods GWAS was performed to identify variants associated with gout/AH compared with normouricemia. The participants were males, enrolled from the Taiwan Biobank and China Medical University, and divided into discovery (n=39,594) and replication (n=891) cohorts for GWAS. For PRS analysis, the discovery cohort was grouped as base (n=21,814) and target (n=17,780) cohorts, and the score was estimated by grouping the polymorphisms into protective or not for the phenotypes in the base cohort. Results The genes ABCG2 and SLC2A9 were found as the major genetic factors governing gouty and AH, and even in those carrying the rs2231142 (ABCG2) wild-genotype. Surprisingly, variants on chromosome 1, such as rs7546668 (DNAJC16), rs10927807 (AGMAT), rs9286836 (NUDT17), rs4971100 (TRIM46), rs4072037 (MUC1), and rs2974935 (MTX1), showed significant associations with gout in both discovery and replication cohorts (all p-values < 1e−8). Concerning the PRS, the rates of gout and AH increased with increased quartile PRS in those SNPs having risk effects on the phenotypes; on the contrary, gout/AH rates decreased with increased quartile PRS in those protective SNPs. Conclusions We found new variants on chromosome 1 significantly relating to gout, and PRS predicts the risk of developing gout/AH more robustly based on the SNPs’ effect types on the trait. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02917-4.
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Affiliation(s)
- Ya-Sian Chang
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Graduate Institute of Integrated Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Chien-Yu Lin
- Graduate Institute of Clinical Medical Sciences, School of Medicine, China Medical University, Taichung, Taiwan.,Division of Laboratory Medicine, China Medical University Hsinchu Hospital, Zhubei City, Taiwan
| | - Ting-Yuan Liu
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Chung-Ming Huang
- Graduate Institute of Integrated Medicine, College of Medicine, China Medical University, Taichung, Taiwan.,Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Chin-Chun Chung
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Graduate Institute of Integrated Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Chia Chen
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Fuu-Jen Tsai
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
| | - Jan-Gowth Chang
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan. .,Graduate Institute of Integrated Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
| | - Shun-Jen Chang
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan. .,Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, No. 700, Kaohsiung University Road, Nanzih District, 81148, Kaohsiung, Taiwan.
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Zhu Y, Wang A, Zhang S, Kim J, Xia J, Zhang F, Wang D, Wang Q, Wang J. Paclitaxel-loaded ginsenoside Rg3 liposomes for drug-resistant cancer therapy by dual targeting of the tumor microenvironment and cancer cells. J Adv Res 2022:S2090-1232(22)00209-0. [PMID: 36167294 DOI: 10.1016/j.jare.2022.09.007] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Inherent or acquired resistance to paclitaxel (PTX) is a pivotal challenge for chemotherapy treatment of multidrug-resistant (MDR) breast cancer. Although various targeted drug-delivery systems, including nanoparticles and liposomes, are effective for MDR cancer treatment, their efficacy is restricted by immunosuppressive tumor microenvironment (TME). METHODS Ginsenosides Rg3 was used to formulate unique Rg3-based liposomes loaded with PTX to establish Rg3-PTX-LPs, which were prepared by the thin-film hydration method. The stability of the Rg3-PTX-LPs was evaluated by particle size analysis through dynamic light scattering. The active targeting effect of Rg3-based liposomes was examined in an MCF-7/T xenograft model by an in a vivo imaging system. To evaluate the antitumor activity and mechanism of Rg3-PTX-LP, MTT, apoptosis assays, TAM regulation, and TME remodeling were performed in MCF-7/T cells in vitro and in vivo. RESULTS Rg3-PTX-LPs could specifically distribute to MCF7/T cancer cells and TME simultaneously, mainly through the recognition of GLUT-1. The drug resistance reversing capability and in vivo antitumor effect of Rg3-PTX-LPs were significantly improved compared with conventional cholesterol liposomes. The TME remodeling mechanisms of Rg3-PTX-LPs included inhibiting IL-6/STAT3/p-STAT3 pathway activation to repolarize protumor M2 macrophages to antitumor M1 phenotype, suppressing myeloid-derived suppressor cells (MDSCs), decreasing tumor-associated fibroblasts (TAFs) and collagen fibers in TME, and promoting apoptosis of tumor cells. Hence, through the dual effects of targeting tumor cells and TME remodeling, Rg3-PTX-LPs achieved a high tumor inhibition rate of 90.3%. CONCLUSION Our multifunctional Rg3-based liposome developed in the present study offered a promising strategy for rescuing the drug resistance tumor treatment.
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Affiliation(s)
- Ying Zhu
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR China; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Anni Wang
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR China
| | - Shuya Zhang
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR China
| | - Jisu Kim
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR China
| | - Jiaxuan Xia
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR China
| | - Fengxue Zhang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Dan Wang
- Xiamen Ginposome Pharmaceutical Co., Ltd., Xiamen 361026, People's Republic of China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
| | - Jianxin Wang
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR China; Institute of Integrated Chinese and Western Medicine, Fudan University, Shanghai 200040, China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
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Sayed MHM, Abdelnaim AKM, Mohamadien NRA. Intrapatient variability of 18F-FDG uptake in normal tissues. J Clin Imaging Sci 2022; 12:37. [PMID: 36128350 PMCID: PMC9479622 DOI: 10.25259/jcis_23_2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 05/31/2022] [Indexed: 11/08/2022] Open
Abstract
Objectives To investigate the effect of serum glucose level and other confounding factors on the variability of maximum standardized uptake value (SUVmax) in normal tissues within the same patient on two separate occasions and to suggest an ideal reference tissue. Materials and Methods We retrospectively reviewed 334 18F-FDG PET/CT scans of 167 cancer patients including 38 diabetics. All patients had two studies, on average 152 ± 68 days apart. Ten matched volumes of interest were drawn on the brain, right tonsil, blood pool, heart, lung, liver, spleen, bone marrow, fat, and iliopsoas muscle opposite third lumber vertebra away from any pathological 18F-FDG uptake to calculate SUVmax. Results SUVmax of the lungs and heart were significantly different in the two studies (P = 0.003 and P = 0.024 respectively). Only the brain uptake showed a significant moderate negative correlation with the level of blood glucose in diabetic patients (r = −0.537, P = 0.001) in the first study, while the SUVmax of other tissues showed negligible or weak correlation with the level of blood glucose in both studies. The liver showed significant moderate positive correlation with body mass index (BMI) in both studies (r = .416, P = <0.001 versus r = 0.453, P = <0.001, respectively), and blood pool activity showed significant moderate positive correlation with BMI in the first study only (r = 0.414, P = <0.001). The liver and blood pool activities showed significant moderate negative correlation with 18F-FDG uptake time in first study only (r = −0.405, P-value = <0.001; and r = −0.409, P-value = <0.001, respectively). In the multivariate analysis, the liver showed a consistent effect of the injected 18F-FDG dose and uptake duration on its SUVmax on the two occasions. In comparison, spleen and muscle showed consistent effect only of the injected dose on the two occasions. Conclusion The liver, muscle, and splenic activities showed satisfactory test/retest stability and can be used as reference activities. The spleen and muscle appear to be more optimal reference than the liver, as it is only associated with the injected dose of 18F-FDG.
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Affiliation(s)
- Mohamed Hosny Mohamed Sayed
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt,
| | - Aya KM Abdelnaim
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt,
| | - Nsreen RA Mohamadien
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt,
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Takashima M, Nakamura K, Kiyohara T, Wakisaka Y, Hidaka M, Takaki H, Yamanaka K, Shibahara T, Wakisaka M, Ago T, Kitazono T. Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects. Commun Biol 2022; 5:653. [PMID: 35780235 PMCID: PMC9250510 DOI: 10.1038/s42003-022-03605-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 06/20/2022] [Indexed: 12/11/2022] Open
Abstract
Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the effects of luseogliflozin, a selective SGLT2 inhibitor, in acute ischemic stroke, using a permanent middle cerebral artery occlusion (pMCAO) model in non-diabetic mice. Pretreatment with low-dose luseogliflozin, which does not affect blood glucose levels, significantly attenuated infarct volume, blood-brain barrier disruption, and motor dysfunction after pMCAO. SGLT2 was expressed predominantly in brain pericytes and was upregulated in peri- and intra-infarct areas. Notably, luseogliflozin pretreatment reduced pericyte loss in ischemic areas. In cultured pericytes, luseogliflozin activated AMP-activated protein kinase α and increased mitochondrial transcription factor A expression and number of mitochondria, conferring resistance to oxygen-glucose deprivation. Collectively, pre-stroke inhibition of SGLT2 induces ischemic tolerance in brain pericytes independent of the glucose-lowering effect, contributing to the attenuation of ischemic brain injury. Pre-treatment of non-diabetic mice with the SGLT2 inhibitor, luseogliflozin, reduces brain damage and neurological dysfunction following middle cerebral artery occlusion by acquiring ischemic tolerance in pericytes.
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Affiliation(s)
- Masamitsu Takashima
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kuniyuki Nakamura
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Takuya Kiyohara
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoshinobu Wakisaka
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masaoki Hidaka
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hayato Takaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kei Yamanaka
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomoya Shibahara
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masanori Wakisaka
- Wakisaka Internal Medicine Clinic, 1-24-19 Fujisaki, Sawara-ku, Fukuoka, 814-0013, Japan
| | - Tetsuro Ago
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Adams Y, Jensen AR. Cerebral malaria - modelling interactions at the blood-brain barrier in vitro. Dis Model Mech 2022; 15:275963. [PMID: 35815443 PMCID: PMC9302004 DOI: 10.1242/dmm.049410] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The blood–brain barrier (BBB) is a continuous endothelial barrier that is supported by pericytes and astrocytes and regulates the passage of solutes between the bloodstream and the brain. This structure is called the neurovascular unit and serves to protect the brain from blood-borne disease-causing agents and other risk factors. In the past decade, great strides have been made to investigate the neurovascular unit for delivery of chemotherapeutics and for understanding how pathogens can circumvent the barrier, leading to severe and, at times, fatal complications. One such complication is cerebral malaria, in which Plasmodium falciparum-infected red blood cells disrupt the barrier function of the BBB, causing severe brain swelling. Multiple in vitro models of the BBB are available to investigate the mechanisms underlying the pathogenesis of cerebral malaria and other diseases. These range from single-cell monolayer cultures to multicellular BBB organoids and highly complex cerebral organoids. Here, we review the technologies available in malaria research to investigate the interaction between P. falciparum-infected red blood cells and the BBB, and discuss the advantages and disadvantages of each model. Summary: This Review discusses the available in vitro models to investigate the impact of adhesion of Plasmodium falciparum-infected red blood cells on the blood–brain barrier, a process associated with cerebral malaria.
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Affiliation(s)
- Yvonne Adams
- Centre for Medical Parasitology at the Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Anja Ramstedt Jensen
- Centre for Medical Parasitology at the Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
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Sharma V, Singh TG, Mannan A. Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia. Neurochem Res 2022; 47:2173-2186. [PMID: 35596882 DOI: 10.1007/s11064-022-03620-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 01/05/2023]
Abstract
Cerebral ischemia is a leading cause of death in the globe, with a large societal cost. Deprivation of blood flow, together with consequent glucose and oxygen shortage, activates a variety of pathways that result in permanent brain damage. As a result, ischemia raises energy demand, which is linked to significant alterations in brain energy metabolism. Even at the low glucose levels reported in plasma during ischemia, glucose transport activity may adjust to assure the supply of glucose to maintain normal cellular function. Glucose transporters in the brain are divided into two groups: sodium-independent glucose transporters (GLUTs) and sodium-dependent glucose cotransporters (SGLTs).This review assess the GLUT structure, expression, regulation, pathobiology of GLUT in cerebral ischemia and regulators of GLUT and it also provides the synopsis of the literature exploring the relationship between GLUT and the various downstream signalling pathways for e.g., AMP-activated protein kinase (AMPK), CREB (cAMP response element-binding protein), Hypoxia-inducible factor 1 (HIF)-1, Phosphatidylinositol 3-kinase (PI3-K), Mitogen-activated protein kinase (MAPK) and adenylate-uridylate-rich elements (AREs). Therefore, the aim of the present review was to elaborate the therapeutic implications of GLUT in the cerebral ischemia.
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Affiliation(s)
- Veerta Sharma
- Chitkara College of Pharmacy, Chitkara University, 140401, Patiala, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, 140401, Patiala, Punjab, India.
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, 140401, Patiala, Punjab, India
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Wang R, Quan Z, Zheng T, Wang K, Liu Y, Han Z, Wang X, Ma S, Liu L, Lau WY, Sun X. Pathophysiological mechanisms of ALPPS: experimental model. Br J Surg 2022; 109:510-519. [PMID: 35576390 DOI: 10.1093/bjs/znac007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage strategy that may increase hepatic tumour resectability and reduce postoperative liver failure rate by inducing rapid hypertrophy of the future liver remnant (FLR). Pathophysiological mechanisms after the first stage of ALPPS are poorly understood. METHODS An ALPPS model was established in rabbits with liver VX2 tumour. The pathophysiological mechanisms after the first stage of ALPPS in the FLR and tumour were assessed by multiplexed positron emission tomography (PET) tracers, dynamic contrast-enhanced MRI (DCE-MRI) and histopathology. RESULTS Tumour volume in the ALPPS model differed from post-stage 1 ALPPS at day 14 compared to control animals. 18F-FDG uptake of tumour increased from day 7 onwards in the ALPPS model. Valid volumetric function measured by 18F-methylcholine PET showed good values in accurately monitoring dynamics and time window for functional liver regeneration (days 3 to 7). DCE-MRI revealed changes in the vascular hyperpermeability function, with a peak on day 7 for tumour and FLR. CONCLUSION Molecular and functional imaging are promising non-invasive methods to investigate the pathophysiological mechanisms of ALPPS with potential for clinical application.
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Affiliation(s)
- Ruifeng Wang
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China.,Department of Gastroenterology, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Zhen Quan
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Tongsen Zheng
- Department of Gastrointestinal Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Kai Wang
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Yang Liu
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Zhaoguo Han
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China.,Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA
| | - Xiance Wang
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Shiling Ma
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Lianxin Liu
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, Heilongjiang Province 150001, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wan Yee Lau
- Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR 999077, China
| | - Xilin Sun
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China.,Department of Nuclear Medicine, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
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40
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Chakrabarty R, Yousuf S, Singh MP. Contributive Role of Hyperglycemia and Hypoglycemia Towards the Development of Alzheimer's Disease. Mol Neurobiol 2022; 59:4274-4291. [PMID: 35503159 DOI: 10.1007/s12035-022-02846-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/20/2022] [Indexed: 11/30/2022]
Abstract
Alzheimer's disease (AD) is one of the causes of dementia that results from several infections/biological conditions leading to either cell disruption or loss of neuronal communication. Studies have documented the accumulation of two proteins, beta-amyloid (Aβ), which accumulates on the exteriors of neurons, and tau (Tau), which assembles at the interiors of brain cells and is chiefly liable for the progression of the disease. Several molecular and cellular pathways account for the accumulation of amyloid-β and the formation of neurofibrillary tangles, which are phosphorylated variants of Tau protein. Moreover, research has revealed a potential connection between AD and diabetes. It has also been demonstrated that both hypoglycemia and hyperglycemia have a significant role in the development of AD. In addition, SUMO (small ubiquitin-like modifier protein) plays a crucial role in the pathogenesis of AD. SUMOylation is the process by which modification of amyloid precursor protein (APP) and Tau takes place. Furthermore, Drosophila melanogaster has proven to be an efficient model organism in studies to establish the relationship between AD and variations in blood glucose levels. In addition, the review successfully identifies the common pathway that links the effects of fluctuations in glucose levels on AD pathogenesis and advancements.
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Affiliation(s)
- Riya Chakrabarty
- School of Bioengineering and Biosciences, Lovely Professional University, Jalandhar-Ludhiana National Highway, Phagwara, Punjab, 144411, India
| | - Sumaira Yousuf
- School of Bioengineering and Biosciences, Lovely Professional University, Jalandhar-Ludhiana National Highway, Phagwara, Punjab, 144411, India
| | - Mahendra P Singh
- School of Bioengineering and Biosciences, Lovely Professional University, Jalandhar-Ludhiana National Highway, Phagwara, Punjab, 144411, India.
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41
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Yang L, Zhi S, Yang G, Qin C, Yan X, Niu M, Zhang W, Liu M, Zhao M, Nie G. Molecular identification of glucose transporter 4: The responsiveness to starvation, glucose, insulin and glucagon on glucose transporter 4 in common carp (Cyprinus carpio L.). JOURNAL OF FISH BIOLOGY 2021; 99:1843-1856. [PMID: 34418098 DOI: 10.1111/jfb.14885] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/27/2021] [Accepted: 08/18/2021] [Indexed: 06/13/2023]
Abstract
Glucose transporter 4 (GLUT4) is comprehensively investigated in mammals, while the comparative research of GLUT4 in common carp is deficient. To investigate the function of GLUT4, carp glut4 was first isolated. The open reading frame of carp glut4 was 1518 bp in length, encoding 505 amino acids. A high-sequence homology was identified in carp and teleost, and the phylogenetic tree displayed that the carp GLUT4 was clustered with the teleost. A high level of glut4 mRNA was analysed in fat, red muscle and white muscle. After fasting treatment, glut4 mRNA expression was increased significantly in muscle. In the oral glucose tolerance test experiment, glut4 mRNA was also significantly elevated in muscle, gut and fat. Furthermore, intraperitoneal injection of insulin resulted in the upregulation of glut4 gene expression significantly in white muscle, gut and fat. On the contrary, the glut4 mRNA level in the white muscle, gut and fat was markedly downregulated after glucagon injection. These results suggest that GLUT4 might play important roles in food intake and could be regulated by nutrient condition, insulin and glucagon in common carp. Our study is the first to report on GLUT4 in common carp. These data provide a basis for further study on fish GLUT4.
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Affiliation(s)
- Liping Yang
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Shaoyang Zhi
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Guokun Yang
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Chaobin Qin
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Xiao Yan
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Mingming Niu
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Wenlei Zhang
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Mingyu Liu
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Mengjuan Zhao
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
| | - Guoxing Nie
- College of Fisheries, Engineering Technology Research Center of Henan Province for Aquatic Animal Cultivation, Henan Normal University, Xinxiang, China
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42
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Luo Z, Li T, Gao Q, Chen Y, Su G, Zhao Y. Impact of licochalcone A on the progression of diabetic nephropathy in type 2 diabetes mellitus of C57BL/6 mice. Food Funct 2021; 12:10676-10689. [PMID: 34605512 DOI: 10.1039/d1fo01630j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Diabetic nephropathy (DN) is the most common chronic microvascular complication of diabetes. Therefore, it is of great significance to effectively prevent and treat DN. Licochalcone A (LicA) is a flavonoid found in licorice; previous studies have shown that LicA can reduce blood glucose, blood lipids and improve insulin resistance. There has been no research on whether LicA can prevent and treat DN. In this study, an animal model of type 2 diabetes mellitus (T2DM) mice induced by high fat diet/streptozotocin was established, and the intervention of LicA was applied to investigate the protective effect of LicA on the kidneys of DN mice. After 4 weeks of intervention, LicA could effectively reduce blood glucose and alleviate the phenomenon of weight loss in mice. Meanwhile, the levels of MDA, SOD and GSH-Px in the kidney tissue and serum were recovered to different degrees. Besides, LicA decreased the levels of TC, TG and LDL-C in the kidney tissue and increased the level of HDL-C in the kidney tissue. The 24 h urinary protein, blood urea nitrogen (BUN) and serum creatinine (SCr) levels of mice in the treatment group of LicA were significantly lower than those in the model group. Furthermore, HE staining, PAS staining and Masson staining indicated that LicA improved the pathological damage of kidneys, and the kidney index of mice also decreased. Western blotting results indicated that LicA could significantly down-regulate the protein expression of AGEs/RAGE, TGF-β1, HIF-1α and GLUT1, and up-regulate the protein expression of Nrf2. It provides a theoretical basis for the further development and utilization of LicA.
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Affiliation(s)
- Zhonghua Luo
- Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Tao Li
- Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Qingqing Gao
- Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Yu Chen
- Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Guangyue Su
- Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Yuqing Zhao
- Shenyang Pharmaceutical University, Shenyang 110016, China. .,Key Laboratory of Structure-based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
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43
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Páníková T, Mitrová K, Halamová T, Mrzílková K, Pícha J, Chrudinová M, Kurochka A, Selicharová I, Žáková L, Jiráček J. Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities. J Med Chem 2021; 64:14848-14859. [PMID: 34591477 DOI: 10.1021/acs.jmedchem.1c01388] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Insulin is a lifesaver for millions of diabetic patients. There is a need for new insulin analogues with more physiological profiles and analogues that will be thermally more stable than human insulin. Here, we describe the chemical engineering of 48 insulin analogues that were designed to have changed binding specificities toward isoforms A and B of the insulin receptor (IR-A and IR-B). We systematically modified insulin at the C-terminus of the B-chain, at the N-terminus of the A-chain, and at A14 and A18 positions. We discovered an insulin analogue that has Cα-carboxyamidated Glu at B31 and Ala at B29 and that has a more than 3-fold-enhanced binding specificity in favor of the "metabolic" IR-B isoform. The analogue is more resistant to the formation of insulin fibrils at 37 °C and is also more efficient in mice than human insulin. Therefore, [AlaB29,GluB31,amideB31]-insulin may be interesting for further clinical evaluation.
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Affiliation(s)
- Terezie Páníková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
- Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague, Czech Republic
| | - Katarína Mitrová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Tereza Halamová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Karolína Mrzílková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Jan Pícha
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Martina Chrudinová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Andrii Kurochka
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Irena Selicharová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Lenka Žáková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
| | - Jiří Jiráček
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo n. 2, 116 10 Prague 6, Czech Republic
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Shi Z, Liu J, Wang F, Li Y. Integrated analysis of Solute carrier family-2 members reveals SLC2A4 as an independent favorable prognostic biomarker for breast cancer. Channels (Austin) 2021; 15:555-568. [PMID: 34488531 PMCID: PMC8425726 DOI: 10.1080/19336950.2021.1973788] [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] [Indexed: 11/02/2022] Open
Abstract
Most of Solute carrier family-2 (SLC2) members play a key role of facilitative transporters, and glucose transporter (GLUT) proteins encoded by SLC2s can transport hexoses or polyols. However, the function and mechanism of SLC2s remain unclear in human cancers. Here, we explored the dysregulated expression, prognostic values, epigenetic, genetic alterations, and biomolecular network of SLC2s in human cancers. According to the data from public-omicsrepository, SLC2A4 (GLUT4) was found to be significantly downregulated in most cancers, and higher messenger RNA (mRNA) expression of SLC2A4 significantly associated with better prognosis of breast cancer (BRCA) patients. Moreover, DNA hypermethylation in the promoter of SLC2A4 may affect the regulation of its mRNA expression, and SLC2A4 was strongly correlated with pathways, including the translocation of SLC2A4 to the plasma membrane and PID INSULIN PATHWAY. In conclusion, these results provide insight into SLC2s in human cancers and suggest that SLC2A4 could be an unfavorable prognostic biomarker for the survival of BRCA patients.
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Affiliation(s)
- Zhenyu Shi
- Department of Predictive Medicine,Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, HenanUniversity,Kaifeng,China
| | - Jiahao Liu
- Department of Predictive Medicine,Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, HenanUniversity,Kaifeng,China
| | - Fei Wang
- Department of Predictive Medicine,Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, HenanUniversity,Kaifeng,China
| | - Yongqiang Li
- Department of Predictive Medicine,Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, HenanUniversity,Kaifeng,China
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45
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Kubicka A, Matczak K, Łabieniec-Watała M. More Than Meets the Eye Regarding Cancer Metabolism. Int J Mol Sci 2021; 22:9507. [PMID: 34502416 PMCID: PMC8430985 DOI: 10.3390/ijms22179507] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/20/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022] Open
Abstract
In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not "give up" on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation.
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Affiliation(s)
- Anna Kubicka
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland;
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Karolina Matczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland;
| | - Magdalena Łabieniec-Watała
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland;
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46
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A Role for SGLT-2 Inhibitors in Treating Non-diabetic Chronic Kidney Disease. Drugs 2021; 81:1491-1511. [PMID: 34363606 DOI: 10.1007/s40265-021-01573-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2021] [Indexed: 02/06/2023]
Abstract
In recent years, inhibitors of the sodium-glucose co-transporter 2 (SGLT2 inhibitors) have been shown to have significant protective effects on the kidney and the cardiovascular system in patients with diabetes. This effect is also manifested in chronic kidney disease (CKD) patients and is minimally due to improved glycaemic control. Starting from these positive findings, SGLT2 inhibitors have also been tested in patients with non-diabetic CKD or heart failure with reduced ejection fraction. Recently, the DAPA-CKD trial showed a significantly lower risk of CKD progression or death from renal or cardiovascular causes in a mixed population of patients with diabetic and non-diabetic CKD receiving dapagliflozin in comparison with placebo. In patients with heart failure and reduced ejection fraction, two trials (EMPEROR-Reduced and DAPA-HF) also found a significantly lower risk of reaching the secondary renal endpoint in those treated with an SGLT2 inhibitor in comparison with placebo. This also applied to patients with CKD. Apart from their direct mechanism of action, SGLT2 inhibitors have additional effects that could be of particular interest for patients with non-diabetic CKD. Among these, SGLT2 inhibitors reduce blood pressure and serum acid uric levels and can increase hemoglobin levels. Some safety issues should be further explored in the CKD population. SGLT2 inhibitors can minimally increase potassium levels, but this has not been shown by the CREDENCE trial. They also increase magnesium and phosphate reabsorption. These effects could become more significant in patients with advanced CKD and will need monitoring when these agents are used more extensively in the CKD population. Conversely, they do not seem to increase the risk of acute kidney injury.
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47
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Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22158142. [PMID: 34360906 PMCID: PMC8348194 DOI: 10.3390/ijms22158142] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/06/2021] [Accepted: 07/28/2021] [Indexed: 12/16/2022] Open
Abstract
The most common cause of dementia, especially in elderly people, is Alzheimer’s disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer’s disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.
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48
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Park GB, Jeong JY, Kim D. GLUT5 regulation by AKT1/3-miR-125b-5p downregulation induces migratory activity and drug resistance in TLR-modified colorectal cancer cells. Carcinogenesis 2021; 41:1329-1340. [PMID: 32649737 DOI: 10.1093/carcin/bgaa074] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/26/2020] [Accepted: 07/08/2020] [Indexed: 12/16/2022] Open
Abstract
In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development.
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Affiliation(s)
- Ga-Bin Park
- Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea
| | - Daejin Kim
- Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea
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Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems. Sci Rep 2021; 11:13751. [PMID: 34215797 PMCID: PMC8253845 DOI: 10.1038/s41598-021-93063-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/14/2021] [Indexed: 01/07/2023] Open
Abstract
Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi-Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.
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50
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Muñoz-Montesino C, Peña E, Roa FJ, Sotomayor K, Escobar E, Rivas CI. Transport of Vitamin C in Cancer. Antioxid Redox Signal 2021; 35:61-74. [PMID: 33607936 DOI: 10.1089/ars.2020.8166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Significance: Vitamin C is a powerful antioxidant that has an intricate relationship with cancer and has been studied for more than 60 years. However, the specific mechanisms that allow malignant cells to uptake, metabolize, and compartmentalize vitamin C remain unclear. In normal human cells, two different transporter systems are responsible for its acquisition: glucose transporters (GLUTs) transport the oxidized form of vitamin C (dehydroascorbic acid) and sodium-coupled ascorbic acid transporters (SVCTs) transport the reduced form (ascorbic acid [AA]). In this study, we review the mechanisms described for vitamin C uptake and metabolization in cancer. Recent Advances: Several studies performed recently in vivo and in vitro have provided the scientific community a better understanding of the differential capacities of cancer cells to acquire vitamin C: tumors from different origins do not express SVCTs in the plasma membrane and are only able to acquire vitamin C in its oxidized form. Interestingly, cancer cells differentially express a mitochondrial form of SVCT2. Critical Issues: Why tumors have reduced AA uptake capacity at the plasma membrane, but develop the capacity of AA transport within mitochondria, remains a mystery. However, it shows that understanding vitamin C physiology in tumor survival might be key to decipher the controversies in its relationship with cancer. Future Directions: A comprehensive analysis of the mechanisms by which cancer cells acquire, compartmentalize, and use vitamin C will allow the design of new therapeutic approaches in human cancer. Antioxid. Redox Signal. 35, 61-74.
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Affiliation(s)
- Carola Muñoz-Montesino
- Departamento de Fisiología and Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Eduardo Peña
- Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Francisco J Roa
- Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Kirsty Sotomayor
- Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Elizabeth Escobar
- Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Coralia I Rivas
- Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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