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  • SGLT inhibitors have been accepted as a new class of

    2021-11-26

    SGLT-2 inhibitors have been accepted as a new class of antidiabetic agent (Kurosaki and Ogasawara, 2013). They limit renal glucose reabsorption and promote urinary excretion of glucose, thereby reducing plasma glucose levels (de Leeuw and de Boer, 2016, Jojima et al., 2016, Pérez López et al., 2010, Tahara et al., 2016). Most research in this area focuses on the function of SGLT-2 and SGLT-2 inhibitors within the context of diabetes and development of antidiabetic agents. Although SGLT has now garnered attention as a possible novel therapeutic target, its potential in for pathologies such as cancer, cardiac disease, cerebral ischemia, and intestinal ischemia has not been reviewed. Here, we summarize the physiological role of SGLT in cerebral ischemia, which is being studied by our group. In addition, we also review the recent studies investigating the role of SGLT in cancer, cardiac disease, and intestinal ischemia. In this review, we explore the role of SGLT in selected diseases and its value as a novel therapeutic target.
    Role of cerebral SGLT in cerebral ischemia
    SGLT as a potential therapeutic target in cancer treatment
    Physiological role of SGLT-1 in cardiac disease
    Small intestinal SGLT-1 has an important role in intestinal ischemia In the small intestine, SGLT-1 is localized at the apical plasma membrane of epithelial cells and plays a role in the Benidipine HCl sale of glucose from the intestinal lumen into these cells. GLUT 2, located at the basolateral membrane of the epithelial cells, transports glucose from the cells to the blood (Scheepers et al., 2004a, Scheepers et al., 2004b). SGLT-1 also transports galactose (Wright et al., 2007), and mutations of the SGLT-1 gene cause glucose-galactose malabsorption, which is manifested as severe diarrhea and dehydration (Wright et al., 2007). SGLT-1, therefore, has a critical role in intestinal function. Intestinal ischemia can occur in patients following severe trauma and mesenteric artery embolism (Bradley and Schonfeld, 1962). Mucosal barrier damage and bacterial translocation can be induced by intestinal ischemia, leading to sepsis and systemic inflammation ( Bradley and Schonfeld, 1962). It was reported that epithelial apoptosis, mucosal barrier damage, and mucosal inflammation were induced by intestinal ischemia/reperfusion in rats, and this damage was attenuated by enteric instillation of glucose (Huang et al., 2011). In addition, phlorizin treatment suppressed this ameliorative effect (Huang et al., 2011). Thus, SGLT-1 in epithelial cells attenuated the epithelial barrier damage associated with intestinal ischemia (Huang et al., 2011). In this study, glucose uptake through SGLT-1 activated antiapoptotic PI3K/Akt signaling. Targeting SGLT-1 is a potential new strategy for promoting the survival of epithelial cells in intestinal ischemic disease (Fig. 4).
    Conclusions
    Funding This work was supported by a Grant-in-Aid for Scientific Research (C) (17K01882) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
    Introduction Glucose transporters (GLUTs) are the main carriers of glucose that facilitate the diffusion of glucose in mammalian cells; specifically, GLUT1 is a rate-limiting transporter for glucose uptake, and the overexpression of GLUTs is a common characteristic of most cancers [1]. Thus, GLUT-mediated molecular bioprobes have become widely used in biochemical research as well as in clinical diagnostic analysis by the biological research community [2], [3]. Among these sugar-tagged molecules, fluorescent glucose bioprobes are undoubtedly some of the most promising tools for GLUT-mediated bioimaging [4], which can be effectively applied in the real-time monitoring systems for cellular glucose uptake and for diagnosis of various diseases, especially metabolic diseases [5], [6], [7], [8]. However, only a few fluorescent glycoconjugates have been reported for the past 30 years. The first fluorescent-tagged glucose bioprobe, 6-deoxy-N-(7-nitrobenz-2-oxa-l,3-diazol-4-yl) -aminoglucose (6-NBDG), was synthesized by Kutchai's laboratory in 1985 [5], [9]. Following this molecule, another structurally similar analogue, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG), was developed and extensively studied by Yoshioka et al., in 1996 [3]. 2-NBDG has now been widely applied in various studies, especially for tumor imaging and the examination of GLUT-related cell metabolism [3], [10], [11], [12], [13]. Nevertheless, these NBDGs have several limitations due to the fluorophore, including the weak fluorescence intensity, incompatibility to the physiological environment, and high treatment dosage [11], [14]. These limitations are expected to limit the biomedical benefits of these probes as molecular imaging tools for glucose transporter-mediated bioimaging. Therefore, to overcome the limitations of these bioprobes, discovery of novel fluorescent bioprobe for glucose transporter-mediated bioimaging remains attractive and a challenge; Owing to this reason, several fluorescent glycoconjugates have been developed and evaluated for fluorescence bioimaging and applications in biomedical and diagnostic studies [4], [6], [15], [16], [17]. For example, the near-infrared (NIR) fluorphor derived glucose analogue Cy5.5-2DG shows greater stability in the mouse model (4 days post injection) as compared with 2-NBDG, according to the research group of Gambhir at Stanford University in 2006 [17]. Cy3-derived glucose conjugate, Cy3-Glc-α was developed by Park in 2007 which was found more sensitive in labeling cancer cells than 2-NBDG [4].