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  • Introduction Glucose is the most

    2022-01-06

    Introduction Glucose is the most important energy carrier of the brain. Glucose transporter type 1 (Glut1) is located at the blood–brain barrier and assures the energy-independent, facilitative transport of glucose into the brain [1]. Twelve transmembrane segments of the protein and an intracellular N- and C-terminus (Fig. 1A) are forming the protein pore (Fig. 1B) [5]. The original name of Glut1 was HepG2/erythrocyte/brain transporter since it also expressed at the surface of red blood cells [6]. The protein is encoded by SLC2A1, a gene on chromosome 1p34.2 which contains 10 exons and spans 35 kb [2].
    The clinical phenotypes associated with Glut1 defects
    Phenotype–genotype correlations The reason for the broad clinical spectrum associated with SLC2A1 mutations is unclear. Special genetic features of mutations and their functional consequences are discussed as the main reasons, but they cannot explain all phenotypic variations.
    Diagnostics
    Therapy The ketogenic diet (KD) as a therapy for patients with epilepsy was proclaimed for the first time in the early twenties [36]. Ketogenic diet is defined as a high-fat and calorie-reduced diet which produces ketone bodies that bypass the Glut1 defect by diffusing across the blood–brain barrier facilitated by a monocarboxylic orexin sale transporter. Ketone bodies serve as an alternative energy source for brain metabolism. For the other forms of epilepsies, the anticonvulsant effect of ketone is still unclear but may reduce seizure activity significantly in pharmacoresistant epilepsies in up to 50% of cases [37], [38]. For patients with Glut1 defect, the KD is a precision medicine therapy and should be started early in the disease stage. We know from case reports that children respond very well to KD, which help in the prevention of mental retardation and in the restoration from mental decline [39]. In our own hands, patients with Glut1 deficiency benefit also from late onset KD in adulthood (unpublished observation). In classical KD, the serum ketones should be 3–4 mg/dl, but very often at that level, side effects such as diarrhea or fatigue occur and are intolerable. Especially for adult patients with Glut1, the classical KD is not compatible with daily life. In our hands, modified KD with lower ketone serum levels (e.g., 1–2 mg/dl) such as the Atkins diet can be better tolerated and is similarly effective (unpublished observation). For the future, gene therapy might be an option for patients with Glut1 defect [40].
    Conclusions Glucose transporter type 1 defect syndromes are rare but should be diagnosed early since a precision therapy via the KD is available and should be started as soon as possible. Characterizing history features are episodic seizures induced by fasting state or permanent voluntary movement. Laboratory diagnostics include CSF/serum glucose ratio, EEG, and SLC2A1 sequencing coding for Glut1.
    Introduction Gastric cancer is one of the most common causes of cancer-related death worldwide. The prognosis of gastric cancer has remained poor during the past decades (Siegel et al., 2017). Novel chemotherapeutic drugs can lead to improvement of patient survival; however, chemoresistance always becomes as an obstacle during cancer treatment (Yoon et al., 2016). The mechanisms underlying the development of chemoresistance are quite complex and investigation of biomarkers related to chemotherapeutic drug sensitivities are therefore of great importance to overcome this obstacle. Metabolic reprogramming is an important cancer hallmark characterized by the upregulation of glycolysis. Cancer cells prefers glycolysis to generate energy, which is called the Warburg effect (Lunt and Vander Heiden, 2011) and attenuation or inhibition of glycolysis has been found effective in preventing the development of some cancers. Ajuba belong to the Ajuba LIM family of proteins which contains Ajuba LIMD1 and WTIP (Das Thakur et al., 2010). They contain a LIM protein domain and serve as adaptor proteins which have the ability to connect cell adhesion and nuclear signaling, resulting in remodeling of the epithelium (Langer et al., 2008; Marie et al., 2003). Ajuba has been reported as a negative regulator of Hippo signaling in both Drosophila tissues and mammalian cells (Das Thakur et al., 2010; Jagannathan et al., 2016). Ajuba LIM proteins interact with LATS and WW45 to inhibit phosphorylation of YAP (Das Thakur et al., 2010; Jagannathan et al., 2016). The role of Ajuba in human cancers has been investigated recently. It promotes the migration and invasion of esophageal squamous cell carcinoma cells (Shi et al., 2016). Ajuba is phosphorylated in vitro and in vivo by cyclin-dependent kinase 1, which promote cell proliferation and anchorage-independent growth in vitro and tumorigenesis in vivo (Chen et al., 2016). Ajuba also promotes colorectal cancer cell survival via inhibiting apoptosis (Jia et al., 2017). Mutations of Ajuba predict the sensitivity of head and neck squamous cell carcinoma and exogenous expression of wild-type AJUBA in an AJUBA-mutant cell line rescued the phenotype of PLK1 inhibitor-induced apoptosis, suggesting its role in regulating drug sensitivity (Zhang et al., 2017b). AJUBA expression is elevated in the cervical cancers and increases cisplatin resistance in cervical cancer cells (Bi et al., 2018). These reports suggest that Ajuba is a potential cancer related protein. There are reports showing Ajuba inhibits proliferation in MCF10A, malignant mesothelioma and hepatocellular cell lines (Jagannathan et al., 2016; Liu et al., 2018; Tanaka et al., 2015). Thus, the roles of Ajuba may vary depending on the cell context. To data, its expression patterns and biological roles in human gastric cancers have not been characterized. In addition, it is unclear whether Ajuba is involved in mitochondrial function and glucose metabolism in cancer cells.