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Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The OCT transporters belong to the SLC22 family and include three subtypes: OCT1, OCT2 and OCT3. In addition to transporting monoamines, they mediate cellular uptake and efflux of many drugs, thus influencing their disposition as well as their pharmacological and toxicological activities [36]. OCT3 (SLC22A3) was originally identified as a corticosterone-sensitive extra-neuronal monoamine transporter [59]. The abundance of the OCTs within the brain is rated as OCT3>OCT1>>OCT2. The OCTs are expressed in the cerebellum, subfornical organ, dorsal raphe, hippocampus and hypothalamic nuclei and are especially enriched in brain microvessels. Using brain-derived endothelial cells, a proton-coupled OCT antiporter was found to play a role in the transport of apomorphine, a DA agonist, across the BBB [60]. OCT3 is also expressed in skeletal muscle, placenta, salivary glands, heart, adrenal gland, small intestine, kidney, and uterus [36], and it has variable affinity for DA, NE, Ser, and histamine [61]. In the kidney, the OCTs mediate tubular DA uptake [62], but only scant information is available on their role in DA homeostasis in other peripheral sites where they are expressed. OCT knockout mice are viable and fertile, have reduced uptake of MPP+ into the heart, but otherwise they show no significant phenotypic differences from wild-type mice [63].
Current Trends of Drugs Acting on Oral Squamous Cell Carcinoma (OSCC)
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Sowmiya Renjith, Sathya Chandran
Most HNSCCs exhibit a persistent activation of the PI3K–mTOR signaling pathway. A study has shown that metformin, an oral antidiabetic drug that is also used to treat lipodystrophy in HIV-infected (HIV+) individuals, diminishes mTOR activity and prevents the progression of chemically induced experimental HNSCC premalignant lesions. They explored the preclinical activity of metformin in HNSCCs harboring PIK3CA mutations and HPV oncogenes, both representing frequent HNSCC alterations, aimed at developing effective targeted preventive strategies. The biochemical and biologic effects of metformin were evaluated in representative HNSCC cells expressing mutated PIK3CA or HPV oncogenes (HPV+). The oral delivery of metformin was optimized to achieve clinical relevant blood levels. Molecular determinants of metformin sensitivity were also investigated, and their expression levels were examined in a large collection of HNSCC cases. They found that metformin inhibits mTOR signaling and tumor growth in HNSCC cells expressing mutated PIK3CA and HPV oncogenes, and that these activities require the expression of organic cation transporter 3 (OCT3/SLC22A3), a metformin uptake transporter. Coexpression of OCT3(octamer-binding transcription factor 3) and the mTOR pathway activation marker pS6 were observed in most HNSCC cases, including those arising in HIV+ patients. Activation of the PI3K–mTOR pathway is a widespread event in HNSCC, including HPV− and HPV+ lesions arising in HIV+ patients, all of which coexpress OCT3. These observations may provide a rationale for the clinical evaluation of metformin to halt HNSCC development from precancerous lesions, including HIV+ individuals at risk of developing HPV-associated cancers (Madera et al. 2015).
Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options
Published in Annals of Medicine, 2020
Andreja Rehberger Likozar, Mark Zavrtanik, Miran Šebeštjen
The SNP rs3798220 encodes a nonsynonymous variant of LPA, and it has been reported to have strong association with Lp(a) levels [25], moderate association with LDL cholesterol levels [26], and a connection with risk of CVD [25]. Clarke et al. [24] reported on a more definitive assessment of the strength of association between rs3798220 and CAD risk. In their study, which involved almost 8000 patients with CVD, they found four haplotypes of rs3798220, which might explain and improve part of the association between the SLC22A3–LPAL2–LPA gene cluster and CVD [24]. The second SNP, rs10455872, indicated intron 25 in the LPA gene, where the allele frequency of the high-risk variant was about 7% [27]. Clarke et al. [24] did not find any associations between either rs10455872 or rs3798220 and plasma levels of apoB, fibrinogen or C-reactive protein.
The human organic cation transporter OCT1 and its role as a target for drug responses
Published in Drug Metabolism Reviews, 2019
Nicolas Brosseau, Dindial Ramotar
The genes SLC22A1, SLC22A2 and SLC22A3 encoding OCT1 and the two homologs OCT2 and OCT3, respectively, are located in a cluster on chromosome 6 (6q25.3) in the human genome (Figure 2). SLC22A1 is oriented on the plus DNA strand and starts from base pair 160 121 808 and ends at 160 160 590, encompassing 38,782 bases (https://www.ncbi.nlm.nih.gov/gene/6580). SLC22A1 is composed of eleven exons that generate at least two transcript variants derived by alternative splicing and these are detected in the cDNA isolated from human liver (Hayer et al. 1999). The longer transcript produces the OCT1 protein, which harbors the transporter function (Hayer et al. 1999). The shorter transcript produces an isoform that lacks exon 9, spanning 33 amino acid residues, and it is not known whether this form serves a unique function, such as being capable of recognizing some but not all substrates (Hayer et al. 1999).
Cranio-spinal Rosai Dorfman disease: case series and literature review
Published in British Journal of Neurosurgery, 2019
Shashank S. Joshi, Shilpa Joshi, Girish Muzumdar, Keki E. Turel, Rajan M. Shah, Indoo Ammbulkar, Muhammad Masood Hussain, Kishor A. Choudhari
3) Inherited genetic disorders- Recently two inherited disorders, Auto-immune lympho-proliferative syndrome (ALPS) and Faisalabad histiocytosis (FHC) have been found to be associated with RDD.18 ALPS is a rare inherited disorder which has resulted from defective apoptotic pathway mediated by Fas and Fas ligand. Apparently, this results in failure of apoptosis of mature lymphocytes which tend to collect in the lymphoreticular organs causing organomegaly.18,30 The majority of ALPS cases have mutation of the TNFRSF6 gene which encodes for Fas protein.18,31 FHC is an autosomal recessive disorder presenting with histology similar to RDD. Genetic studies confirmed its linkage to chromosome 10q22.1 and showed mutations in SLC29A3. SLC29A3 gene encodes an intracellular nucleotide transporter (hENT3). The exact mechanism is not known but hENT3 is supposed to alter apoptotic pathways.18,32