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Nontoxic RsDPLA As a Potent Antagonist of Toxic Lipopolysaccharide
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Nilofer Qureshi, Bruce W. Jarvis, Kuni Takayama
We found that the induction of immunoglobulin kappa (k) light chain expression in the pre-B cell line, 70Z/3 cells, by toxic LPS is effectively blocked by RsDPLA. Induction of k expression by LPS is dependent on at least two transcription factors, Oct-2 and NF-kB. RsDPLA alone activated NF-kB binding activity within 30 minutes of treatment, but the activation was not sustained beyond 9 hours as observed with LPS. The NF-kB complexes activated by both RsDPLA and LPS were composed predominantly of the p50-RelA (p65) heterodimer. In addition, RsDPLA antagonized the activation of Oct-2 mRNA by toxic LPS. These results suggest that the physiological receptors on B cells transmit quantitatively different signals depending on the nature of the ligand that binds to them; furthermore, the fatty acyl groups of LPS play an important role in activating signal transduction (53).
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].
Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
These conserved sequence elements serve as binding sites for proteins that regulate gene transcription. Octamer-binding proteins have been the most extensively studied, three have been identified to date, Oct-1,2, and 3. Oct-1 is present in most cells and binds to OCTA type sequences in several different genes (for example, histones, snRNAs). Oct-2 is also found in several types of cells, including all B cells, and many developing and mature T cells. Oct-3 has recently been identified in embryonal carcinoma cells. Additional OCTA-binding proteins continue to be identified.
Effects of single-nucleotide polymorphism on the pharmacokinetics and pharmacodynamics of metformin
Published in Expert Review of Clinical Pharmacology, 2022
Shaoqian Li, Bo Xu, Shangzhi Fan, Bo Kang, Lijing Deng, Danjun Chen, Bo Yang, Fan Tang, Zunbo He, Yong Xue, Jie-Can Zhou
OCT2 is expressed in the kidney, which mediates renal clearance of metformin [56]. The inhibition of OCT2 will relate to decreasing the clearance of metformin in vivo and may rise the adverse results of metformin, particularly lactic acidosis [44]. Studies have confirmed that Oct2 A270S gene polymorphism was associated with decreased renal clearance of metformin in Chinese population [57]. In a Diabetes Slc22a2 study in Pakistan, a single nucleotide polymorphism (rs201919874) may be associated with the pharmacokinetics of metformin by creating significantly damaging structural changes in domains [58]. Some studies have also found that the lack of metformin reaction is associated with rs3119309 and rs7757336 located in the 5’ flanking region of the Oct2 encoding gene [59]. A non-synonymous variant of Oct2 (A270s, rs316019) altered the renal clearance of metformin in healthy volunteers [57,60,61]. This result may be due to the lower uptake of metformin caused by OCT2 mutation.
Rutaecarpine enhances the anti-diabetic activity and hepatic distribution of metformin via up-regulation of Oct1 in diabetic rats
Published in Xenobiotica, 2021
Xian-Mei Song, Bing-Jie Li, Yan-Yan Zhang, Wen-Jing Ge, She-Feng Zhang, Wei-Feng Cui, Geng-Sheng Li, Rui-Feng Liang
To understand whether rutaecarpine regulates the expression of Oct1, Oct2, and Mate1, we carried out a quantitative real-time PCR analysis. As shown in Figure 5, the mRNA level of Oct1 in the liver and kidney from diabetic rats was significantly lower than that of normal control rats. Administration of rutaecarpine alone or with metformin significantly increased the mRNA levels of Oct1. The renal mRNA expression of Oct2 dropped in diabetic rats, there was no obvious alteration in the renal expression of Oct2 following drug administration. Moreover, mRNA levels of Mate1 in the liver and kidney were comparable among all groups of rats. These results suggested that treatment with rutaecarpine significantly upregulated the expressions of Oct1 in diabetic rats, which could lead to increase Oct1 substrates (such as metformin) uptake.
Interactions of organophosphorus pesticides with solute carrier (SLC) drug transporters
Published in Xenobiotica, 2019
Lisa Chedik, Arnaud Bruyere, Olivier Fardel
The structural requirements for both OCT1 and OCT2 inhibition by OPs have been investigated in a more detailed manner. They include various molecular descriptors, which belong to different blocks, thus highlighting their diversity. It is however noteworthy that the exact signification and/or practical relevance of most of these descriptors may be rather complex to apprehend. More intuitive descriptors, notably those linked to lipophilicity (LogP), polar surface area or number of hydrogen bond donors or acceptors, failed to discriminate OPs inhibitors from non-inhibitors for OCT1/OCT2 activity. By contrast, some of these basic molecular descriptors have been demonstrated to be associated with OCT1 or OCT2 inhibition in previous studies (Ahlin et al., 2008; Kido et al., 2011). Such studies are however based on the analysis of much larger sets of chemicals (n = 191) (Ahlin et al., 2008) or n = 910 (Kido et al., 2011), than that of OPs (n = 13) used in the present study. Moreover, they include compounds belonging to various and diverse structurally-unrelated chemical classes, whereas our study was restricted to one structural chemical family, i.e. that of OPs. Such differences in the number, the nature and the perimeter of analyzed chemicals may contribute to the discrepancies observed in terms of relevant discriminating molecular factors for OCT1/OCT2 inhibition.