Townsendblackburn2934

Solute carrier organic anion transporter family member 2A1 (SLCO2A1, also known as PGT, OATP2A1, PHOAR2, or SLC21A2) is a plasma membrane transporter consisting of 12 transmembrane domains. It is ubiquitously expressed in tissues, and mediates the membrane transport of prostaglandins (PGs, mainly PGE2, PGF2α, PGD2) and thromboxanes (e.g., TxB2). SLCO2A1-mediated transport is electrogenic and is facilitated by an outwardly directed gradient of lactate. PGs imported by SLCO2A1 are rapidly oxidized by cytoplasmic 15-hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD). Accumulated evidence suggests that SLCO2A1 plays critical roles in many physiological processes in mammals, and it is considered a potential pharmacological target for diabetic foot ulcer treatment, antipyresis, and non-hormonal contraception. Furthermore, whole-exome analyses suggest that recessive inheritance of SLCO2A1 mutations is associated with two refractory diseases, primary hypertrophic osteoarthropathy (PHO) and chronic enteropathy associated with SLCO2A1 (CEAS). Intriguingly, SLCO2A1 is also a key component of the Maxi-Cl channel, which regulates fluxes of inorganic and organic anions, including ATP. Further study of the bimodal function of SLCO2A1 as a transporter and ion channel is expected to throw new light on the complex pathology of human diseases. Here, we review and summarize recent information on the molecular functions of SLCO2A1, and we discuss its pathophysiological significance.The carcinogenicity and chronic toxicity of acrolein was examined by whole body inhalation to groups of 50 F344/DuCrlCrlj rats and 50 B6D2F1/Crlj mice of both sexes for two years. The concentration of acrolein was 0, 0.1, 0.5 or 2 ppm (v/v) for male and female rats; and 0, 0.1, 0.4 or 1.6 ppm for male and female mice. Two-year administration of acrolein induced the squamous cell carcinomas in nasal cavity which is rare tumor in one male and two female rats. In females, rhabdomyoma in nasal cavity was observed in four rats exposed to 2 ppm. In mice, since the survival rate of male and female of mice control group were lowered than 25% in late of the administration periods due to renal lesion and/or amyloid deposition, the mice study was terminated at 93rd week in males, and was terminated at 99th week in females. The incidences of adenomas in nasal cavity were observed in 16 females and significantly increased only in female mice. Thus, acrolein is carcinogenic in two species, i.e. rats and mice. Additionally, non-neoplastic nasal cavity lesions in rats and mice were observed.Piezo1 (also known as Fam38A) is a mechanosensing channel required for mechanotransduction in various cell types. In astrocytes, Piezo1 activation is associated with the pathogenesis of central nervous system neurodegeneration. Expression of Piezo1 has been detected in mouse optic nerve head astrocytes, however, the functional role of Piezo1 has not been identified. In this study, we investigated the role of Piezo1 in optic nerve head astrocyte reactivity. Primary mouse optic nerve head astrocytes were cultured and subjected to mechanical stretch. The expression level of Piezo1 was determined by quantitative PCR and immunocytochemistry staining. Astrocytes were further treated with Yoda1, a specific Piezo1 agonist. The intracellular calcium concentration and expression of F-actin and fibronectin were determined in Yoda1 treated cells. We found that mechanical stretch activated Piezo1 in optic nerve head astrocytes. Yoda1 induced robust Ca2+ responses in a dose dependent manner. In addition, Yoda1 treated cells showed a redistribution of F-actin cytoskeleton and an increased expression of fibronectin which indicated astrocyte reactivity. Our results suggest that Piezo1 responses to mechanical stimulation and plays a role in astrocyte reactivity. This study provides new insights into optic nerve head astrocyte mechanotransduction.Somatostatin plays important roles in modulating neuronal functions by activating the five specific G-protein coupled receptors (sst1-sst5). Previous studies have demonstrated that sst5 were expressed in retinal ganglion cells (RGCs) and sst5 agonist attenuated the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-induced retinal neurotoxicity. In this study, we investigated effects and underlying mechanisms of the sst5 agonist L-817,818 on RGC injury induced by elevated intraocular pressure (COH) in experimental glaucoma. Our results showed that intraperitoneal administration of L-817,818 significantly reduced RGC loss and decreased the number of terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL)-positive RGCs in COH retinas, suggesting that L-817,818 may attenuate RGC apoptosis. Consistently, in COH retinas with L-817,818 administration, both the down-regulated mRNA and protein levels of anti-apoptotic Bcl-2 and the up-regulated mRNA and protein levels of pro-apoptotic Bax were partially reversed. L-817,818 administration downregulated the expression of apoptosis-related proteins caspase-9 and caspase-3 in COH retinas. In addition, L-817,818 administration reduced the concentrations of reactive oxygen species/reactive nitrogen species and malondialdehyde, and ameliorated the functions of mitochondrial respiratory chain complex (MRCC). Our results imply that administration of the sst5 agonist L-817,818 reduces RGC loss in COH rats through decreasing RGC apoptosis, which is mediated by regulating Bcl-2/Bax balance, reducing oxidative stress and rescuing activities of MRCC. Activation of sst5 may provide neuroprotective roles for RGCs in glaucoma.We previously found that epigallocatechin-3-gallate (EGCG) could inhibit the myofibroblast transformation of human Tenon's fibroblasts, however, the underlying mechanism remained unclear. We therefore investigated whether the autophagic regulation involved in the anti-fibrotic function of EGCG. The fibroblasts were subjected to transforming growth factor beta-1 (TGF-β1) induction followed by EGCG treatments. The autophagic flux was examined by transmission electron microscopy and autophagic flux analysis. Vismodegib price The levels of autophagy-related proteins (LC3β and p62) and alpha-smooth muscle actin (α-SMA) were measured by Western blot and immunofluorescence. Results showed that TGF-β1 partially inhibited the autophagic function of Tenon's fibroblasts. But this inhibition effect was rescued by LY2157299, a TGF-βR1 selective inhibitor. Compared with the cells treated with TGF-β1 alone, EGCG treatments increased the amount of autophagosomes and autolysosomes, evaluated the ratio of LC3-II to LC3-I and decreased p62 level.