Academic literature on the topic 'YC 5824'

An indazole derivative, YC-1, was identified in this study to be capable of reversibly and effectively inhibiting proliferation of rat A10 vascular smooth-muscle cells (VSMCs) in vitro. YC-1 (1-100 microM) dose-dependently inhibited [3H]thymidine incorporation into DNA in rat A10 VSMCs that were synchronized by serum depletion and then restimulated by addition of 10% foetal calf serum (FCS), whereas FCS-induced [3H]thymidine incorporation into rat synchronized endothelial cells was unaffected by this agent. The dose of YC-1 required to cause inhibition of FCS-induced proliferation was similar to that necessary for the formation of cellular cyclic GMP (cGMP). Guanylate cyclase activity in soluble fractions of VSMCs was activated by YC-1 (1-100 microM), whereas cGMP-specific phosphodiesterase activity was unaffected by this compound. The anti-proliferative effect of YC-1 was mimicked by 8-bromo-cGMP, a membrane-permeable cGMP analogue, and was antagonized by KT 5823 (0.2 microM), a selective inhibitor of protein kinase G. The anti-proliferative effect of YC-1 was also antagonized by Methylene Blue (50 microM), a guanylate cyclase inhibitor, and was potentiated by 3-isobutyl-1-methylxanthine (500 microM), a phosphodiesterase inhibitor. These results verified that YC-1 is a direct soluble guanylate cyclase activator in A10 VSMCs, and the anti-proliferative effect of YC-1 is mediated by cGMP. YC-1 still inhibited FCS-induced DNA synthesis even when added 10-18 h after restimulation of the serum-deprived A10 VSMCs with 10% FCS. Flow cytometry in synchronized populations revealed an acute blockage of FCS-inducible cell-cycle progression at a point in the G1/S-phase in YC-1 (100 microM)-treated cells. The inhibition of proliferation by YC-1 was demonstrated to be independent of cell damage, as documented by several criteria of cell viability. In conclusion, YC-1 reversibly and effectively inhibited the proliferation of VSMCs, suggesting that it has potential as a therapeutic agent in the prevention of vascular diseases.

A purification scheme has been devised for two ethoxyquin-inducible Alpha-class glutathione S-transferases (GSTs) which possess at least 25-fold greater activity towards aflatoxin B1 (AFB1)-8,9-epoxide than that exhibited by the GSTs (i.e. F, L, B and AA) that have been described previously. These two enzymes are both heterodimers and both contain a subunit of Mr 25,800. This subunit has been isolated from both of the GST isoenzymes and, after cleavage with CNBr, it has been subjected to automated amino acid sequencing. The primary structure of the Mr 25,800 subunit revealed that it forms part of a subfamily of Alpha-class GSTs which possess closest identity (about 92%) with the Yc subunit of apparent Mr 27,500, which is encoded by the recombinant cDNA clone pGTB42 [Telakowski-Hopkins, Rodkey, Bennett, Lu & Pickett (1985) J. Biol. Chem. 260, 5820-5825]. As these two GSTs possess less than 70% sequence identity with the Ya1 and Ya2 subunits, both of Mr 25,500, the constitutively expressed Yc subunit of Mr 27,500 has been renamed Yc1 and the ethoxyquin-inducible GST of Mr 25,800 has been designated Yc2. Using this nomenclature, the two GSTs with high activity for AFB1-8,9-epoxide are Ya1Yc2 and Yc1Yc2. Although evidence suggests that induction of Yc2 is responsible for the high detoxification capacity of livers from ethoxyquin-treated rats for AFB1-8,9-epoxide, resistance towards AFB1 may be multifactorial in this instance as dietary ethoxyquin also induces the Ya1, Ya2 and Yc1 subunits about 2.2-, 10.9- and 2.7-fold respectively. Besides the induction of GST by ethoxyquin, activity towards AFB1-8,9-epoxide is also elevated in the livers of neonatal rats and in livers that contain preneoplastic nodules. Western blotting experiments show that Yc2 is not present in hepatic cytosol from adult rats fed on normal diets but is expressed in neonatal rat livers and in the livers of adult rats that contain preneoplastic nodules that have arisen as a consequence of consuming diets contaminated with AFB1.

Bradykinin (BK) promotes insulin sensitivity and glucose uptake in adipocytes and other cell types. We demonstrated that in rat adipocytes BK enhances insulin-stimulated glucose transport via endothelial nitric oxide synthase, nitric oxide (NO) generation, and decreased activity of the mitogen-activated protein kinase (MAPK) JNK (c-Jun NH2-terminal kinase). In endothelial cells, NO increases soluble guanylate cyclase (sGC) activity, which, in turn, activates protein kinase G (PKG) by increasing cGMP levels. In this study, we investigated whether BK acts via the sGC-cGMP-PKG pathway to inhibit the negative effects of JNK on insulin signaling and glucose uptake in rat adipocytes. BK augmented cGMP concentrations. The BK-induced enhancement of insulin-stimulated glucose uptake was mimicked by the sGC activator YC-1 and a cell-permeable cGMP analog, CPT-cGMP, and inhibited by the sGC inhibitor ODQ and the PKG inhibitor KT 5823. Transfection of dominant-negative PKG reduced the BK augmentation of insulin-induced Akt phosphorylation. The activation of JNK and ERK1/2 by insulin was attenuated by BK, which was mediated by the sGC-cGMP-PKG pathway. Whereas insulin-stimulated phosphorylation of upstream activators of JNK and ERK, i.e., MKK4 and MEK1/2, was unaffected, BK augmented insulin-mediated induction of MKP-5 mRNA and protein levels. Furthermore, zaprinast, a phosphodiesterase inhibitor, enhanced cGMP and MKP-5 and prolonged the action of BK. These data indicate that BK enhances insulin action by inhibition of negative feedback by JNK and ERK via upregulation of MKP-5, mediated by the sGC-cGMP-PKG signaling pathway.

We examined whether cGMP-dependent protein kinase (PKG) and mitochondrial ATP-sensitive potassium (KATP) channels are involved in S-nitroso- N-acetyl penicillamine (SNAP)-induced reactive oxygen species (ROS) generation. SNAP significantly increased ROS generation in cardiomyocytes. This increase was suppressed by both 5-hydroxydecanoate (5-HD) and glibenclamide. Direct opening of mitochondrial KATP channels with diazoxide led to ROS generation. The increased ROS generation was reversed by N-(2-mercaptopropionyl)glycine (MPG), a scavenger of ROS. Myxothiazol partially suppressed the ROS generation. KT-5823, an inhibitor of PKG, prevented ROS generation, indicating that PKG is required for ROS generation. In addition, 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP), an activator of PKG, induced ROS generation. The effect of 8-BrcGMP was reversed by either 5-HD or MPG. YC-1, an activator of guanylyl cyclase, also increased ROS production, which was reversed by 5-HD. Neither LY-294002 nor wortmannin, the inhibitors of phosphatidylinositol 3-kinase (PI3-kinase), affected SNAP's action. In a whole heart study, SNAP significantly reduced infarct size. The anti-infarct effect of SNAP was abrogated by either MPG or 5-HD. This effect was also blocked by PD-98059, an ERK inhibitor, but not by LY-294002. A Western blotting study showed that SNAP significantly enhanced phosphorylation of ERK, which was reversed by MPG. These results suggest that SNAP-induced ROS generation is mediated by activation of PKG and mitochondrial KATP channels and that opening of mitochondrial KATP channels is the downstream event of PKG activation. ROS and mitochondrial KATP channels participate in the anti-infarct effect of SNAP. Moreover, phosphorylation of ERK is the downstream signaling event of ROS and plays a role in the cardioprotection of SNAP.

Renal dopamine D2 receptor (D2R) dysfunction is associated with increased oxidative stress and high blood pressure. We have reported that DJ-1 is regulated by D2R in the kidney. Nrf2 is a transcription factor that regulates the expression of several antioxidant genes. We hypothesize that Nrf2 is involved in the DJ-1-mediated regulation of reactive oxygen species (ROS) production in the kidney. DJ-1 and Nrf2 co-inmunoprecipitate in mouse kidney. Selective renal silencing of D2R in mice by the renal subcapsular infusion of D2R siRNA (~50%) decreases Nrf2 expression (63.4%±3.4, n=7, P<0.05), and silencing of D2R expression in mouse proximal tubule cells (mRPTCs) decrease Nrf2 promoter activity (53±2%, n=5, P<0.05). Silencing DJ-1 expression in mRPTCs, via siRNA, decreases the expression of DJ-1 (75±4.5%, n=4, P<0.05), Nrf2 (63.2±6%, n=3, P<0.05), NQO1 (71±1%, n=3, P<0.05), and GST Yc-2 (42±1%, n=4, P<0.05) and Nrf2 promoter activity (58±1%, n=5, P<0.05). Selective renal silencing of DJ-1 in mice by renal subcapsular infusion of DJ-1 siRNA decreases expression of DJ-1 (31±2.6%, n=3, P<0.05), Nrf2 (57±7.9%,n=3, P<0.05), NQO1 (46±9.3%, n=3, P<0.05) and GST Yc2 (28±2.2%, n=3, P<0.05) and increases blood pressure (BP). DJ-1 -/- mice also have increased systolic BP (30.7±1%, P<0.01, n=5 under anesthesia) and renal expression of nitro-tyrosine (76.8±13.5%, P<0.05, n=5), and decreases the expression of Nrf2 (46.8±6.8%, n=5, P<0.05) and NQO1 (19.4±2.7%, n=5, P<0.05). Silencing Nrf2 expression mRPTCs via siRNA decreases the expression of Nrf2 (34±1.8%, n=4, P<0.05), NQO1 (29.1±0.5%, n=4, P<0.05), and increases Nox2 (137±23.7%, n=4, P<0.05), but the expression of Nox4 and DJ-1 are not affected. Quinpirole a D2R agonist, does not modify the expression of Nrf2, NQO1, GST Yc-2, and Nrf2 promoter activity in MPCTS. However, in the presence of H 2 O 2 , quinpirole increases Nrf2 promoter activity (220±58.4%, n=5, P<0.05) and an effect that is blocked by pretreatment with D2R antagonist L741,626. Therefore, the inhibitory effect of DJ-1 on renal ROS production is, in part, mediated by positive regulation of Nrf2. Moreover, D2R and DJ-1 are necessary for normal Nrf2 activity to keep a normal redox balance in the kidney.

Embora as rotas de transmissão da COVID-19 ainda não estejam totalmente identificadas, a transmissão homem-a-homem já é uma realidade em muitos países. Este trabalho tem por objetivo reunir recomendações dos órgãos de saúde e de estudos em artigos científicos relacionadas a condutas especiais do cirurgião bucomaxilofacial no período perioperatório de urgência e emergência. A justificativa é a possibilidade de infecção cruzada por meio da inalação de partículas produzidas durante os procedimentos cirúrgicos. A abordagem desse trabalho está relacionada à rota de transmissão e a possibilidade de contaminação cruzada da COVID-19 por meio de gotículas de salivas transformadas em aerossóis. Considera-se que a adoção de condutas especiais no período periorperatório por parte do cirurgião bucomaxilofacial pode representar auxílio quanto a prevenção de transmissão do vírus tanto em relação aos profissionais quanto aos pacientes.Descritores: Infecções por Coronavírus; Assistência Perioperatória; Aerossóis; Transmissão de Doença Infecciosa do Paciente para o Profissional.ReferênciasShoji H, Fonseca EKUN, Teles GBDS, et al. Structured thoracic computed tomography report for COVID-19 pandemic. Einstein (Sao Paulo). 2020;18:eED5720.Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-42.Sabino-Silva R, Jardim ACG, Siqueira WL. Coronavirus COVID-19 impacts to dentistry and potential salivary diagnosis. Clin Oral Investig. 2020;24(4):1619-21.Rodrigues MFB, Rocha LLDA, Acioly RDF, Souza DDD, Carvalho DDC, Rocha RCLD, Rocha CCLD. Special precautions in oral and maxillofacial surgeries regarding COVID-19 transmission. Preprints 2020, 2020050135 (doi: 10.20944/preprints202005.0135.v1).To KKW, Tsang OTY, Leung WS, Tam AR, Wu TC, Lung DC et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020;20(5):565-74.Ather A, Patel B, Ruparel NB, Diogenes A, Hargreaves KM. Coronavirus Disease 19 (COVID-19): Implications for Clinical Dental Care. J Endod. 2020;46(5):584-95.Meng L, Hua F, Bian Z. Coronavirus Disease 2019 (COVID-19): Emerging and Future Challenges for Dental and Oral Medicine. J Dent Res. 2020;99(5):481-87.Ge ZY, Yang LM, Xia JJ, Fu XH, Zhang YZ. Possible aerosol transmission of COVID-19 and special precautions in dentistry. J Zhejiang Univ Sci B. 2020;21(5):361-68. Wang WK, Chen SY, Liu IJ, Chen YC, Chen HL, Yang CF et al. Detection of SARS-associated coronavirus in throat wash and saliva in early diagnosis. Emerg Infect Dis. 2004;10(7):1213-19.Chang L, Yan Y, Wang L. Coronavirus Disease 2019: Coronaviruses and Blood Safety. Transfus Med Rev. 2020;34(2):75-80.Spagnuolo G, De Vito D, Rengo S, Tatullo M. COVID-19 Outbreak: An Overview on Dentistry. Int J Environ Res Public Health. 2020;17(6):2094.Zucco L, Levy N, Ketchandji D, Aziz M, Ramachandran SK. Considerações perioperatórias para o novo coronavírus 2019 (COVID-19). Rochester: ASPF; 2020.Abosadegh MM, Saddki N, Al-Tayar B, Rahman SA. Epidemiology of maxillofacial fractures at a tea- ching hospital in Malaysia: a retrospective study. BioMed Res Int. 2019: 9024763.Colégio Brasileiro de Cirurgia e Traumatologia Bucomaxilofacial (CTBMF). COVID-19 - Guia de Práticas em CTBMF. Disponível em: https://www.bucomaxilo.org.br/site/noticiasdetalhes.php?cod=344amp;q=COVID19%2B%20%2BGuia%2Bde%2BPr%C3%A1ticas%2Bem%2BCTBMFamp;bsc=ativar. Acesso em: 07 de abr. de 2020.American Association of Oral and Maxillofacial Surgeons (AAOMS). Member Alert: COVID-19 Guidance for OMS Practices. Disponível em: https://www.aaoms.org/news/member-alert-covid-19-guidance-for-oms-practices. Acesso em: 10 de fev. de 2020.AOCMF International Task Force Recommendations on Best Practices for Maxillofacial Procedures during COVID-19 Pandemic. Disponível em: https://aocmf3.aofoundation.org/-/media/project/aocmf/aocmf/files/covid-19/ao_cmf_covid-19_task_force_guidelines.pdf. Acesso em: 10 de fev. de 2020.

Die in den letzten Jahren erhobenen genetischen Befunden untermauern das Konzept, daß ein Ungleichgewicht von Proteasen und ihren Inhibitoren wesentlich an der Pathogenese der chronischen Pankreatitis beteiligt ist. Die Identifizierung von Mutationen im kationischen Trypsinogen bei Patienten mit hereditärer Pankreatitis hat das Verständnis der Erkrankung entscheidend beeinflußt. Der Nachweis von SPINK1-, CFTR- und PRSS1-Mutationen bei Patienten ohne Familienanamnese für eine Pankreatitis deutet darauf hin, daß auch die idiopathische Pankreatitis genetisch determiniert ist. Die bisher durchgeführten Studien legen nahe, daß die erblich bedingte chronische Pankreatitis eine genetisch heterogene Erkrankung ist, die in Abhängigkeit von den defekten Genen bzw. den zugrundeliegenden Mutationen einem autosomal dominanten, einem autosomal rezessiven oder einem komplexen Erbgang folgt. Das gehäufte Auftreten von SPINK1-Mutationen bei alkoholischer chronischer Pankreatitis ist ein Hinweis darauf, daß genetische Faktoren auch zur Suszeptibilität von primär nicht erblichen Formen der chronischen Pankreatitis beitragen. Im weiteren konnte gezeigt werden, daß genetische Dispositionsfaktoren auch bei der Pathogenese der tropischen Pankreatitis einen wesentlichen Stellenwert besitzen. Diese Daten stellen das Konzept der tropischen Pankreatitis als eigene, tropenspezifische Krankheitsentität in Frage. In der vorliegenden Arbeit wurde die Bedeutung genetischer Faktoren bei der Entstehung der hereditären und idiopathischen wie der alkoholischen Pankreatitis untersucht. Die vollständige Aufklärung der genetischen Ursachen wird vermutlich die Unterscheidung zwischen hereditärer und idiopathischer bzw. tropischer chronischer Pankreatitis obsolet werden lassen. Nach Ausschluß sekundärer Ursachen sollte auch bei Patienten ohne Familienanamnese eine Genanalyse auf Mutationen in den obengenannten Genen veranlaßt werden.
The recent discoveries of trypsinogen (PRSS1) and trypsin inhibitor (SPINK1) mutations in patients with hereditary and idiopathic chronic pancreatitis support the hypothesis that an inappropriate activation of pancreatic zymogens to active enzymes within the pancreatic parenchyma initiates the inflammatory process. Thus, pancreatitis may be the result of an imbalance of proteases and their inhibitors within the pancreatic parenchyma. Since the first description of inherited pancreatitis reported an autosomal dominant trait, hereditary CP was defined as an rare dominant inherited disease. Subsequently, the fact of familial clustering in one generation only, which indicates other inheritance pattern such as recessive or complex trait, was blinded out in the disease concept of hereditary CP for a long time. The Identification of PRSS1, SPINK1 and CFTR mutations in patients with so-called idiopathic chronic pancreatitis, however, shows that inherited cases of CP are much more frequent and that different mutations in different genes might lead to different inheritance pattern. Evaluation of patients with CP without an obvious predisposing factor should include genetic testing for mutations in the above mentioned genes even in the absence of a family history of pancreatitis. The finding of SPINK1 mutations in alcohol-induced pancreatitis indicates that genetic factors genetic factors may increase disease susceptibility to primary non-hereditary CP types. This work summarises the significance of genetic factors in the pathogenesis of hereditary and idiopathic as well as alcoholic chronic pancreatitis. Thus, the identification of further genes involved into the pathogenesis of inherited CP probably will also enhance our knowledge about more common types of CP such as alcoholic or tropical CP.