A new and efficient sulfide monooxygenase-producing strain, ECU0066, was isolated and identified as a Rhodococcus sp. that could transform phenylmethyl sulfide (PMS) to (S)-sulfoxide with 99% enantiomeric excess via two steps of enantioselective oxidations. Its enzyme activity could be effectively induced by adding PMS or phenylmethyl sulfoxide (PMSO) directly to a rich medium at the early log phase (6 h) of fermentation, resulting in over 10-times-higher production of the enzyme. This bacterial strain also displayed fairly good activity and enantioselectivity toward seven other sulfides, indicating a good potential for practical application in asymmetric synthesis of chiral sulfoxides.
Background: We investigated whether urinary mRNA of connective tissue growth factor (CCN2) and nephroblastoma overexpressed gene (CCN3) can provide clinical insight into the management of patients with nondiabetic CKD.Methods: Urinary mRNA expression of CCN2 and CCN3 were measured by Real-time PCR in 35 CKD patients and 12 controls.Results: Urinary mRNA of CCN2 and CCN3 were distinctively greater in CKDs than healthy controls. Urinary CCN3/CCN2 mRNA ratio correlated to the degree of glomerular histological changes in those who received renal biopsy.Conclusion: Urinary CCN3/CCN2 mRNA ratio may be a useful noninvasive biomarker for evaluating patients with nondiabetic CKD prior to renal biopsy.
Our previous work has demonstrated essential protective roles for the endogenous cardiomyocyte alpha-1A adrenergic receptor (α1A-AR) subtype in mouse models of heart failure. However, the underlying mechanism of this protective phenotype is unclear. To address this gap in knowledge, we bred a mouse line lacking α1A-ARs on cardiomyocytes by crossing αMHC-cre mice with floxed α1A mice (CMKO= cre+ fl/fl, CMWT= cre- fl/fl), and subjected males to permanent LAD ligation. CMKO mice had increased serum HMGB1 level, larger infarcts and higher mortality. We found that RIP1/3-mediated programmed necrosis (necroptosis), but not apoptosis was exaggerated in CMKO mice 3 days after ligation. We then tested whether RIP1 inhibition with Nec-1s could mitigate this injury. Mice were given Nec-1s (1.65 mg/kg) or vehicle 10 mins prior to LAD ligation, followed by daily IV injection. Nec-1s treatment diminished post-ligation RIP1 (0.62±0.02 vs. 0.78±0.23 A.U., p=NS) and RIP3 expression (0.33±0.1 vs. 0.26±0.10 A.U., p=NS) in CMWT and CMKO mice respectively. Serum level of HMGB1 on D3 was markedly reduced in both CMWT (45.1%) and CMKO (61.1 %) after Nec-1s treatment. There was no difference between Nec-1s treated CMWT and CMKO mice (147±53 vs. 174±37 pg/mL, p=NS), indicating that blocking the RIP kinase pathway abrogates the exaggerated cell death in CMKO mice after ligation. Likewise, Nec-1s-treated CMKO mice had similar infarct areas to CMWT controls (16.2±4.5 vs. 19.9±4.6%, p=NS), further confirming that targeting necroptosis abrogates pathological damage. Collectively these Nec-1s data suggest that RIP-mediated necroptosis may account for larger infarcts in CMKO mice. Interestingly, expression of the apoptosis markers c-caspase-3 and PARP was similar between CMWT and CMKO mice, suggesting that the α1A-AR specifically regulates necroptosis. In sum, our data demonstrate that RIP kinase-mediated necroptosis contributes to susceptibility to injury in mice lacking cardiomyocyte α1A-ARs.
α1-Adrenergic receptors (ARs) are catecholamine-activated G protein-coupled receptors (GPCRs) that are expressed in mouse and human myocardium and vasculature, and play essential roles in the regulation of cardiovascular physiology. Though α1-ARs are less abundant in the heart than β1-ARs, activation of cardiac α1-ARs results in important biologic processes such as hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) indicate that nonselectively blocking α1-ARs is associated with a twofold increase in adverse cardiac events, including heart failure and angina, suggesting that α1-AR activation might also be cardioprotective in humans. Mounting evidence implicates the α1A-AR subtype in these adaptive effects, including prevention and reversal of heart failure in animal models by α1A agonists. In this review, we summarize recent advances in our understanding of cardiac α1A-ARs.
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