The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus

Cellular arachidonic acid (AA), an unsaturated fatty acid found ubiquitously in plasma membranes, is metabolized to different prostanoids, such as prostacyclin (PGI₂) and prostaglandin E₂ (PGE₂), by the three-step reactions coupling the upstream cyclooxygenase (COX) isoforms (COX-1 and COX-2) with the corresponding individual downstream synthases. While the vascular actions of these prostanoids are well-characterized, their specific roles in the hippocampus, a major brain area for memory, are poorly understood. The major obstacle for its understanding in the brain was to mimic the biosynthesis of each prostanoid. To solve the problem, we utilized Single-Chain Hybrid Enzyme Complexes (SCHECs), which could successfully control cellular AA metabolites to the desired PGI₂ or PGE₂. Our in vitro studies suggested that neurons with higher PGI₂ content and lower PGE₂ content exhibited survival protection and resistance to Amyloid-β-induced neurotoxicity. Further extending to an in vivo model, the hybrid of PGI₂-producing transgenic mice and Alzheimer’s disease (AD) mice showed restored long-term memory. These findings suggested that the vascular prostanoids, PGI₂ and PGE₂, exerted significant regulatory influences on neuronal protection (by PGI₂), or damage (by PGE₂) in the hippocampus, and raised a concern that the wide uses of aspirin in cardiovascular diseases may exert negative impacts on neurodegenerative protection.

Our study intended to understand the crosstalk of prostanoids in the hippocampus, a major brain area impacted in AD, by using hybrid enzymes to redirect the synthesis of prostanoids to PGE₂ and PGI₂, respectively. Our data indicated that during inflammation, the vascular mediators, PGI₂ and PGE₂, exerted significant regulatory influences on neuronal protection (by PGI₂), or damage (by PGE₂) in the hippocampus. These findings also raised a concern that the widely uses of non-steroidal anti-inflammatory drugs in cardiovascular diseases may exert negative impacts on neurodegenerative protection.

     

从用药分析的视角看临床药学的发展

通过分别从医生和临床药师的角度对同一张处方进行用药分析,探讨临床药师应具备的素质,并对此进行展望。     

Impaired prostaglandin E(2)/prostaglandin I(2) receptor-G(s) protein interactions in isolated renal resistance arterioles of spontaneously hypertensive rats

The protective effect of vasodilator agents linked to the cAMP pathway is less effective for buffering the vasoconstrictor effect of angiotensin II in young animals with genetic hypertension. To determine the underlying cellular mechanism, experiments were performed on freshly isolated preglomerular resistance arterioles obtained from kidneys of 7-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Specific high-affinity saturable binding of (3)H-prostaglandin (PG) E(2) revealed 1 receptor class in renal microvessels; PGE(2) receptor density was similar in SHR and WKY (106 versus 115 fmol/mg; P>0.8), as was receptor affinity (3.6 versus 3.5 nmol/L; P>0.7). Basal cAMP activity was similar in renal arterioles from SHR and WKY. A major finding was that PGE(2), PGI(2), and isoproterenol produced weaker stimulation of cAMP formation in arteriolar cells of SHR (P<0.02). In contrast, GTPgammas and forskolin stimulated cAMP generation to a similar degree in both rat strains, which suggests normal adenylate cyclase activity in hypertension-prone SHR. Immunoblots revealed the presence of 3 classes of G proteins (G(s), G(i), and G(q)) in preglomerular arterioles. The relative amounts of discernible G-protein alpha-subunits in renal resistance vessels did not differ between SHR and WKY. These results extend previous in vivo studies of abnormal renal vascular reactivity in SHR and more directly localize defective coupling of the prostaglandin and beta-adrenergic receptors to a stimulatory G protein and cAMP production in freshly isolated preglomerular arteriolar cells of young SHR. This dysfunction may be due to an abnormal interaction between prostaglandin receptors and G(s) protein that leads to inefficient coupling of initiating steps in the cAMP-protein kinase A cascade during the development of hypertension.     

HIV incidence, retention rate, and baseline predictors of HIV incidence and retention in a prospective cohort study of injection drug users in Xinjiang, China.

OBJECTIVE: To determine HIV seroincidence, study participant retention rate, and baseline predictors of HIV incidence and study retention among high-risk injection drug users (IDUs) in Xinjiang, China. METHODS: A total of 508 eligible seronegative high-risk IDUs were enrolled. Study participants were tested for HIV-1 and counseled at the baseline, 6-month, and 12-month follow-up visits. Sociodemographic and behavioral data were collected during each study visit. The HIV-1 incidence rate and the retention rate were analyzed as a function of sociodemographic, behavioral, and recruitment variables. RESULTS: At 12 months of follow-up, the HIV-1 incidence rate was 8.8 per 100 person-years (95% CI 6.3-12.0%) and the participant retention rate was 93%. Marital status at baseline was the only predictor of HIV incidence. No baseline variables were predictive of study retention. CONCLUSIONS: HIV incidence is high among IDUs in Xinjiang, China. Baseline predictors of incidence and retention were minimal. The participant retention rate in this study is promising for the undertaking of future HIV intervention studies.     

黄芪和丹参注射液联用对早期糖尿病肾病血液流变学和肾功能的影响

目的　探讨黄芪和丹参注射液联用对早期糖尿病肾病 (EDN)血液流变学和肾功能的影响。方法　将2 0 0 1- 0 3～ 2 0 0 4 - 0 3广东省东莞市人民医院 16 0例EDN患者随机分为治疗组和对照组各 80例。两组均采用饮食控制和糖尿病常规治疗。治疗组加用黄芪和丹参注射液治疗 ,疗程 4周。结果　治疗组血液流变学各项指标较治疗前显著下降 (P <0 0 5或P <0 0 1) ;尿白蛋白排泄率 (UAER)、血肌酐 (SCr)、尿素氮 (BUN)和血脂明显下降 (P <0 0 5或P <0 0 1) ,且明显优于对照组 (P <0 0 1或P <0 0 5 )。结论　黄芪和丹参注射液联用能改善EDN患者的血液流变学、血脂和微循环 ,减少尿白蛋白的排出 ,减轻肾损害 ,改善肾功能。     

Clinical implications of procalcitonin in Kawasaki disease: a useful candidate for differentiating from sepsis and evaluating IVIG responsiveness

Clinical and Experimental Medicine - Kawasaki disease (KD) is an acute systemic vasculitis and suspected to be triggered by several potential infections in which procalcitonin (PCT) experiences an...     

Interpretation of the mechanism of 3,3′-dichloro-4,4′-diamino diphenylmethane synthesis over HY zeolites

Catalytic activities of zeolites HY, Hβ and HZSM-5 in the heterogeneous synthesis of 3,3′-dichloro-4,4′-diaminodiphenyl methane (MOCA) from o-chloroaniline and formaldehyde were pre-screened in an autoclave, and HY demonstrated better performance than others. Kinetic behaviors of MOCA synthesis over HY(11) were further investigated in a fixed bed continuous flow reactor, and under the conditions of the catalyst bed volume = 20 mL (8.14 g), n(o-chloroaniline) : n(HCHO) = 4 : 1, LHSV = 3.5 h⁻¹, 0.5 MPa and 443 K, HCHO conversion and MOCA selectivity steadily fluctuated at high levels of 90–92% and 75–77% during 16 h, respectively. Catalysts were characterized by BET, NH₃-TPD and XRD, products analyzed by HPLC, and reaction intermediates identified by LC/MS and ¹H NMR. The mechanism of MOCA synthesis has been interpreted in detail, which also suggested that deposition of basic intermediates on active sites and accumulation of polymeric by-products in pore channels of the catalyst could cause significant decay of HY(11) activity and selectivity under severe conditions. Supplementary tests on catalyst regeneration confirmed that the acidity and surface area of spent HY(11) could be well recovered after burning off the deposited by-products.

Catalytic activities of zeolites HY, Hβ and HZSM-5 in the heterogeneous synthesis of 3,3′-dichloro-4,4′-diaminodiphenyl methane (MOCA) from o-chloroaniline and formaldehyde were pre-screened in an autoclave, and HY demonstrated better performance than others.