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.
Objectives Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality.Methods By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32 415 adults with a cancer diagnosis at Vanderbilt and 79 258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index.Results Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR.Conclusions EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data. 相似文献
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. 相似文献
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. 相似文献
