Protective effect of antihypertensive drugs on the risk of Parkinson's disease lacks causal evidence from mendelian randomization.

Background: Evidence from observational studies concerning the causal role of blood pressure (BP) and antihypertensive medications (AHM) on Parkinson's disease (PD) remains inconclusive. A two-sample Mendelian randomization (MR) study was performed to evaluate the unconfounded association of genetic proxies for BP and first-line AHMs with PD. Methods: Instrumental variables (IV) from the genome-wide association study (GWAS) for BP traits were used to proxy systolic BP (SBP), diastolic BP, and pulse pressure. SBP-associated variants either located within encoding regions or associated with the expression of AHM targets were selected and then scaled to proxy therapeutic inhibition of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, and thiazides. Positive control analyses on coronary heart disease (CHD) and stroke were conducted to validate the IV selection. Summary data from GWAS for PD risk and PD age at onset (AAO) were used as outcomes. Results: In positive control analyses, genetically determined BP traits and AHMs closely mimicked the observed causal effect on CHD and stroke, confirming the validity of IV selection methodology. In primary analyses, although genetic proxies identified by "encoding region-based method" for ß-blockers were suggestively associated with a delayed PD AAO (Beta: 0.115; 95% CI: 0.021, 0.208; p = 1.63E-2; per 10-mmHg lower), sensitivity analyses failed to support this association. Additionally, MR analyses found little evidence that genetically predicted BP traits, overall AHM, or other AHMs affected PD risk or AAO. Conclusion: Our data suggest that BP and commonly prescribed AHMs may not have a prominent role in PD etiology.

Chrysin, which targets PLAU, protects PC12 cells from OGD/R-stimulated damage through repressing the NF-κB signaling pathway.

Cerebral ischemia reperfusion injury (CIRI) is a great challenge for the patients with brain ischemia, but its pathophysiological mechanism has not been clearly explored. This study aims to decipher the effect of chrysin and plasminogen activator urokinase (PLAU) in CIRI. The immune-related genes were collected from the ImmPort website, and the differentially expressed genes were determined based on the Gene Expression Omnibus (GEO) database. PC12 cells were used to establish an ischemic stroke model under the condition of oxygen-glucose deprivation and reoxygenation (OGD/R). Small interfering RNA strategy was employed to knock down the PLAU expression of PC12 cells. The proliferation and apoptosis rates of PC12 cells treated by OGD/R or/and chrysin were detected with Cell Counting Kit 8 (CCK-8) and flow cytometry. The protein and mRNA expressions were measured using western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). PLAU was identified as a candidate for CIRI treatment and expressed at higher levels in CIRI tissues compared with that in normal controls. Chrysin was determined as a crucial agent that could decrease the expression of PLAU. Chrysin significantly promoted the cell proliferation, inhibited the protein levels of PLAU, p-NF-κB, and p-IKκB in PC12 cells after OGD/R. Silencing of PLAU strengthened the protective effect of chrysin on PC12 cells treated by OGD/R, including the improvement of cell viability and suppression of apoptosis. Chrysin inactivated the NF-κB pathway via targeting PLAU in OGD/R-stimulated PC12 cells. Chrysin prevented PC12 cells from OGD/R-stimulated damage via decreasing PLAU expression and inactivating the NF-κB signaling pathway.

Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41.

A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (-)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (-)-gossypol, oligopeptide derivative of (-)-gossypol and taurine derivative of (-)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (-)-gossypol.