This study investigated the hypocholesterolaemic effects of bitter melon aqueous extracts (BMAE) in vitro, the inhibitory effects of BMAE on pancreatic cholesterol esterase (CEase) and incorporation of cholesterol into micelles were investigated. BMAE decreased the in vitro micellar solubility of cholesterol in a dose-dependent manner. The conformation of CEase was investigated by means of circular dichroism (CD) and fluorescence. The result revealed the decrease of α-helix contents, increase of β-sheet and exposure of aromatic amino acid residuals. The incorporation of cholesterol into micelles was inhibited by BMAE. A complex was observed by transmission electron microscopy (TEM), which indicated interaction between cholesterol and BMAE. The result revealed that BMAE can play a role in decreased intestinal cholesterol absorption via inhibition of CEase, and of micelle formation. 相似文献
This retrospective study aimed to evaluate radiation-induced pneumonitis (RIP) and a related condition that we define in this report—prolonged minimal RIP (pmRIP)—after stereotactic body radiotherapy (SBRT) for Stage I primary lung cancer in patients with chronic obstructive pulmonary disease (COPD). We assessed 136 Stage I lung cancer patients with COPD who underwent SBRT. Airflow limitation on spirometry was classified into four Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades, with minor modifications: GOLD 1 (mild), GOLD 2 (moderate), GOLD 3 (severe) and GOLD 4 (very severe). On this basis, we defined two subgroups: COPD-free (COPD −) and COPD-positive (COPD +). There was no significant difference in overall survival or cause-specific–survival between these groups. Of the 136 patients, 44 (32%) had pmRIP. Multivariate analysis showed that COPD and the Brinkman index were statistically significant risk factors for the development of pmRIP. COPD and the Brinkman index were predictive factors for pmRIP, although our findings also indicate that SBRT can be tolerated in early lung cancer patients with COPD. 相似文献
Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CLh) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CLh involving OATP1B-mediated hepatic uptake. CLh can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CLh and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction. 相似文献
AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain. 相似文献
The purpose of this study was to compare the outcomes of trauma patients who were injured in a motor vehicle crash and tested positive for alcohol upon hospital arrival versus those who tested negative.
Methods
Study data came from the US National Trauma Data Bank (2007–2010). Any blood alcohol concentration (BAC) found at or above the legal limit (≥0.08?g/dL) was considered “alcohol positive”, and if no alcohol was identified through testing, the patient was considered “alcohol negative”. Patients’ demographics including age >?=?14, race, gender, drug test results, systolic blood pressure, heart rate, injury severity score (ISS), and Glasgow Coma Scale (GCS) were included in the study. Propensity score and exact pair matching were performed between the groups using baseline characteristics.
Results
From a total of 88,794 patients, 30.9% tested positive and 69.1% tested negative for alcohol. There were significant differences found between the groups regarding age, gender, race, and GCS (all p?<?0.001) as well as a significantly higher in-hospital mortality rate (3.5% vs. 2.7%, p?<?0.001) and median time to patient expiration (4 vs. 3 days, p?<?0.001) in the alcohol negative group. After running both matching scenarios, there was no evidence of a significant difference seen in the rates of in-hospital mortality or the median time to patient expiration between the alcohol groups in either matched comparison.
Conclusion
Patients who tested positive for alcohol following a traumatic motor vehicle crash showed no significant increase in in-hospital mortality or time to expiration when compared to propensity score and exact matched patients who tested negative for alcohol. 相似文献
Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer’s disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD.
Here, our aim was to study the interaction between BChE and fluoxetine.
Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the Vm, Km, kcat and kcat/Km values were found to be 20.59?±?0.36?U mg?1 protein, 194?±?14?µM, 1.3?×?108?s?1 and 6.7?×?105?µM?1s?1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC50 value of 104?µM and a Ki value of 36.3?±?4.7?µM.
Overall, both the low Ki value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents. 相似文献
BackgroundPrepulse inhibition (PPI) is a neurophysiological phenomenon whereby a weak stimulus modulates the reflex response to a subsequent strong stimulus. Its physiological purpose is to avoid interruption of sensory processing by subsequent disturbing stimuli at the subcortical level, thereby preventing undesired motor reactions. An important hub in the PPI circuit is the pedunculopontine nucleus, which is also involved in the control of posture and sleep/wakefulness.ObjectiveTo study the effect of posture (supine versus standing) on PPI, induced by somatosensory prepulses to either upper or lower limb. PPI was measured as the percentage inhibition of the blink reflex response to electrical supraorbital nerve (SON) stimulation.MethodsSixteen healthy volunteers underwent bilateral blink reflex recordings following SON stimulation either alone (baseline) or preceded by an electrical prepulse to the median nerve (MN) or sural nerve (SN), both in supine and standing. Stimulus intensity was 8 times sensory threshold for SON, and 2 times sensory threshold for MN and SN, respectively. Eight stimuli were applied in each condition.ResultsBaseline blink reflex parameters did not differ significantly between the two postures. Prepulse stimulation to MN and SN caused significant inhibition of R2. In supine but not in standing, R2 was significantly more inhibited by MN than by SN prepulses. In standing, SN stimulation caused significantly more inhibition of R2 than in supine, while the inhibition caused by MN prepulses did not differ significantly between postures.SignificancePPI induced by lower limb afferent input may contribute to postural control while standing. 相似文献