The Association between CYP2C19 Genetic Polymorphism and Prognosis in Patients Receiving Endovascular Therapy.

Background: Potentially substantial impacts on the prognosis have been observed in individuals undergoing endovascular treatment due to cytochrome P450 2c19 (CYP2C19) polymorphism. In an attempt to improve prognosis and lower the recurrence rate, this study investigated the CYP2C19 polymorphism in acute ischemic stroke patients. Materials and Methods: A retrospective analysis was performed on 292 patients with cerebral infarction who had acute endovascular recanalization at the Department of Neurology of Chongqing Hospital of Traditional Chinese Medicine between May 2017 and 2019. The patients were categorized into rapid-, medium-, and slow-metabolism groups based on CYP2C19 gene polymorphism, and their prognosis was monitored. In addition, the prognosis of 188 patients selectively receiving carotid artery stenting at a selected time was also observed. Results: Among the 292 cerebral infarction cases receiving acute endovascular recanalization, the patients in the CYP2C19 rapid-metabolism group regularly took clopidogrel and aspirin combined with antiplatelet therapy and suffered from reoccurrence of apoplexy and cerebral hemorrhage; the 90-day good prognosis had a statistical difference (P < 0.05, prognostic assessment includes hospitalization and 6 months after discharge) and the other adverse events had no statistical difference (including mortality). The 188 patients selectively receiving carotid artery stenting had a recurrence of apoplexy, cerebral hemorrhage, and restenosis rate with a statistical difference (P < 0.05), and the other adverse events had no statistical difference. Conclusions: In conclusion, the findings of the current study indicate that irrespective of whether patients are undergoing selective carotid artery stenting or acute endovascular recanalization, those with rapid CYP2C19 metabolism have a significantly lower likelihood of experiencing adverse prognostic events compared to those with intermediate and slow metabolism. Furthermore, this group also has a more favorable prognosis than the other two groups.

Utilizing bis(imino)dihydroacridanide pincer ligands in p-block chemistry: synthesis and catalysis of an antimony monocation salt.

We present the synthesis and characterization of an Sb(III) monocation salt stabilized by a bulky bis(imino)dihydroacridanide pincer ligand. The Lewis acidity of the Sb cation is quantified using the Guttmann-Beckett method and confirmed by its reaction with 4-dimethylaminopyridine, which forms a Lewis acid-base adduct. This Sb cation exhibits catalytic activity in the cyanosilylation of arylketones. The electronic structure of the Sb cation as well as the mechanism of the catalytic transformation are explored by density functional theory computations.

Effects of Changyu Daotan Decoction on Depression via Restoration of Mice Hippocampus and Alteration of Expression of Relevant Neurotrophic Factors.

Depression, a sort of common psychological disorder, is a serious hazard to people's health and social progress. Conventional clinical means for this disorder nowadays are mostly chemical medicine treatments accompanied by psychological counseling. Chinese application of using TCM to treat mental diseases like depression could be traced from hundreds of years ago, in comparison to the long-term depression course and the chemical medicine administration demerits like side effects and resistance, traditional Chinese medicines are milder, more lasting, stable and are the optimal choice for perennial depression treatment. This study was committed to making a comprehensive investigation of Changyu Daotan Decoction's efficacy in the depression mice model, and it turned out that the Changyu Daotan Decoction was capable of restoring the hippocampus of the depression mice and altering the expressions of neurotrophic factors (the expressions of ß-Catenin, cyclin D1 and in GSK-3ß BDNF, GFAP, NGF, and Wnt signaling pathways). Results of metabonomics analysis showed that the contents of GABA, His, Tyr, Trp, PA, and 5-HIAA in the mice of the Changyu Daotan Decoction group were restored after administration and showed a conspicuous relevance with the metabolic.

Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

Case Report: Prenatal Diagnosis of a Fetus With Harlequin Ichthyosis Identifies Novel Compound Heterozygous Variants: A Case Report.

BACKGROUND: Harlequin ichthyosis (HI) is the most severe form of the keratinizing disorders, and it is characterized by whole-body hard stratum corneum. ABCA12 has been identified as the major disease-causing gene of HI. METHODS: A case of HI was prenatally diagnosed by ultrasonography and genetic tests. The fetus had been found with dentofacial deformity and profound thickening of the palm and plantar soft tissues. Chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were then performed on the amniotic fluid to identify germline pathogenic variants for the fetus. Candidate variants were verified by Sanger sequencing. RESULTS: Compound heterozygous frameshift variants (p.Q719QfsX21; p.F2286LfsX6) of ABCA12 were identified for the fetus, suggesting the former variants were maternally inherited and the latter paternally inherited. The fetus was terminated. CONCLUSION: A prenatal molecular diagnosis is an important approach for the prevention of HI. In the study, we provided a successful case of genetic counseling for a family with an HI baby.

Increased expression of DOC2A in human and rat temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of intractable epilepsy. Currently, the molecular mechanisms underlying epileptogenesis in TLE remain elusive; however, synaptic transmission may play an important role in the pathogenesis of epilepsy. Synaptic transmission is regulated by diverse mechanisms, including presynaptic modulators of synaptic vesicle formation and release, modulators of neurotransmission and distinct Ca2+ sensors. DOC2A, a novel Ca2+ sensor, can regulate spontaneous synaptic transmission and has been implicated in Ca2+-dependent neurotransmitter release. In this study, we demonstrate for the first time that DOC2A expression is significantly increased in human TLE and in two different rat models of TLE (pilocarpine- and kindling-induced) compared to the control groups. Localization of DOC2A in the human TLE patients and pilocarpine post-SE rat model was observed in neurons but not in astrocytes; DOC2A was also concentrated at the presynaptic terminals and colocalized with VMAT2. Our results suggest that the abnormal protein expression of DOC2A in epileptic brain tissue may play an important role in epilepsy.

Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats.

The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which plays an essential role in lipid homeostasis and glucose metabolism. However, whether or not FXR can prevent rise in blood pressure remains unknown. Here, we investigate the possibility of using chenodeoxycholic acid (CDCA), a natural ligand of FXR, to attenuate elevated blood pressure in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were treated with CDCA (30 mg/kg) for 8 weeks. Compared with vehicle control, CDCA attenuated rise in blood pressure in SHR. In addition, CDCA improved vasorelaxation and diminished the contractile response to endothelin-1 (ET-1) in mesenteric arteries from SHR. CDCA also stimulated endothelial nitric oxide synthase (eNOS) expression, repressed ET-1 levels, and inhibited NF-κB activities in mesenteric arteries of the SHR. Overall, we showed that CDCA treatment reduces systolic blood pressure, improves vascular relaxation, and inhibits vasoconstriction activity in SHR. The repressed ET-1 level, the raised eNOS expression, and the ameliorated inflammation in mesenteric arteries could be responsible for the vasorelaxant and hypotensive effect of CDCA. These findings support a potential role for FXR as a regulator in vascular activities and in the development of treatment for hypertension.

Effect of treadmill exercise on 5-HT, 5-HT1A receptor and brain derived neurophic factor in rats after permanent middle cerebral artery occlusion.

It has been well documented that exercise promotes neurological rehabilitation in patients with cerebral ischemia. However, the exact mechanisms have not been fully elucidated. This study aimed to discuss the effect of treadmill exercise on expression levels of 5-HT, 5-HT1A receptor (5-HT1AR) and brain derived neurophic factor (BDNF) in rat brains after permanent middle cerebral artery occlusion (pMCAO). A total of 55 rats were randomly divided into 3 groups: pMCAO group, pMCAO and treadmill exercise (pMCAO + Ex) group, and sham-operated group. Rats in pMCAO + Ex group underwent treadmill exercise for 16 days. Neurological function was evaluated by modified Neurological Severity Scores (mNSS). High-performance liquid chromatography-electrochemical detection system was used to determine the content of 5-HT in cortex tissues. The protein levels of 5-HT1AR, BDNF and synaptophysin were measured by Western blot. The mNSS in pMCAO + Ex group was lower than that in pMCAO group on day 19 post-MCAO (p < 0.001). The content of 5-HT dropped to 3.81 ± 1.86 ng/ml in pMCAO group (43.84 ± 2.05 ng/ml in sham-operated group), but increased in pMCAO + Ex group (10.06 ± 1.80 ng/ml). The protein expressions levels of synaptophysin, 5-HT1AR and BDNF were downregulated after cerebral ischemia (p < 0.05), and upregulated after treadmill exercise (p < 0.05). These results indicate that treadmill exercise improves neurologic function, enhances neuronal plasticity and upregulates the levels of 5-HT, 5-HT1AR and BDNF in rats with pMCAO.