Evaluation of the inhibitory effects of antigout drugs on human carboxylesterases in vitro.

Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 µM for benzbromarone towards CES1 and CES2, respectively, and 2.94 µM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.

Inhibitory effects of phthalate esters (PAEs) and phthalate monoesters towards human carboxylesterases (CESs).

Phthalate esters (PAEs), accompanied by phthalate monoesters as hydrolysis metabolites in humans, have been widely used as plasticizers and exhibited disruptive effects on the endocrine and metabolic systems. The present study aims to investigate the inhibition behavior of PAEs and phthalate monoesters on the activity of the important hydrolytic enzymes, carboxylesterases (CESs), to elucidate the toxicity mechanism from a new perspective. The results showed significant inhibition on CES1 and CES2 by most PAEs, but not by phthalate monoesters, above which the activity of CES1 was strongly inhibited by DCHP, DEHP, DiOP, DiPP, DNP, DPP and BBZP, with inhibition ratios exceeding 80%. Kinetic analyses and in vitro-in vivo extrapolation were conducted, revealing that PAEs have the potential to disrupt the metabolism of endogenous substances catalyzed by CES1 in vivo. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of PAEs towards CES1. These findings will be beneficial for understanding the adverse effect of PAEs and phthalate monoesters.

Functional Connectivity Alterations and Molecular Characterization of the Anterior Cingulate Cortex in Tinnitus Pathology without Hearing Loss.

Compared with individuals with hearing loss, tinnitus patients without hearing loss have more psychological or emotional problems. Tinnitus is closely associated to abnormal metabolism and function of the limbic system, a key brain region for emotion experience, but the underlying molecular mechanism remains unknown. Using whole-brain microvasculature dynamics imaging, the anterior cingulate cortex (ACC) is identified as a key brain region of limbic system involve in the onset of salicylate-induced tinnitus in mice. In the tinnitus group, there is enhanced purine metabolism, oxidative phosphorylation, and a distinct pattern of phosphorylation in glutamatergic synaptic pathway according to the metabolome profiles, quantitative proteomic, and phosphoproteomic data of mice ACC tissue. Electroencephalogram in tinnitus patients with normal hearing thresholds show that the functional connectivity between pregenual anterior cingulate cortex and the primary auditory cortex is significantly increased for high-gamma frequency band, which is positively correlated with the serum glutamate level. These findings indicate that ACC plays an important role in the pathophysiology of tinnitus by interacting with the primary auditory cortex and provide potential molecular targets in the ACC for tinnitus treatment.

Effect of Electrode Insertion Angle on Cochlear Implantation Outcomes in Adult and Children Patients with Sensorineural Hearing Loss.

Purpose: To determine the role played by electrode insertion angle in cochlear implantation (CI) outcomes in adult and children patients with sensorineural hearing loss (SNHL). Methods: Adults (n = 10) and children (n = 19) with SNHL undergoing CI in a tertiary specialized hospital were retrospectively enrolled. The measurements were evaluated before and after CI surgery using sound field audiometry and speech recognition tests. Questionnaires were used to assess subjective benefits. Electrode insertion angles were determined using postoperative X-rays. Results: Both adult and children patients showed significant improvements in hearing, speech performance, and audiology and speech-related quality of life after CI. The angular insertion depths of adult and children group were 323.70 ± 43.57° and 341.53 ± 57.07°, respectively, showing no significant difference. In the adult group, deeper insertion depths were found to be strongly linked to lower postoperative pure tone thresholds at 12 months and higher postoperative disyllabic Word Recognition and Sentence Recognition Scores at 6 months (all P < 0.05). In the children group, deeper insertion depth had a positive correlation with postoperative monosyllabic Word Recognition Scores 6 and 12 months after CI surgery (both P < 0.05). Multiple linear regression models were constructed to predict disyllabic Word Recognition Scores at 6 and 12 months postoperatively in the children group, in which insertion angle, duration of hearing loss, and preoperative questionnaire result were identified as dependent variables. Conclusions: Greater angular insertion depths resulted in improved hearing and speech performances after CI. The benefits of greater angular insertion depths can be found in both adult and children patients and last for at least 12 months. Clinicians are expected to determine the optimal implantation direction during CI and ensure the insertion depth to improve the speech rehabilitation of patients.