Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents.

The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 µM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.

Esketamine use is associated with shortened postoperative hospital stay in patients after knee arthroscopic surgery: a propensity score-matched cohort study.

BACKGROUND: Previous studies have examined anesthetics to improve postoperative prognosis after knee arthroscopic surgery. However, it is currently unknown whether perioperative anesthetics can influence postoperative hospital stay. We investigated the impact of esketamine after knee arthroscopic surgery on post-operative length of stay, fever and surgical site infection. METHODS: This study included 455 patients who underwent knee surgery between January2020 and August 2021at a tertiary hospital in China. Patient characteristics, preoperative laboratory values, intra-operative anesthetic data, and postoperative outcomes were collected. Univariate and multivariate logistic regression analyses with or without propensity score matching were performed to identify factors related to post-operative discharge within 3 days(PD3). RESULTS: A total of 297 cases met our inclusion criteria. The mean age of patients was 42 ± 14 years, mean body mass index, 24.1 ± 3.5 kg/m2, 157(53%) patients were male. Meniscus-related procedures accounted for the most part of all the procedures with a percentage of 40.4%, followed by combined procedures of 35.4%. After we adjusted for demographic and intraoperative characteristics with propensity score matching, esketamine use was significantly associated with PD3 with the highest odds ratio of 2.28 (95% confidence interval (CI): 1.18-4.41, p = 0.014). CONCLUSION: Esketamine use was associated with PD3 in patients underwent knee arthroscopic surgery. The findings of this study will be useful to anesthesiologists in making informed decisions regarding the choice of anesthetics for knee joint diseases. TRIAL REGISTRATION: This study was approved by the Ethics Committee (Approval No.:2023-041-01) of the Eighth Affiliated Hospital, Sun Yat-sen University and retrospectively registered.

TRPC6 Deletion Enhances eNOS Expression and Reduces LPS-Induced Acute Lung Injury.

Acute lung injury (ALI) is characterized by endothelial barrier disruption and associated inflammatory responses, and transient receptor potential cation channel 6 (TRPC6)-mediated Ca2+ influx is critical for endothelial hyperpermeability. In this study, we investigated the role of TRPC6 in LPS-induced ALI, analyzed gene expression in WT and TRPC6-/- lungs using RNA sequencing, and explored the effects of TRPC6 in the LPS-induced hyperpermeability in human umbilical vein endothelial cells (HUVECs) to elucidate the underlying mechanisms. Intratracheal instillation of LPS caused edema in the mouse lungs. Deletion of TRPC6 reduced LPS-induced lung edema and decreased cell infiltration. RNA sequencing analysis suggested that downregulated cell adhesion molecules in TRPC6-/- lungs may be responsible for their resistance to LPS-induced injury. In addition, downregulation of TRPC6 significantly alleviated the LPS-induced decrease in eNOS expression in lung tissue as well as in HUVECs. Moreover, inhibition of TRPC6 with the channel antagonist larixyl led to a decrease in LPS-induced hyperpermeability and ROS production in HUVECs, which could be reversed by blocking eNOS. Our findings suggest that inhibition of TRPC6 ameliorates LPS-induced ALI, which may be achieved by acting on the cell adhesion molecule signaling pathway and participating in the regulation of eNOS levels in endothelial cells.

Numerical reconstruction of turbid slab optical properties using global optimization algorithms.

The detection and reconstruction of the optical properties within turbid slabs/plate parallel mediums have been widely investigated for its applications in medical diagnosis, atmosphere detection, etc., where the scattering of light would be expected. Although the scattering signal can be utilized for diagnostics purposes, the multiple scattering in the intermediate scattering regime (with an optical depth ~ 2-9) has posed a remarkable challenge. Existing optical tomography methods usually only reconstruct the reduced scattering coefficient to investigate the properties of the scattering target, while reconstruction efforts in analyzing the exact scattering phase function are rare. Solving such issues can provide much more information for proper interpretation of the characteristics of the turbid slab. This work demonstrates an inversion method based on optimization algorithms and the angular distribution of the transmitted light at the entrance plane and the exit plane of the sought medium. Candidate phase functions were pre-calculated and the optimization algorithm is able to reconstruct the phase function spatial distribution of the turbid slab with a satisfactory computational cost. Parametric studies were also performed to analyze the performance of each optimization algorithm used and the sensitivity of this Markov reconstruction scheme to noise.

Ulinastatin attenuates isoflurane-induced cognitive dysfunction in aged rats by inhibiting neuroinflammation and ß-amyloid peptide expression in the brain.

Objective: Postoperative neurocognitive disease (PNCD) in the aged is a major clinical problem with unclear mechanisms. This study was designed to explore the mechanisms for ulinastatin (UTI) to attenuate isoflurane-induced cognitive decline in Fischer-344 rats. Methods: The rats were divided into four groups: Control (0.9% saline only), Isoflurane (exposure to 1.2% isoflurane), Isoflurane-plus-UTI (exposure to 1.2% isoflurane followed by 100,000 U/kg UTI injection i.v.) and UTI-plus-isoflurane (i.v. of 100,000 U/kg UTI followed by 1.2% isoflurane exposure). After respective tests, the concentrations of tumour necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the brain were determined by ELISA the expression of ß-amyloid peptide (Aß) and cleaved caspase-3 were measured by Western blot. Ratio of apoptotic cells after Barnes maze challenge was assessed by TUNEL assay. Results: In both Barnes Maze training and challenge, results indicated isoflurane-impaired learning capacity, while pre-and post-treatment with UTI could attenuate this phenomenon. The ratio of apoptotic cells and the expression of cleaved caspase-3 were increased after isoflurane exposure, indicating that isoflurane could induce neuronal apoptosis, while both pre- and post-treatment with UTI could diminish these effects. Moreover, UTI inhibited the expression of TNF-α, IL-1ß and Aß induced by isoflurane in rat brain harvested at 16 h after isoflurane exposure. Conclusion: These results suggest that UTI inhibits neuronal apoptosis in rat brain by attenuating increased expression of Aß42 and inflammatory cytokines, which may contribute to its alleviation of isoflurane-induced cognitive dysfunction in rats. Moreover, UTI pre-treatment before isoflurane exposure showed more effective than post-treatment.

Lidocaine Attenuates Cognitive Impairment After Isoflurane Anesthesia by Reducing Mitochondrial Damage.

Mitochondrial dysfunction has been proposed to be one of the earliest triggering events in isoflurane-induced neuronal damage. Lidocaine has been demonstrated to attenuate the impairment of cognition in aged rats induced by isoflurane in our previous study. In this study, we hypothesized that lidocaine could attenuate isoflurane anesthesia-induced cognitive impairment by reducing mitochondrial damage. H4 human neuroglioma cells and 18-month-old male Fischer 344 rats were exposed to isoflurane or isoflurane plus lidocaine. Cognitive function was tested at 14 days after treatment by the Barnes Maze test in male Fischer 344 rats. Morphology was observed under electron microscope, and mitochondrial transmembrane potential, electron transfer chain (ETC) enzyme activity, complex-I-IV activity, immunofluorescence and flow cytometry of annexin V-FITC binding, TUNEL assay, and Western blot analyses were applied. Lidocaine attenuated cognitive impairment caused by isoflurane in aged Fischer 344 rat. Lidocaine was effective in reducing mitochondrial damage, mitigating the decrease in mitochondrial membrane potential (ΔΨm), reversing isoflurane-induced changes in complex activity in the mitochondrial electron transfer chain and inhibiting the apoptotic activities induced by isoflurane in H4 cells and Fischer 344 rats. Additionally, lidocaine suppressed the ratio of Bax (the apoptosis-promoting protein) to Bcl-2 (the apoptosis-inhibiting protein) caused by isoflurane in H4 cells. Lidocaine proved effective in attenuating isoflurane-induced POCD by reducing mitochondrial damage.