Yong-Hao Yu

Background: Remimazolam, a novel ultra-short-acting benzodiazepine, is a potential sedative for non-general anesthesia surgery in the elderly. This study aimed to investigate the appropriate sedative dosage of remimazolam and its effects on perioperative cognitive function in elderly patients undergoing non-general anesthesia surgery.Methods: This multicenter, placebo-controlled trial enrolled 330 elderly patients undergoing non-general anesthesia procedures at eight centers in China from July 2021 to February 2022, with 238 ultimately completing the study. The primary endpoints were the dose of successful sedation with remimazolam and the changes in perioperative cognitive function. Adverse events were recorded to assess drug safety.Results: The induction dose of remimazolam for sedation in spinal anesthesia in elderly patients was 5.38 mg (95% confidence interval [CI], 5.20–5.56), maintained at a rate of 0.223 mg·kg⁻¹·h⁻¹ (95% CI, 0.201–0.237) with no serious adverse effects. Compared with the standard saline group, there was no statistical difference in the MMSE scores on Day 2 morning (P = 0.886), Day 2 afternoon (P = 0.864), and Day 7 (P = 0.613), and no statistical difference in the MoCA scores on Day 2 morning (P = 0.687), Day 2 afternoon (P = 0.827), and Day 7 (P = 0.483) in remimazolam group.Conclusion: Remimazolam besylate is an effective sedative for elderly patients undergoing neuraxial anesthesia. It was successfully induced at a dose of 5.38 mg and maintained at 0.223 mg·kg⁻¹·h⁻¹, demonstrating a good safety profile without affecting short-term postoperative cognitive function.Clinical Trial Registration: http://www.chictr.org.cn (ChiCTR2100048744).

Background: Diabetic peripheral neuropathy (DPN) is a common neurological complication of diabetes mellitus without efficient interventions. Both lysine demethylase 5B (KDM5B) and sirtuin‐3 (SIRT3) have been found to regulate islet function and glucose homeostasis. KDM5B was predicted to bind to the SIRT3 promoter by bioinformatics. Here, we investigated whether KDM5B affected DPN development via modulating SIRT3.Methods: The db/db mice and high glucose‐stimulated Schwann cells (RSC96) were used as in vivo and in vitro models of DPN, respectively. Glucose level, glucose and insulin tolerance of mice were measured. Neurological function was evaluated by motor nerve conduction velocity (MNCV), tactile allodynia assay and thermal sensitivity assay. Adenosine triphosphate level, oxygen consumption rate, extracellular acidification rate, β‐oxidation rate, acetyl‐CoA level, acetylation levels and activities of long‐chain acyl CoA dehydrogenase (LCAD) and pyruvate dehydrogenase (PDH) were detected. Methyl thiazolyl tetrazolium assay was adopted to determine cell viability. Reactive oxygen species (ROS) production was detected by MitoSox staining. Western blotting for measuring target protein levels. Molecular mechanisms were investigated by co‐immunoprecipitine (Co‐IP), chromatin immunoprecipitation (ChIP) and luciferase reporter assay.Results: KDM5B was up‐regulated, while SIRT3 was down‐regulated in DPN models. SIRT3 overexpression or AMPK activation ameliorated mitochondrial metabolism dysfunction and ROS overproduction during DPN. KDM5B overexpression triggered mitochondrial metabolism disorder and oxidative stress via directly transcriptional inhibiting SIRT3 expression by demethylating H3K4me3 or indirectly repressing AMPK pathway‐regulated SIRT3 expression.Conclusion: KDM5B contributes to DPN via regulating SIRT3‐mediated mitochondrial glucose and lipid metabolism. KDM5B inhibition may be an effective intervention for DPN.

Aims: The pathogenesis of diabetic peripheral neuropathy (DPN) is complex, and its treatment is extremely challenging. MicroRNA‐7a‐5p (miR‐7a‐5p) has been widely reported to alleviate apoptosis and oxidative stress in various diseases. This study aimed to investigate the mechanism of miR‐7a‐5p in DPN.Methods: DPN cell model was constructed with high‐glucose–induced RSC96 cells. Cell apoptosis and viability were detected by flow cytometry analysis and cell counting kit‐8 (CCK‐8) assay respectively. The apoptosis and Jun N‐terminal kinase (JNK)/c‐JUN signalling pathway‐related proteins expression were detected by Western blotting. The intracellular calcium content and oxidative stress levels were detected by flow cytometry and reagent kits. Mitochondrial membrane potential was evaluated by tetrechloro‐tetraethylbenzimidazol carbocyanine iodide (JC‐1) staining. The targeting relationship between miR‐7a‐5p and voltage‐dependent anion‐selective channel protein 1 (VDAC1) was determined by RNA pull‐down assay and dual‐luciferase reporter gene assay. The streptozotocin (STZ) rat model was constructed to simulate DPN in vivo. The paw withdrawal mechanical threshold (PTW) was measured by Frey capillary line, and the motor nerve conduction velocity (MNCV) was measured by electromyography.Results: MiR‐7a‐5p expression was decreased, while VDAC1 expression was increased in HG‐induced RSC96 cells and STZ rats. In HG‐induced RSC96 cells, miR‐7a‐5p overexpression promoted cell proliferation, inhibited apoptosis, down‐regulated calcium release, improved mitochondrial membrane potential and repressed oxidative stress response. MiR‐7a‐5p negatively regulated VDAC1 expression. VDAC1 knockdown improved cell proliferation activity, suppressed cell apoptosis and mitochondrial dysfunction by inhibiting JNK/c‐JUN pathway activation. MiR‐7a‐5p overexpression raised PTW, restored MNCV and reduced oxidative stress levels and nerve cell apoptosis in STZ rats.Conclusion: MiR‐7a‐5p overexpression ameliorated mitochondrial dysfunction and inhibited apoptosis in DPN by regulating VDAC1/JNK/c‐JUN pathway.

Background: During procedures that are not performed under general anesthesia, elderly patients often have adverse emotions such as nervousness and anxiety due to their consciousness. Sedation is frequently used to relieve these symptoms. However, the adverse effects from currently prescribed sedative drugs such as midazolam, dexmedetomidine, and propofol are common and unavoidable. There has been limited research on the use of remimazolam besylate, a new sedative drug, to determine the effectiveness of the medication in reducing perioperative cognitive dysfunction in elderly patients undergoing non-general anesthesia procedures and to assess the efficacy of the medication in reducing sedation. Methods: This prospective, multicenter, randomized, single-blind, placebo-controlled trial was conducted from July 2021 to February 2022. The study included 330 elderly patients aged > 65 years who underwent non-general anesthesia procedures. Patients were randomly assigned (2:1) to two groups: the remimazolam besylate group and control group. Outcomes: The primary outcomes included sedation levels achieved at target doses and changes in perioperative cognitive function. Additionally, time to awakening, the incidence of postoperative delirium, change in anxiety level, change in sleep rhythm, and the incidence of adverse events during sedation were measured as secondary outcomes.