SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a-PINK1-Parkin signaling pathway to activate mitophagy.

INTRODUCTION: Painful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development of PDN, but its pathogenesis and mechanism have not been fully investigated. METHODS: In this study, we used high-fat diet/low-dose streptozotocin-induced rats as a model of type 2 diabetes mellitus. Behavioral testing, whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons, and complex sensory nerve conduction velocity studies were used to assess peripheral neuropathy. Mitochondrial membrane potential (MMP), ATP, tissue reactive oxygen species, and transmission electron microscopy were used to evaluate the function and morphology of mitochondria in DRG. Real-time PCR, western blot, and immunofluorescence were performed to investigate the mechanism. RESULTS: We found that damaged mitochondria were accumulated and mitophagy was inhibited in PDN rats. The expression of sirtuin 3 (SIRT3), which is an NAD+-dependent deacetylase in mitochondria, was inhibited. Overexpression of SIRT3 in DRG neurons by intrathecally administered LV-SIRT3 lentivirus ameliorated neurological and mitochondrial dysfunctions. This was evidenced by the reversal of allodynia and nociceptor hyperexcitability, as well as the restoration of MMP and ATP levels. Overexpression of SIRT3 restored the inhibited mitophagy by activating the FoxO3a-PINK1-Parkin signaling pathway. The effects of SIRT3 overexpression, including the reversal of allodynia and nociceptor hyperexcitability, the improvement of impaired mitochondria and mitophagy, and the restoration of PINK1 and Parkin expression, were counteracted when FoxO3a siRNA was intrathecally injected. CONCLUSION: These results showed that SIRT3 overexpression ameliorates PDN via activation of FoxO3a-PINK1-Parkin-mediated mitophagy, suggesting that SIRT3 may become an encouraging therapeutic strategy for PDN.

Programmed Intermittent Bolus for Erector Spinae Plane Block Versus Intercostal Nerve Block With Patient-controlled Intravenous Analgesia in Video-assisted Thoracoscopic Surgery: A Randomized Controlled Noninferiority Trial.

OBJECTIVE: Postoperative analgesia is crucial after video-assisted thoracoscopic surgery (VATS). This study was designed to investigate whether the analgesic effect of programmed intermittent bolus (PIB) erector spinae plane block (ESPB) is noninferior to that of intercostal nerve block with patient-controlled intravenous analgesia (ICNB-PCIA) for VATS. METHODS: The study was a single-center, open labeled, randomized noninferiority trial. A total of 80 patients (American Society of Anesthesiologists I to III) undergoing elective video-assisted thoracoscopic lobectomy or bulla resection were randomly allocated to the ICNB-PCIA (n=40) or the ESPB (n=40) group using a PIB injection. The primary outcome was pain intensity at movement at 4 hours postoperatively using the Numeric Rating Scale (NRS). Secondary outcomes included pain scores at rest and movement in the recovery room, at 8, 24, and 48 hours postoperatively, perioperative analgesics, adverse effects, hospital stay, and patient satisfaction. RESULTS: The mean difference in NRS scores at movement at 4 hours postoperatively between the ESPB (n=39) and the ICNB-PCIA (n=37) groups was under the noninferiority margin. NRS scores were significantly higher in the ICNB-PCIA group than the ESPB group at movement postoperatively. At rest, NRS scores were significantly elevated in the ICNB-PCIA at 4, 8, and 24 hours. The postoperative opioids consumption was decreased in the ESPB group. No difference was found in rescue analgesics, hospital stay, and patient satisfaction. DISCUSSION: ESPB using a PIB injection offers noninferior analgesia to ICNB-PCIA after VATS.

Bibliometric Analysis of Research Studies on Postoperative Pain Management of Cesarean Section.

Purpose: Cesarean section (C-section) is associated with moderate-to-severe postoperative pain. Many studies on pain management after C-section have been published in recent decades, many of which focused on new regional techniques. The purpose of this study is to outline the connections within the dynamic evolution of postcesarean delivery analgesia research publications using retrospective bibliometric analysis. Patients and Methods: Published studies on postoperative pain management of C-section were retrieved from the Science Citation Index Expanded (SCI-E) of Web of Science (WOS) Core collection database. All papers published from 1978 to October 22, 2022 were searched. The research progress and growing trend were quantitatively analyzed by total publications, research institutions, journal impact factors, and author's contribution. Total citations frequency, average citations per item and h-index were used for evaluating literature quantity. Top 20 journals with the highest number of publications were charted. The keywords co-occurrence overlay map was visualized by the VOSviewer software. Results: From 1978 to 2022, a total of 1032 articles in postcesarean delivery analgesia research field were published, with 23,813 times cited, average citations of 23.07 per item, and an h-index of 68. The most high-yield publication year, countries, journals, authors, institutions were 2020 (n=79), the United States (n=288), Anesthesia and Analgesia (n=108), Carvalho B (n=25), and Stanford University (n=33), respectively. The United States had the most cited papers. The future research interest might be "prescription", "quadratus lumborum block", "postnatal depression", "persistent pain", "dexmedetomidine", "enhanced recovery", and "multimodal analgesia". Conclusion: By employing the online bibliometric tool and VOSviewer software, we found that studies on postcesarean analgesia had grown markedly. The focus had evolved to nerve block, postnatal depression, persistent pain, and enhanced recovery.

Gallic acid enhances anti-lymphoma function of anti-CD19 CAR-T cells in vitro and in vivo.

Chimeric antigen receptor T (CAR-T) cell targeting CD19 antigen has achieved exhilarative clinical efficacy in B-cell malignancies. However, challenges still remain for the currently approved anti-CD19 CAR-T therapies, including high recurrence rates, side effects and resistance. Herein, we aim to explore combinatorial therapy by use of anti-CD19 CAR-T immunotherapy and gallic acid (GA, an immunomodulatory natural product) for improving treatment efficacy. We assessed the combinatorial effect of anti-CD19 CAR-T immunotherapy with GA in cell models and a tumor-bearing mice model. Then, the underlying mechanism of GA on CAR-T cells were investigated by integrating network pharmacology, RNA-seq analysis and experimental validation. Furthermore, the potential direct targets of GA on CAR-T cells were explored by integrating molecular docking analysis with surface plasmon resonance (SPR) assay. The results showed that GA significantly enhanced the anti-tumor effects, cytokine production as well as the expansion of anti-CD19 CAR-T cells, which may be mainly through the activation of IL4/JAK3-STAT3 signaling pathway. Furthermore, GA may directly target and activate STAT3, which may, at least in part, contribute to STAT3 activation. Overall, the findings reported here suggested that the combination of anti-CD19 CAR-T immunotherapy with GA would be a promising approach to increase the anti-lymphoma efficacy.

Characterization of the Therapeutic Effects of Novel Chimeric Antigen Receptor T Cells Targeting CD38 on Multiple Myeloma.

Multiple myeloma (MM) is a tumor type characterized by the unregulated proliferation of clonal plasma cells in the bone marrow. Immunotherapy based on chimeric antigen receptor T cell (CAR-T) therapy has achieved exciting success in the treatment of hematological malignant tumors. CD38 is highly and evenly expressed in MM and is an attractive target for MM treatment. Here, we successfully constructed two novel second-generation CAR-T cells targeting CD38 by retroviral vector transduction. CD38 CAR-T cells could be activated effectively after stimulation with CD38-positive tumor cells and secrete cytokines such as IFN-γ and TNF-α to promote tumor cell apoptosis in in vitro experiments. Real-time fluorescence monitoring experiments, luciferase detection experiments and flow cytometry experiments revealed the efficient and specific killing abilities of CD38 CAR-T cells against CD38-positive tumor cells. The proliferation ability of CD38 CAR-T cells in vitro was higher than that of untransduced T cells. Further antitumor experiments in vivo showed that CD38 CAR-T cells could be quickly activated to secrete IFN-γ and eliminate tumors. Thus, novel CD38-targeted second-generation CAR-T cells have efficient and specific antitumor activity and may become a novel therapy for the clinical treatment of MM.

Determining correct tracheal tube insertion depth by measuring distance between endotracheal tube cuff and vocal cords by ultrasound in Chinese adults: a prospective case-control study.

OBJECTIVES: Unrecognised malposition of the endotracheal tube can lead to severe complications in patients under general anaesthesia. The purpose of this study was to verify the feasibility of using ultrasound to measure the distance between the upper edge of saline-inflated cuff and the vocal cords. DESIGN: Prospective case-control study. SETTING: A tertiary hospital in Beijing, China. METHODS: In this prospective study, 105 adult patients who required general anaesthesia were enrolled. Prior to induction, ultrasound was used to identify the position of the vocal cords. After intubation, the endotracheal tube (ETT) was fixed at a depth of 23 cm at the upper incisors in men and 21 cm in women. The depth of intubation was verified by video-assisted laryngoscopy. The distance between the upper edge of the saline-inflated cuff and the vocal cords was measured by ultrasound; the ideal distance was considered to be 1.9-4.1 cm. RESULTS: Among the 105 cases, two cuffs were too close to the vocal cords and one too far away from the vocal cords. These diagnoses were made by ultrasound and were in agreement with results from direct laryngoscopy. The overall accuracy of ultrasound in identifying malposition of the cuff was 100.0% (95% CI: 96.6% to 100%). The sensitivity, specificity, positive predictive value and negative predictive value of ultrasound were, respectively, 100% (95% CI: 96.5% to 100%), 100% (95% CI: 29.2% to 100%), 100% (95% CI: 96.5% to 100%) and 100% (95% CI: 29.2% to 100%). CONCLUSION: Identification of the upper edge of the saline-inflated cuff and the vocal cords by ultrasound to assess the location of the ETT is a reliable method. It can be used to avoid malposition of the ETT cuff and reduce the incidence of vocal cords injury after intubation. TRIAL REGISTRATION NUMBER: ChiCTR-DDD-17011048.