Mitochondria-derived peptide is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha -mediated mitochondrial biogenesis.

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.

Rac1/PAK1 signaling contributes to bone cancer pain by Regulation dendritic spine remodeling in rats.

Bone cancer pain (BCP) is severe chronic pain caused by tumor metastasis to the bones, often resulting in significant skeletal remodeling and fractures. Currently, there is no curative treatment. Therefore, insight into the underlying mechanisms could guide the development of mechanism-based therapeutic strategies for BCP. We speculated that Rac1/PAK1 signaling plays a critical role in the development of BCP. Tumor cells implantation (TCI) into the tibial cavity resulted in bone cancer-associated mechanical allodynia. Golgi staining revealed changes in the excitatory synaptic structure of WDR (Wide-dynamic range) neurons in the spinal cord, including increased postsynaptic density (PSD) length and thickness, and width of the cleft. Behavioral and western blotting test revealed that the development and persistence of pain correlated with Rac1/PAK1 signaling activation in primary sensory neurons. Intrathecal injection of NSC23766, a Rac1 inhibitor, reduced the persistence of BCP as well as reversed the remodeling of dendrites. Therefore, we concluded that activation of the Rac1/PAK1 signaling pathway in the spinal cord plays an important role in the development of BCP through remodeling of dendritic spines. Modulation of the Rac1/PAK1 pathway may be a potential strategy for BCP treatment.

Semirecumbent Positioning During Anesthesia Recovery and Postoperative Hypoxemia: A Randomized Clinical Trial.

Importance: The efficacy of a semirecumbent position (SRP) in reducing postoperative hypoxemia during anesthesia emergence is unclear despite its widespread use. Objective: To determine the differences in postoperative hypoxemia between patients in an SRP and a supine position. Design, Setting, and Participants: This randomized clinical trial was performed at a tertiary hospital in China between March 20, 2021, and May 10, 2022. Patients scheduled to undergo laparoscopic upper abdominal surgery under general anesthesia were enrolled. Study recruitment and follow-up are complete. Interventions: Patients were randomized to 1 of the following positions at the end of the operation until leaving the postanesthesia care unit: supine (group S), 15° SRP (group F), or 30° SRP (group T). Main Outcomes and Measures: The primary outcome was the incidence of postoperative hypoxemia in the postanesthesia care unit. Severe hypoxemia was also evaluated. Results: Out of 700 patients (364 men [52.0%]; mean [SD] age, 47.8 [11.3] years), 233 were randomized to group S (126 men [54.1%]; mean [SD] age, 48.2 [10.9] years), 233 to group F (122 men [52.4%]; mean [SD] age, 48.1 [10.9] years), and 234 to group T (118 women [50.4%]; mean [SD] age, 47.2 [12.1] years). Postoperative hypoxemia differed significantly among the 3 groups (group S, 109 of 233 [46.8%]; group F, 105 of 233 [45.1%]; group T, 76 of 234 [32.5%]; P = .002). This difference was statistically significant for groups T vs S (risk ratio [RR], 0.69 [95% CI, 0.55-0.87]; P = .002) and groups T vs F (RR, 0.72 [95% CI, 0.57-0.91]; P = .007), but not for groups F vs S (RR, 0.96 [95% CI, 0.79-1.17]; P = .78). Severe hypoxemia also differed among the 3 groups (group S, 61 of 233 [26.2%]; group F, 53 of 233 [22.7%]; group T, 36 of 234 [15.4%]; P = .01). This difference was statistically significant for groups T vs S (RR, 0.59 [95% CI, 0.41-0.85]; P = .005). Conclusions and Relevance: In this randomized clinical trial of SRP during anesthesia recovery in patients undergoing laparoscopic upper abdominal surgery, postoperative hypoxemia was significantly reduced in group T compared with group F or group S. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100045087.

Deep Neuromuscular Block Attenuates Chronic Postsurgical Pain and Enhances Long-Term Postoperative Recovery After Spinal Surgery: A Randomized Controlled Trial.

INTRODUCTION: The effects of deep neuromuscular block (DNMB) on chronic postsurgical pain (CPSP) have not been conclusively determined. Moreover, a limited number of studies have examined the impact of DNMB on long-term recovery quality after spinal surgery. We investigated the impact of DNMB on CPSP and the quality of long-term recovery in patients who had been subjected to spinal surgery. METHODS: This was a randomized, controlled, double-blind, single-center study performed from May 2022 to November 2022. A total of 220 patients who underwent spinal surgery under general anesthesia were randomly assigned to receive either DNMB (post-tetanic count at 1-2) (the D group) or moderate NMB (MNMB) (train-of-four at 1-3) (the M group). The primary endpoint was the incidence of CPSP. The secondary endpoints included the visual analogue scale (VAS) score in the post-anesthesia recovery unit (PACU), at 12, 24, 48 h and 3 months after surgery; postoperative opioid consumption; quality of recovery-15 (QoR-15) scores on the second postoperative day, before discharge, and 3 months after surgery. RESULTS: The incidence of CPSP was significantly lower in the D group (30/104, 28.85%) than in the M group (45/105, 42.86%) (p = 0.035). Besides, VAS scores were significantly reduced at the third month in the D group (p = 0.016). In the PACU and 12 h after surgery, VAS scores were also significantly lower in the D group than in the M group (p < 0.001, p = 0.004, respectively). The total amount of postoperative opioid consumption (expressed in total oral morphine equivalents) was significantly less in D group than M group (p = 0.027). At 3 months after surgery, QoR-15 scores were significantly higher in D group than M group (p = 0.003). CONCLUSIONS: Compared with MNMB, DNMB significantly reduced CPSP and postoperative opioid consumption in spinal surgery patients. Moreover, DNMB improved the long-term recovery of patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2200058454).

Effects of sarcopenia and frailty on postoperative recovery in elderly patients: A prospective cohort study.

BACKGROUND: Sarcopenia and frailty are both age-related declines in functional reserve that are linked to adverse health outcomes. It is critical to know about the outcomes of a combination of these conditions. The study aimed to investigate the effects of sarcopenia and frailty on postoperative recovery in elderly patients and to explore risk factors. METHODS: This prospective cohort study was conducted among 608 patients aged ≥60 years, American Society of Anesthesiologists I-III, who were scheduled to undergo thoracic (non-cardiac) and abdominal surgery from 1 March 2022 to 31 October 2022 at the Affiliated Hospital of Xuzhou Medical University. Frailty was measured by the 28-item frailty index, and sarcopenia was assessed sarcopenia was assessed by skeletal muscle index in computed tomographic scan, handgrip strength and 6-m walk. Participants were classified as follows: Group A: both sarcopenia and frailty; Group B: sarcopenia only; Group C: frailty only; and Group D: neither frailty nor sarcopenia. The primary outcome was 90-day morbidity. Multivariable logistic regression model was used to estimate the association between sarcopenia, frailty and 90-day morbidity. RESULTS: The median (interquartile range) age of participants was 68 (64-72) years, and 62.7% were men. The prevalence rates of sarcopenia and frailty were 32.8% and 47.6%, respectively. The 90-day morbidity in Group A was 58.5%, in Group B was 46.2%, in Group C was 42.0% and in Group D was 28.8%, and the difference was significant (P < 0.001). In the multivariable analysis, both sarcopenia and frailty [odds ratio (OR), 2.21; 95% confidence interval (CI), 1.26-3.89], sarcopenia only (OR, 1.84; 95% CI, 1.01-3.36), frailty only (OR, 1.77; 95% CI, 1.03-3.03), women (OR, 0.67; 95% CI, 0.45-0.99), body mass index (OR, 0.94; 95% CI, 0.88-0.99), pre-operative albumin (OR, 0.96; 95% CI, 0.91-1.00) and operative stress score (OSS) [OSS 3 (OR, 2.09; 95% CI, 1.21-3.67); OSS 4-5 (OR, 3.81; 95% CI, 2.31-6.42)] were independently associated with 90-day morbidity. In the multivariable analysis with inverse probability weighting adjusted cohort, sarcopenia and frailty were also significantly associated with 90-day morbidity. CONCLUSIONS: Sarcopenia and frailty were associated with higher risks of postoperative 90-day morbidity in elderly patients alone and in combination. Sex, body mass index, pre-operative albumin and operative stress were also independent factors for postoperative morbidity within 90 days.