Let-7b-TLR7 Signaling Axis Contributes to the Anesthesia/Surgery-Induced Cognitive Impairment.

Perioperative neurocognitive disorders (PNDs) are severe and common neurological complications among elderly patients following anesthesia and surgery. As the first line of defense of the innate immune system, Toll-like receptors (TLRs) have been found to be involved in the occurrence of neurodegenerative diseases in recent years. However, the role of TLR7 in the pathology and development of PNDs remains largely unclear. In our current study, we hypothesized that increased microRNA let-7b (let-7b) during anesthesia and surgical operation would activate TLR7 signaling pathways and mediate PNDs. Using a mouse model of PNDs, 18-20 months wild-type (WT) mice were undergoing unilateral nephrectomy, and increased TLR7 and let-7b expression levels were found in the surgery group compared with the Sham group. Of note, increased TLR7 was found to be co-localized with let-7b in the hippocampal area CA1 in the PNDs model. In addition, TLR7 and let-7b inhibition could improve hippocampus-dependent memory and attenuate the production of inflammatory cytokines. Together, our results indicated that TLR7 activation and up-regulation might be triggered by increased let-7b under stressful conditions and initiated the downstream inflammatory signaling, playing a substantial role in the development of PNDs.

Extracellular RNAs-TLR3 signaling contributes to cognitive impairment after chronic neuropathic pain in mice.

Chronic pain is often associated with cognitive decline, which could influence the quality of the patient's life. Recent studies have suggested that Toll-like receptor 3 (TLR3) is crucial for memory and learning. Nonetheless, the contribution of TLR3 to the pathogenesis of cognitive decline after chronic pain remains unclear. The level of TLR3 in hippocampal neurons increased in the chronic constriction injury (CCI) group than in the sham group in this study. Importantly, compared to the wild-type (WT) mice, TLR3 knockout (KO) mice and TLR3-specific neuronal knockdown mice both displayed improved cognitive function, reduced levels of inflammatory cytokines and neuronal apoptosis and attenuated injury to hippocampal neuroplasticity. Notably, extracellular RNAs (exRNAs), specifically double-stranded RNAs (dsRNAs), were increased in the sciatic nerve, serum, and hippocampus after CCI. The co-localization of dsRNA with TLR3 was also increased in hippocampal neurons. And the administration of poly (I:C), a dsRNA analog, elevated the levels of dsRNAs and TLR3 in the hippocampus, exacerbating hippocampus-dependent memory. In additon, the dsRNA/TLR3 inhibitor improved cognitive function after CCI. Together, our findings suggested that exRNAs, particularly dsRNAs, that were present in the condition of chronic neuropathic pain, activated TLR3, initiated downstream inflammatory and apoptotic signaling, caused damage to synaptic plasticity, and contributed to the etiology of cognitive impairment after chronic neuropathic pain.

The emerging power and promise of non-coding RNAs in chronic pain.

Chronic pain (CP) is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage lasting longer than 3 months. CP is the main reason why people seek medical care and exerts an enormous economic burden. Genome-wide expression analysis has revealed that diverse essential genetic elements are altered in CP patients. Although many possible mechanisms of CP have been revealed, we are still unable to meet all the analgesic needs of patients. In recent years, non-coding RNAs (ncRNAs) have been shown to play essential roles in peripheral neuropathy and axon regeneration, which is associated with CP occurrence and development. Multiple key ncRNAs have been identified in animal models of CP, such as microRNA-30c-5p, ciRS-7, and lncRNA MRAK009713. This review highlights different kinds of ncRNAs in the regulation of CP, which provides a more comprehensive understanding of the pathogenesis of the disease. It mainly focuses on the contributions of miRNAs, circRNAs, and lncRNAs to CP, specifically peripheral neuropathic pain (NP), diabetic NP, central NP associated with spinal cord injury, complex regional pain syndrome, inflammatory pain, and cancer-induced pain. In addition, we summarize some potential ncRNAs as novel biomarkers for CP and its complications. With an in-depth understanding of the mechanism of CP, ncRNAs may provide novel insight into CP and could become new therapeutic targets in the future.

Effects of Glucocorticoids on Postoperative Neurocognitive Disorders in Adult Patients: A Systematic Review and Meta-Analysis.

Background: Postoperative neurocognitive disorders (PNDs) is common among surgical patients, however, the effect of glucocorticoids for preventing PNDs is not clear. This review aims to evaluate the effect of glucocorticoids on the incidence of PNDs in adult patients undergoing surgery. Methods: The databases of PubMed/Medline, Embase, the Cochrane Library, and Web of science were searched for all available randomized controlled trials (RCTs) from inception to April 30, 2022. RCTs comparing the effect of glucocorticoids with placebo on the incidence of PNDs in adult surgical patients (≥18 years old) were eligible. Subgroup analyses and meta-regressions were performed to evaluate sources of clinical heterogeneity. The level of certainty for main outcomes were assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: Eleven trials with a total of 10,703 patients were identified. Compared with the control group, glucocorticoids did not reduce the incidence of PNDs (RR: 0.84, 95% CI: 0.67 to 1.06, P = 0.13, GRADE = moderate). Secondary analyses for primary outcome did not change the result. In addition, the length of ICU stay was decreased in glucocorticoids group (RR: -13.58, 95% CI: -26.37 to -0.80, P = 0.04, GRADE = low). However, there were no significant differences between groups with regards to the incidence of postoperative infection (RR: 0.94, 95% CI: 0.84 to 1.06, P = 0.30, GRADE = moderate), blood glucose level (RR: 1.05, 95% CI: -0.09 to 2.19, P = 0.07, GRADE = low), duration of mechanical ventilation (RR: -2.44, 95% CI: -5.47 to 0.59, P = 0.14, GRADE = low), length of hospital stay (RR: -0.09, 95% CI: -0.27 to 0.09, P = 0.33, GRADE = moderate) and 30-day mortality (RR: 0.86, 95% CI: 0.70 to 1.06, P = 0.16, GRADE = moderate). Conclusions: This meta-analysis suggests that perioperative administration of glucocorticoids may not reduce the incidence of PNDs after surgery. The effect of glucocorticoids on decreased length of ICU stay needs further researches. Future high-quality trials using acknowledged criteria and validated diagnostic tools are needed to determine the influence of glucocorticoids on long-term PNDs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022302262, identifier: CRD42022302262.

Perioperative platelet count in peripheral blood is associated with the early stage of PND after major orthopedic surgery: a prospective observational study.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common complications of major surgery among elderly patients, remarkably decreasing patients' life quality. Platelet count has been proved to be an essential factor in inflammation. However, as far as we know, the relationship between platelet count and PND is not clear yet in the orthopedic area. PND could be a long-term disease, which sometimes lasts for several years, and it is meaningful to find a biomarker of PND at the early stage. Thus, we designed this study to find out the association between perioperative platelet count and occurrence of PND, and determine whether preoperative platelet count could be a biomarker of the early stage of PND. METHODS: A prospective observational study was performed on the patients who would take total knee arthroplasty or total hip arthroplasty. Their peripheral platelets were counted by blood routine examination 1 day before and 3 days after the surgery. And we assessed their neurocognitive functions 1 day before and 3 days after the surgery. These data were recorded and analyzed to find out the relationship between platelet count and the occurrence of PND. RESULTS: Eventually, 70 patients finished the whole process, and 14 of them developed PND. The median preoperative platelet count in the PND group was significantly higher than that in the non-PND group (239 vs 168 × 10^9/L, p = 0.009). Preoperative platelet count was an independent risk factor for PND (odds ratio = 1.014, 95% confidence interval [CI] 1.000-1.027, P = 0.043) in the logistic multivariable regression, while the area under the curve of the receiver operating characteristic curve of the prediction model was 0.796 (95% CI 0.676-0.916). CONCLUSIONS: The higher preoperative and postoperative level of platelet count in the peripheral blood were associated with the early stage of PND, and preoperative platelet count could be a potential predictor of the early stage of PND in patients undergoing major orthopedic surgeries. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000033001 , registration date: 17 May 2020.

Evidence for Cognitive Decline in Chronic Pain: A Systematic Review and Meta-Analysis.

Background: People with chronic pain (CP) sometimes report impaired cognitive function, including a deficit of attention, memory, executive planning, and information processing. However, the association between CP and cognitive decline was still not clear. Our study aimed to assess the association of CP as a risk factor with cognitive decline among adults. Methods: We included data from clinical studies. Publications were identified using a systematic search strategy from PubMed, Embase, and Cochrane Library databases from inception to October 10, 2020. We used the mean cognitive outcome data and the standard deviations from each group. The standardized mean difference (SMD) or odds ratio (OR), and 95% confidence intervals (CI) were performed for each cognitive decline outcome. I 2-values were assessed to quantify the heterogeneities. Results: We included 37 studies with a total of 52,373 patients with CP and 80,434 healthy control participants. Because these studies used different evaluative methods, we analyzed these studies. The results showed CP was associated with cognitive decline when the short-form 36 health survey questionnaire (SF-36) mental component summary (SMD = -1.50, 95% CI = -2.19 to -0.81), the Montreal cognitive assessment (SMD = -1.11, 95% CI = -1.60 to -0.61), performance validity testing (SMD = 3.05, 95% CI = 1.74 to 4.37), or operation span (SMD = -1.83, 95% CI = -2.98 to -0.68) were used. However, we got opposite results when the studies using International Classification of Diseases and Related Health Problems classification (OR = 1.58, 95% CI = 0.97 to 2.56), the Mini-Mental State Examination (SMD = -0.42, 95% CI = -0.94 to 0.10; OR = 1.14, 95% CI = 0.91 to 1.42), and Repeatable Battery for the Assessment of Neuropsychological Status memory component (SMD = -0.06, 95% CI = -0.37 to 0.25). Conclusion: There may be an association between CP and the incidence of cognitive decline when some cognitive, evaluative methods were used, such as short-form 36 health survey questionnaire, Montreal cognitive assessment, performance validity testing, and operation span.

Oxygen vacancy regulation in Nb-doped Bi2WO6 for enhanced visible light photocatalytic activity.

Novel Nb-doped Bi2WO6 nanosheets have been successfully synthesized by a simple hydrothermal method. XRD, Raman spectra, XPS and SEM were adopted to analyze the structure and morphology of the samples, then the structure-dependent optical properties, photoelectric behavior and photocatalytic activities were investigated, and the structure-property relationship was also discussed. The results show that doping Nb5+ can increase the oxygen vacancies in the Bi2WO6 lattice and reduce the optical band gap of Bi2WO6. The oxygen vacancies also act as electron traps, which promote the separation of photogenerated carriers. Hence, compared with the pure Bi2WO6, the as-prepared Nb-doped Bi2WO6 nanosheets exhibit enhanced visible-light photocatalytic activity for removing contaminants in water such as rhodamine B and tetracycline.