Sirt1 activation prevents high glucose-induced angiotensin converting enzyme 2 downregulation in renal tubular cells by regulating the TIMP3/ADAM17 pathway.

BACKGROUND: Angiotensin converting enzyme 2 (ACE2) exerts renoprotective effects in diabetic kidney disease (DKD) by converting angiotensin (Ang) II into Ang (1-7). Previous studies have demonstrated that ACE2 expression in renal tubules is downregulated in DKD, but the mechanism is not fully understood. Sirtuin-1 (Sirt1) is a protein deacetylase that may regulate the activity of the renin-angiotensin system. The present study investigated the effects of Sirt1 on ACE2 expression under high glucose (HG) conditions and the underlying signaling pathway. METHODS AND RESULTS: Rats with DKD and NRK-52E cells cultured with HG were employed in this study. Western blotting, immunohistochemistry detection and qRT-PCR were performed for protein and mRNA expression analyses. Rats subjected to DKD displayed downregulated expression of Sirt1 and ACE2 in kidneys. Resveratrol, an activator of Sirt1, restored ACE2 expression and ameliorated renal injuries. Similarly, pharmacological activation of Sirt1 with SRT1720 markedly upregulated ACE2 in NRK-52E cells cultured with HG, while Sirt1 small interfering RNA (siRNA) further suppressed ACE2 expression. In addition, A disintegrin and metalloproteinase (ADAM) 17 was observed to be upregulated, and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), was downregulated in the kidneys of diabetic rats and NRK-52E cells incubated with HG. The TIMP3/ADAM17 pathway was involved in the regulation of ACE2 expression, as evidenced by decreased ACE2 expression levels after TIMP3-siRNA pretreatment. SRT1720 ameliorated the imbalance of TIMP3/ADAM17 induced by HG and consequently enhanced the expression of ACE2. Notably, the above effect of SRT1720 on ACE2 was interrupted by TIMP3-siRNA. CONCLUSIONS: Our findings suggest that Sirt1 activation may prevent HG-induced downregulation of renal tubular ACE2 by modulating the TIMP3/ADAM17 pathway. Sirt1 stimulation might be a potential strategy for the treatment of DKD.

Preoperative prognostic nutritional index value as a predictive factor for postoperative delirium in older adult patients with hip fractures: a secondary analysis.

BACKGROUND: Malnutrition is a common geriatric syndrome and can be targeted preoperatively to decrease the risk of postoperative delirium (POD) in older adult patients. To analyze the value of the prognostic nutritional index (PNI) to predict the incidence of POD in older adult patients with hip fractures. METHODS: This was a prospective, observational, cohort study of older adult patients with hip fractures. Preoperative PNI was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (/µL) using preoperative laboratory results. Patients were divided into POD and non-POD groups using the Confusion Assessment Method (CAM). The risk factors associated with POD as well as the relationship between PNI values and the incidence of POD were analyzed using univariate and multivariate logistic regression analyses. The predictive value of PNI for POD was assessed using receiver operating characteristic curve analysis. RESULTS: In this cohort of 369 patients who underwent hip fracture surgery, 67 patients (18.2%) were diagnosed with POD by the CAM results. Low PNI increased the risk of POD (odds ratio (OR) = 0.928, 95% confidence interval (CI): 0.864-0.997). General anesthesia (OR = 2.307, 95% CI: 1.279-4.162) and Mini-Mental State Examination (MMSE) score (OR = 0.956, 95% CI: 0.920-0.994) were also identified as risk factors for POD. Receiver operating characteristic curve analysis suggested that PNI combined with the anesthetic method and MMSE score may be used as a potential predictive indicator of POD after hip fracture surgery. CONCLUSION: Preoperative PNI value is related to POD in older adult patients with hip fractures. TRIAL REGISTRATION: This secondary analysis study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (approval No. M2022578) and registered in the Chinese Clinical Trial Registry (ChiCTR2300070569).

A Bibliometric Analysis for Low-Intensity Ultrasound Study Over the Past Three Decades.

Low-intensity ultrasound (LI-US) is a non-invasive stimulation technique that has emerged in recent years and has been shown to have positive effects on neuromodulation, fracture healing, inflammation improvement, and metabolic regulation. This study reports the conclusions of a bibliometric analysis of LI-US. Input data for the period between 1995 and 2022, including 7209 related articles in the field of LI-US, were collected from the core library of the Web of Science (WOS) database. Using these data, a set of bibliometric indicators was obtained to gain knowledge on different aspects: global production, research areas, and sources analysis, contributions of countries and institutions, author analysis, citation analysis, and keyword analysis. This study combined the data analysis capabilities provided by the WOS database, making use of two bibliometric software tools: R software and VOS viewer to achieve analysis and data exploration visualization, and predicted the further development trends of LI-US. It turns out that the United States and China are co-leaders while Zhang ZG is the most significant author in LI-US. In the future, the hot spots of LI-US will continue to focus on parameter research, mechanism discussion, safety regulations, and neuromodulation applications.

Hundred most cited articles in perioperative neurocognitive disorder: a bibliometric analysis.

BACKGROUND: In line with aging populations and increased application of anesthesia and surgery, perioperative neurocognitive disorder (PND) has received growing attention worldwide. Considerable researches into PND are being conducted; however, the quantity and quality of such researches have not been reported. Through a retrospective bibliometric analysis, this study aims to identify and characterize the top 100 cited publications on PND. METHODS: We searched the Web of Science database to find the top 100 cited articles focusing on PND. We collected bibliographic information, including year of publication, country of origin, article type, published journal, citation count, and authorship. To determine changes with time, we compared older and newest articles. RESULTS: The top 100 cited articles were published between 1955 and 2016; the number of citations ranged from 111 to 1248. The United States had the most published papers; clinical trial was the most common article type. The specialty journals of Anesthesiology and Anesthesia & Analgesia were the two most cited journals. Newest articles had a comparable number of citations to older articles, but the former had higher annual citation rates, greater funding disclosures, more focus on basic research, and more open access publications. CONCLUSIONS: This study provides a comprehensive overview of the most cited articles and highlights the increasing attention on PND. High-quality clinical trials with a greater journal impact factor receive more citations. However, there has been a growth in the number of basic science studies as an area of research with respect to the pathogenesis of PND.

A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1-7)/MasR axis.

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.

Rapamycin Affects the Hippocampal SNARE Complex to Alleviate Cognitive Dysfunction Induced by Surgery in Aged Rats.

Delayed neurocognitive recovery (dNCR) is a common complication that occurs post-surgery, especially in elderly individuals. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex plays an essential role in various membrane fusion events, such as synaptic vesicle exocytosis and autophagosome-lysosome fusion. Although SNARE complex dysfunction has been observed in several neurodegenerative disorders, the causal link between SNARE-mediated membrane fusion and dNCR remains unclear. We previously demonstrated that surgical stimuli caused cognitive impairment in aged rats by inducing α-synuclein accumulation, inhibiting autophagy, and disrupting neurotransmitter release in hippocampal synaptosomes. Here, we evaluated the effects of propofol anesthesia plus surgery on learning and memory and investigated levels of SNARE proteins and chaperones in hippocampal synaptosomes. Aged rats that received propofol anesthesia and surgery exhibited learning and memory impairments in a Morris water maze test and decreased levels of synaptosome-associated protein 25, synaptobrevin/vesicle-associated membrane protein 2, and syntaxin 1. Levels of SNARE chaperones, including mammalian uncoordinated-18, complexins 1 and 2, cysteine string protein-α, and N-ethylmaleimide-sensitive factor, were all significantly decreased following anesthesia with surgical stress. However, the synaptic vesicle marker synaptophysin was unaffected. The autophagy-enhancer rapamycin attenuated structural and functional disturbances of the SNARE complex and ameliorated disrupted neurotransmitter release. Our results indicate that perturbations of SNARE proteins in hippocampal synaptosomes may underlie the occurrence of dNCR. Moreover, the protective effect of rapamycin may partially occur through recovery of SNARE structural and functional abnormalities. Our findings provide insight into the molecular mechanisms underlying dNCR.

Preoperative serum ribose concentrations may be associated with postoperative delirium in older patients with a hip fracture.

BACKGROUND: Postoperative delirium (POD) is a common postoperative neurocognitive complication, especially in older patients. However, satisfactory biomarkers for predicting individual risks of POD have not been confirmed. D-ribose involvement in protein glycation and aggregation plays a pivotal role in age-related neurodegenerative disorders such as Alzheimer's disease. OBJECTIVES: This study aimed to determine whether serum D-ribose concentrations contribute to the early diagnosis of POD. We also discuss the probable mechanisms underlying the development of POD. METHODS: 110 older patients with hip fracture who had undergone internal fixation or hip replacement under general anesthesia and had completed our assessments were selected. Preoperative venous blood (4 ml) was collected before the induction of anesthesia. Postoperative venous blood was obtained at 07:00 and 20:00 h on postoperative day 1 and at 20:00 h on postoperative day 2. On the first 2 postoperative days, the patients were assessed twice daily (at 8:00 and 20:00 h on each day) using the Confusion Assessment Method-Chinese Revision. RESULTS: 15 patients were finally diagnosed with POD. We also included 15 patients without POD who were matched with the recruited patients with POD (1:1) on the basis of age, sex, body mass index and the Mini-Mental State Examination score. Serum ribose concentrations were measured by high-performance liquid chromatography. The demographic characteristics of the groups were matched. Preoperative serum ribose concentrations were significantly higher in patients with POD than in those without POD (p < 0.05) and were also an independent risk factor for POD. Moreover, when the preoperative serum ribose concentration doubled, the risk of POD increased by 1.672 times. CONCLUSIONS: These results indicate that the serum D-ribose concentration may be a potential predictive molecular biomarker for POD, and provide useful information for further pathological mechanism studies.

Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.

INTRODUCTION: Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of postoperative delayed neurocognitive recovery (dNCR). Mitochondria exist in a dynamic equilibrium that involves fission and fusion to regulate morphology and maintains normal cell function via the removal of damaged mitochondria through mitophagy. Nonetheless, the relationship between mitochondrial morphology and mitophagy, and how they influence mitochondrial function in the development of postoperative dNCR, remains poorly understood. Here, we observed morphological alterations of mitochondria and mitophagy activity in hippocampal neurons and assessed the involvement of their interaction in dNCR following general anesthesia and surgical stress in aged rats. METHODS: Firstly, we evaluated the spatial learning and memory ability of the aged rats after anesthesia/surgery. Hippocampal mitochondrial function and mitochondrial morphology were detected. Afterwards, mitochondrial fission was inhibited by Mdivi-1 and siDrp1 in vivo and in vitro separately. We then detected mitophagy and mitochondrial function. Finally, we used rapamycin to activate mitophagy and observed mitochondrial morphology and mitochondrial function. RESULTS: Surgery impaired hippocampal-dependent spatial learning and memory ability and caused mitochondrial dysfunction. It also increased mitochondrial fission and inhibited mitophagy in hippocampal neurons. Mdivi-1 improved mitophagy and learning and memory ability of aged rats by inhibiting mitochondrial fission. Knocking down Drp1 by siDrp1 also improved mitophagy and mitochondrial function. Meanwhile, rapamycin inhibited excessive mitochondrial fission and improved mitochondrial function. CONCLUSION: Surgery simultaneously increases mitochondrial fission and inhibits mitophagy activity. Mechanistically, mitochondrial fission/fusion and mitophagy activity interact reciprocally with each other and are both involved in postoperative dNCR. These mitochondrial events after surgical stress may provide novel targets and modalities for therapeutic intervention in postoperative dNCR.

Low-Intensity Pulsed Ultrasound Attenuates Postoperative Neurocognitive Impairment and Salvages Hippocampal Synaptogenesis in Aged Mice.

Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.

Protective effect of vitamin C on DNA damage in surgery-induced cognitive dysfunction in APP/PS1 mice.

Postoperative cognitive impairment is more likely to occur in elderly patients and in those with neurodegenerative diseases. The mechanisms underlying this impairment include neuroinflammation and oxidative stress. The increase in reactive oxygen species during oxidative stress causes cellular and molecular injury to neurons, including DNA damage, which aggravate brain dysfunction. Vitamin C has antioxidant effects and improves cognitive function in patients with Alzheimer's disease. However, it is unclear whether it can ameliorate surgery-induced cognitive impairment by inhibiting oxidative stress. In this study, 6-month-old mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were subjected to laparotomy. The open field and fear conditioning tests were used to assess cognitive function. Mice that underwent surgery showed cognitive impairment without changes in spontaneous locomotor activity. Oxidative stress, DNA damage and inflammatory mediators were increased in the hippocampus after surgery. The expression levels of non-homologous end-joining DNA repair-associated proteins, including Ku heterodimer, DNA-dependent protein kinase catalytic subunit, X-ray repair cross complementing 4 (XRCC4) and XRCC4-like factor, were increased after surgery. Vitamin C pretreatment effectively attenuated cognitive dysfunction induced by surgery and reduced oxidative stress and DNA damage. Our findings suggest that DNA damage plays an important role in surgery-induced cognitive dysfunction, and that vitamin C pretreatment may have therapeutic potential as a preventative approach for the cognitive impairment.

Type 2 Diabetes Mellitus with Tight Glucose Control and Poor Pre-Injury Stair Climbing Capacity May Predict Postoperative Delirium: A Secondary Analysis.

(1) Background: Previous evidence demonstrates that tight glycemic control and good physical function could reduce the risk of delirium. This study aimed to investigate whether the occurrence of postoperative delirium (POD) in older hip fracture surgery patients is associated with preoperative glycemic control factors or pre-injury physical performance. (2) Methods: Three-hundred and nine individuals aged over 65 years and scheduled for hip fracture surgery were included at a single center. Glycemic control factors and pre-injury physical performance were assessed preoperatively. The presence of delirium was assessed using the Confusion Assessment Method on postoperative hospitalization days. Univariate and multivariable logistic regression models and a risk prediction model of POD were established. (3) Results: Among the 309 patients, 52 (16.83%) experienced POD during the hospital stay. The numbers of pre-injury physical performance and type 2 diabetes mellitus (T2DM) patients were significantly different in the POD and non-POD groups. The multivariable model showed that development of delirium was significantly explained by preoperative fasting blood glucose (FBG) (OR 0.804, p = 0.004), stair climbing (OR 0.709, p = 0.003), T2DM (odds ratio (OR) 3.654, p = 0.001), and age-adjusted Charlson comorbidity index (ACCI) (OR 1.270, p = 0.038). The area under the receiver operating characteristic curve (AUROC) of the risk prediction model including those covariates was 0.770. (4) Conclusions: More older T2DM patients develop POD after hip fracture surgery than patients without T2DM. A simple assessment of preoperative FBG and pre-injury stair climbing capacity may identify those at high risk for the development of POD. Higher preoperative FBG and good pre-injury stair climbing capacity are protective factors for POD.

Identification of Serum Biomarkers Associated With Emergence Agitation After General Anesthesia in Adult Patients: A Metabolomics Analysis.

Background: Emergence agitation (EA) is a conscious disturbance after general anesthesia in adult patients that can lead to severe respiratory or circulatory complications and serious physical injury to patients and caregivers. However, the pathophysiological mechanisms underlying EA remain unclear. The present study aimed to identify serum metabolites with significant alterations in EA patients after general anesthesia and enable inferences on their associations with EA. Methods: EA patients were identified by Richmond Agitation-Sedation Scale (RASS) ≥ + 2 among a cohort of adult patients who received elective surgery under general anesthesia in Peking University Third Hospital between 01 June 2020 and 30 December 2020. We further selected sex-, age-, and surgery type-matched non-EA control patients at a 1:1.5 ratio. Postoperative serum samples were collected from both groups of patients. An untargeted metabolic method was used to identify differences in serum metabolomic profiles between the EA patients and the non-EA patients. Results: A total of 19 EA patients and 32 matched non-EA patients were included in the study. After screening and mapping with a database, 12 metabolites showed significant postoperative alterations in EA patients compared with non-EA patients, and were mainly involved in lipid, fatty acid and amino acid metabolism pathways. Receiver operating characteristic curve analyses indicated that vanillic acid, candoxatril, tiglylglycine, 5-methoxysalicylic acid, decanoylcarnitine, and 24-epibrassinolide may be involved in EA pathogenesis after general anesthesia. Conclusion: In this study, we found differences in the serum levels of vanillic acid, candoxatril, tiglylglycine, 5-methoxysalicylic acid, decanoylcarnitine, and 24-epibrassinolide involved in fatty acid metabolism, lipid metabolism, and amino acid metabolism pathways in EA patients compared with non-EA patients, which may demonstrate an EA pathogenesis-associated molecular pattern and contribute toward better understanding of EA occurrence.

JNK inhibition alleviates delayed neurocognitive recovery after surgery by limiting microglia pyroptosis.

Delayed neurocognitive recovery (dNCR) is a prevalent complication after surgery in older adults. Neuroinflammation plays a pivotal role in the pathogenesis of dNCR. Recently,compelling evidence suggests that theinvolvement of microglia pyroptosis in the regulation of neuroinflammation in neurologicaldiseases. Nevertheless, the exact role of microglia pyroptosis in dNCR remains elusive. In the study, in vitro and in vivo models of dNCR were used to examine the potential effects of the mitogen­activated protein kinase signaling pathway on Nod-like receptor protein 3 (NLRP3) inflammasome-mediated microglia pyroptosis and cognitive deficits following surgery. In vivo, we observed surgery-induced upregulation of phosphorylated (p)-c-Jun N-terminal kinases (JNK) in microglia and subsequently NLRP3 inflammasome activation, pyroptosis, and inflammatory cytokines release in mice hippocampus. Interestingly, JNK inhibitor SP600125 significantly attenuated surgery-induced cognitive impairments through inhibiting pyroptosis, inflammatory responses, and reducing immunoreactivity of NLRP3 and gasdermin D N terminus (GSDMD-N) in hippocampal microglia. In vitro, NLRP3 inflammasome- and pyroptosis-associated proteins and immunoreactivity of NLRP3, GSDMD-N, and interleukin-1ß were activated in BV2 microglial cells following lipopolysaccharide (LPS) stimulation. These effects were significantly suppressed in BV2 cells by SP600125 treatment. Furthermore, treatment with NLRP3 specific inhibitor, MCC950, attenuated microglia pyroptosis induced by LPS, but did not rescue LPS-induced increased expression of p-JNK. These results indicate that the JNK pathway is largely upstream of the NLRP3 inflammasome, which exerts a crucial regulatory impact on microglia pyroptosis and inflammatory responses, thus providing a promising avenue to prevent dNCR.

Cholecystokinin octapeptide improves hippocampal glutamatergic synaptogenesis and postoperative cognition by inhibiting induction of A1 reactive astrocytes in aged mice.

AIMS: Delayed neurocognitive recovery (dNCR) is a common postoperative complication in geriatric surgical patients for which there is no efficacious therapy. Cholecystokinin octapeptide (CCK-8), an immunomodulatory peptide, regulates memory and learning. Here, we explored the effects and mechanism of action of CCK-8 on dNCR. METHODS: We applied laparotomy to establish a model of dNCR in aged mice. Morris water maze and fear conditioning tests were used to evaluate cognition. Immunofluorescence was used to detect the density of CCK-8, A1 reactive astrocytes, glutamatergic synapses, and activation of microglia in the hippocampus. Quantitative PCR was performed to determine mRNA levels of synapse-associated factors. A1 reactive astrocytes, activated microglia, and glutamatergic synapse-associated protein levels in the hippocampus were assessed by western blotting. RESULTS: Administration of CCK-8 suppressed the activation of microglia, the induction of A1 reactive astrocytes, and the expression of tumor necrosis factor alpha, complement 1q, and interleukin 1 alpha in the hippocampus. Furthermore, it promoted glutamatergic synaptogenesis and neurocognitive recovery in aged dNCR model mice. CONCLUSION: Our findings indicated that CCK-8 alleviated cognitive impairment and promoted glutamatergic synaptogenesis by inhibiting the induction of A1 reactive astrocytes and the activation of microglia. CCK-8 is, therefore, a potential therapeutic target for dNCR.

Predictive Value of Preoperative Profiling of Serum Metabolites for Emergence Agitation After General Anesthesia in Adult Patients.

Background: Emergence agitation (EA) in adult patients under general anesthesia leads to increased postoperative complications and heavy medical burden. Unfortunately, its pathogenesis has not been clarified until now. The purpose of the present study was to explore the relationship between preoperative serum metabolites and EA. Methods: We used an untargeted metabolic analysis method to investigate the different metabolomes in the serum of EA patients and non-EA patients undergoing elective surgical procedures after the induction of general anesthesia. A Richmond Agitation-Sedation Scale score ≥ +2 was diagnosed as EA during postoperative emergence. Non-EA patients were matched with EA patients according to general characteristics. Preoperative serum samples of the two groups were collected to investigate the association between serum metabolites and EA development. Results: The serum samples of 16 EA patients with 34 matched non-EA patients were obtained for metabolic analysis. After screening and alignment with databases, 31 altered metabolites were detected between the two groups. These metabolites were mainly involved in the metabolism of lipids, purines, and amino acids. Analyses of receiver-operating characteristic curves showed that the preoperative alterations of choline, cytidine, glycerophosphocholine, L-phenylalanine, oleamide, and inosine may be associated with adult EA. Conclusion: Multiple metabolic abnormalities (including those for lipids, purines, and amino acids) and other pathological processes (e.g., neurotransmitter imbalance and oxidative stress) may contribute to EA. Several altered metabolites in serum before surgery may have predictive value for EA diagnosis. This study might afford new metabolic clues for the understanding of EA pathogenesis.

Potential Serum Biomarkers for Postoperative Neurocognitive Disorders Based on Proteomic Analysis of Cognitive-Related Brain Regions.

Postoperative neurocognitive disorders (po-NCD), including postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), are common in geriatric surgical patients. However, the ideal diagnostic biomarkers to predict individual risks of po-NCDs have not been identified. In this study, proteomic analysis was used to detect dysregulated proteins in three cognitive-related brain regions, the hippocampus, prefrontal cortex, and temporal lobe, of aged dNCR rats. The common affected proteins in these three brain regions were further verified by real-time polymerase chain reaction and western blotting. Furthermore, serum samples from aged rats with dNCR and elderly hip fracture patients with POD were also assessed with enzyme linked immunosorbent assays to investigate the biomarker potential of these dysregulated proteins. The increased expression levels of haptoglobin, caseinolytic protease (ClpP), and alpha-2 macroglobulin (A2M) as well as decreased expression levels of 14-3-3ß/α and biliverdin reductase-A (BVR-A) were validated by proteomic analysis in the hippocampus, prefrontal cortex, and temporal lobe of aged dNCR rats. The increased expression of haptoglobin and decreased expression of 14-3-3ß/α were further demonstrated in the three brain regions by western blotting. Moreover, increased levels of S100A6 and BVR-A in the hippocampus, S100A6 in the prefrontal cortex, and A2M in the temporal lobe were also observed. More intriguingly, both decreased serum 14-3-3ß/α and increased A2M in geriatric POD patients as well as decreased serum ClpP in aged dNCR rats were verified. These results not only indicate potential diagnostic biomarkers for po-NCD but also provide directions for further pathological investigations. Clinical Trial Registration: www.ClinicalTrials.gov, identifier [ChiCTR1900027393].

Effects of general versus regional anaesthesia on circadian melatonin rhythm and its association with postoperative delirium in elderly patients undergoing hip fracture surgery: study protocol for a prospective cohort clinical trial.

INTRODUCTION: Postoperative delirium (POD) is a common neurological complication after hip fracture surgery and is associated with high morbidity and mortality in elderly patients. Although the specific mechanism of POD remains unclear, circadian rhythm disruptions have recently drawn increased attention. To date, only limited postoperative time points of plasma melatonin level measurements were recorded in previous studies, and such data cannot represent a comprehensive melatonin rhythm. The process of anaesthesia (either general anaesthesia (GA) or regional anaesthesia (RA)) is known to influence the melatonin rhythm. However, how these two anaesthesia methods differently affect the postoperative melatonin rhythm is still unknown. Therefore, we hypothesise that RA may attenuate the disruption of the melatonin rhythm, which might decrease the incidence of POD in elderly patients undergoing hip surgery. METHODS AND ANALYSIS: In this prospective cohort clinical trial, 138 patients scheduled for hip fracture surgery will be divided into two groups to receive either GA or RA. The primary aim is to compare the circadian rhythm of melatonin secretion between the two groups and explore its association with the incidence of POD. ETHICS AND DISSEMINATION: The study has been approved by the Medical Science Research Ethics Committees of Beijing Jishuitan Hospital (JLKS201901-04). The results of the study will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: ChiCTR1900027393.

The Non-peptide Angiotensin-(1-7) Mimic AVE 0991 Attenuates Delayed Neurocognitive Recovery After Laparotomy by Reducing Neuroinflammation and Restoring Blood-Brain Barrier Integrity in Aged Rats.

Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1-7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1-7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1-7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1-7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.

Effects of general versus subarachnoid anaesthesia on circadian melatonin rhythm and postoperative delirium in elderly patients undergoing hip fracture surgery: A prospective cohort clinical trial.

BACKGROUND: Circadian rhythm disturbance is common postoperatively in older patients with hip fractures, which may contribute to the development of postoperative delirium (POD). As a reliable biomarker of endogenous circadian rhythms, melatonin regulates the sleep-wake cycle and environmental adaptation, and its secretory rhythm may be modified by anaesthesia and surgery. This study compared the impact of subarachnoid anaesthesia (SA) and general anaesthesia (GA), on the peak of melatonin secretion (primary outcome), the circadian rhythm of melatonin, cortisol and sleep, and the POD incidence (secondary outcome). METHODS: In this prospective cohort observational study, hip fracture surgery patients were enrolled and assigned to receive either SA or GA. Postoperative plasma melatonin and cortisol levels were dynamically measured every six hours on seven time-points, and the circadian rhythm parameters including mesor, amplitude, and acrophase were calculated. Subjective and objective sleep assessments were performed by sleep diaries and sleep trackers, respectively. The Confusion Assessment Method was used twice daily by a specific geriatrician to screen for POD occurrence. FINDINGS: In a cohort of 138 patients who underwent hip fracture surgery, the circadian rhythm disruption of the patients in the GA group (n=69) was greater than the SA group (n=69). Compared with SA, GA provided the lower peak concentration, mesor, and amplitude of melatonin secretion on postoperative day 1 (p < 0.05). Patients in the GA group experienced higher awakenings, more sleep deprivation, and poor sleep quality on surgery day (p < 0.05). A proportion of 12 patients in the SA group (17.4%) and 24 patients in the GA group (34.8%) experienced POD (p = 0.020). INTERPRETATION: These results suggest that SA may be superior to GA in elderly patients undergoing hip fracture surgery as SA is associated with less impairment of the melatonin rhythm and sleep patterns, and fewer POD occurrences. FUNDING: The study was supported by the National Natural Science Foundation of China (81971012, 81873726, 81901095, 81701052, and 81801070), Key Clinical Projects of Peking University Third Hospital (BYSYZD2019027), and Peking University "Clinical Medicine plus X" Youth Project (PKU2020LCXQ016).

Inhibition of α-Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice.

Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha-synuclein (α-syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus-dependent working memory. Aggregated forms of α-syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α-syn improved both mitochondrial function and mitochondria-dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α-syn (including total α-syn, phosphorylated-Ser129-α-syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery-induced progressive accumulation of various toxic α-syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α-syn accumulation and increased mitochondria-mediated apoptosis in vitro using nerve growth factor-differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α-syn inhibition, we used a lentiviral Snca-shRNA (Lv-shSnca) to knockdown Snca. Of note, Lv-shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α-syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α-syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α-syn for dNCR.