Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice.

Perioperative neurocognitive disorder (PND) is a serious neurologic complication in aged patients and might be associated with sevoflurane exposure. However, the specific pathogenesis is still unclear. The distribution of α5-GABAAR, a γ-aminobutyric acid type A receptor (GABAAR) subtype, at extrasynaptic sites is influenced by the anchor protein radixin, whose phosphorylation is regulated via the RhoA/ROCK2 signaling pathway and plays a crucial role in cognition. However, whether sevoflurane affects the ability of radixin phosphorylation to alter extrasynaptic receptor expression is unknown. Aged mice were exposed to sevoflurane to induce cognitive impairment. Both total proteins and membrane proteins were extracted for analysis. Cognitive function was evaluated using the Morris water maze and fear conditioning test. Western blotting was used to determine the expression of ROCK2 and the phosphorylation of radixin. Furthermore, the colocalization of p-radixin and α5-GABAAR was observed. To inhibit ROCK2 activity, either an adeno-associated virus (AAV) or fasudil hydrochloride was administered. Aged mice treated with sevoflurane exhibited significant cognitive impairment accompanied by increased membrane expression of α5-GABAAR. Moreover, the colocalization of α5-GABAAR and p-radixin increased after treatment with sevoflurane, and this change was accompanied by an increase in ROCK2 expression and radixin phosphorylation. Notably, inhibiting the RhoA/ROCK2 pathway significantly decreased the distribution of extrasynaptic α5-GABAAR and improved cognitive function. Sevoflurane activates the RhoA/ROCK2 pathway and increases the phosphorylation of radixin. Excess α5-GABAAR is anchored to extrasynaptic sites and impairs cognitive ability in aged mice. Fasudil hydrochloride administration improves cognitive function.

CLEC4D as a Novel Prognostic Marker Boosts the Proliferation and Migration of Gastric Cancer via the NF-κB/AKT Signaling Pathway.

Purpose: The functions of C-type lectin domain family 4 member D (CLEC4D), one member of the C-type lectin/C-type lectin-like domain superfamily, in immunity have been well described, but its roles in cancer biology remain largely unknown. Patients and Methods: This study aims to explore the role of CLEC4D in gastric cancer (GC). Bioinformatics preliminarily analyzed the expression of CLEC4D in gastric cancer. Immunohistochemical staining was used to detect the expression level and clinical pathological characteristics of CLEC4D in gastric cancer. The biological function of CLEC4D in gastric cancer cell lines was verified through in vitro and in vivo experiments. Results: In this study, CLEC4D expression was found to be markedly increased in gastric cancer (GC) tissues compared with matched normal gastric tissues, and high CLEC4D expression independently predicted unfavorable overall survival in patients with GC. Knockdown of CLEC4D markedly inhibited GC cell proliferation and migration. Mechanistically, CLEC4D knockdown deactivated the Akt and NF-κB signaling pathways in GC cells. Conclusion: Together, these results demonstrate that aberrantly increased CLEC4D expression promotes cancer phenotypes via the Akt and NF-κB signaling pathways in GC cells.

The changing of α5-GABAA receptors expression and distribution participate in sevoflurane-induced learning and memory impairment in young mice.

BACKGROUND: Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5-GABAAR. METHODS: Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%-3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL-6 24 h post-anesthesia. Western blot and RT-PCR were performed to measure the levels of α5-GABAAR, Radixin, P-ERM, P-Radixin, Gephyrin, IL-6, and ROCK. The spatial distribution and expression of α5-GABAAR on neuronal somata were analyzed using histological and three-dimensional imaging techniques. RESULTS: MWM test indicated that partial long-term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL-6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5-GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5-GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5-GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra-synaptic space, the expression level of α5-GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel. CONCLUSION: Dysregulated α5-GABAAR expression and distribution contributes to sevoflurane-induced partial long-term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies.

Different Endotracheal Intubations for Non-Small Cell Lung Cancer Surgery: A Retrospective-Case-Matched Study on Postoperative Complications and Quality of Life.

BACKGROUND: Lung isolation and separation is still controversial in thoracic surgery. Preferences of the surgeon can drive the decision to use single- vs. double-lumen endotracheal intubation. We aimed to compare complications and quality of life (QOL) after radical lung cancer resection with a single-lumen tube (ST) and a double-lumen tube (DT) for patients with non-small cell lung cancer (NSCLC). METHODS: A total of 309 patients who underwent radical lung cancer resection with video-assisted thoracoscopy-lobectomy were subsequently included in the study. Based on the type of endotracheal intubation tube used during surgery, we divided all the patients into a single-lumen tube group (ST-G) and double-lumen tube group (DT-G). Then, we applied propensity score matching (1:1) to balance the baseline characteristics between the two groups. The Analysis of Variance (ANOVA) of two-factor repeated measures data was performed to compare postoperative complications at three and six months after surgery and postsurgical QOL at baseline at one month, three months, six months, and twelve months. RESULTS: Within three months after surgery, patients in the ST-G presented less cough symptoms in Lung Cancer Symptom Scale (LCSS), lower cough symptom scores (CSS) (one month and three months, p < 0.05) and better performance of Leicester Cough Questionnaire (LCQ) scores in physical part (one month, three months and six months, p < 0.05) with better overall QOL (one month and three months, p < 0.05) than those in the DT-G. CONCLUSIONS: Patients with STs displayed less postoperative cough symptoms and higher overall QOL than those with DTs. Although DT is the gold standard for thoracic surgeries, we suggest that postoperative cough symptoms should be given sufficient attention by surgeons.

Hydrogen prevents lipopolysaccharide-induced pulmonary microvascular endothelial cell injury by inhibiting store-operated Ca2+ entry regulated by STIM1/Orai1.

BACKGROUND: Sepsis is a type of life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The lung is the most vulnerable target organ under septic conditions. Pulmonary microvascular endothelial cells (PMVECs) play a critical role in acute lung injury (ALI) caused by severe sepsis. The impairment of PMVECs during sepsis is a complex regulatory process involving multiple mechanisms, in which the imbalance of calcium (Ca2+) homeostasis of endothelial cells is a key factor in its functional impairment. Our preliminary results indicated that hydrogen gas (H2) treatment significantly alleviates lung injury in sepsis, protects PMVECs from hyperpermeability, and decreases the expression of plasma membrane stromal interaction molecule 1 (STIM1), but the underlying mechanism by which H2 maintains Ca2+ homeostasis in endothelial cells in septic models remains unclear. Thus, the purpose of the present study was to investigate the molecular mechanism of STIM1 and Ca2+-release-activated- Ca2+ channel protein1 (Orai1) regulation by H2 treatment and explore the effect of H2 treatment on Ca2+ homeostasis in lipopolysaccharide (LPS)-induced PMVECs and LPS-challenged mice. METHODS: We observed the role of H2 on LPS-induced ALI of mice in vivo. The lung wet/dry (W/D) weight ratio, total protein in the bronchoalveolar lavage (BAL) fluid and Evans blue dye (EBD) assay were used to evaluate the pulmonary endothelial barrier damage of LPS-challenged mice. The expression of STIM1 and Orai1 were also detected using epifluorescence microscopy. Moreover, we also investigated the role of H2- rich medium in regulating PMVECs under LPS treatment, which induced injury similar to sepsis in vitro. The expression of STIM1 and Orai1 as well as the Ca2+ concentration in PMVECs were examined. RESULTS: In vivo, we found that H2 alleviated ALI of mice through decreasing lung W/D weight ratio, total protein in the BAL fluid and permeability of lung. In addition, H2 also decreased the expression of STIM1 and Orai1 in pulmonary microvascular endothelium. In vitro, LPS treatment increased the expression levels of STIM1 and Orai1 in PMVECs, while H2 reversed these changes. Furthermore, H2 ameliorated Ca2+ influx under sepsis-mimicking conditions. Treatment with the sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA) inhibitor, thapsigargin (TG), resulted in a significant reduction in cell viability as well as a reduction in the expression of junctional proteins, including VE-cadherin and occludin. Treatment with the store-operated Ca2+ entry (SOCE) inhibitor, YM-58483 (BTP2), increased the cell viability and expression of junctional proteins. CONCLUSIONS: The present study suggested that H2 treatment alleviates LPS-induced PMVEC dysfunction by inhibiting SOCE mediated by STIM1 and Orai1 in vitro and in vivo.

Effect of postoperative application of esketamine on postoperative depression and postoperative analgesia in patients undergoing pancreatoduodenectomy: a randomized controlled trial protocol.

BACKGROUND: Pancreatoduodenectomy (PD) is traumatic, difficult to perform, and has a high incidence of postoperative complications and perioperative mortality. Postoperative complications and pain occur frequently and seriously affect the psychological status of patients. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has analgesic and antidepressant effects. In this study, we aim to investigate the effect of esketamine on postoperative depression and pain in patients undergoing PD. METHODS/DESIGN: This prospective, single-center, randomized control trial will include 80 patients who will undergo elective PD. The patients will be randomly assigned to two groups: the experimental group that will receive esketamine (n = 40) and the control group (n = 40). In the esketamine group, the analgesic pump will be connected immediately after surgery. A solution of esketamine 1.5 mg/kg + sufentanil 2 µg/kg, diluted to 150 mL, will be administered continuously for 72 h at the background infusion and impact doses of 1 mL/h and 2 mL/time, respectively; the locking time will be 10 min. The control group will receive sufentanil 2 µg/kg that will be administered as per the esketamine group. The primary outcome will be the Hamilton Depression Scale (HAMD-17) score on the third day post-surgery (POD3). Secondary study indicators will include (1) visual analog scale (VAS) score and HAMD-17 score prior to surgery, immediately after entering the postanesthesia care unit (PACU) and 1, 2, 3, 4, and 5 days after surgery; (2) Richmond Agitation-Sedation Scale (RASS) score at 1, 2, 3, 4, and 5 days after surgery; (3) consumed doses of sufentanil and esketamine after surgery; (4) postoperative analgesia pump effective press times, rescue analgesia times, and rescue drug dosage, recording the number of rescue analgesia and rescue drug dosage at 6, 24, 48, and 72 h after the patient enters the PACU; (5) postoperative complications and adverse events; (6) postoperative hospital stay; (7) concentrations of brain-derived neurotrophic factor (BDNP), 5-hydroxytryptamine (5-HT), tumor necrosis factor (TNF-α) and interleukin-6, at 1, 3, and, 5 days post-surgery; and (8) the patient survival rate at 6 and 12 months post-surgery. DISCUSSION: The study hypothesis is that the postoperative HAMD-17 and VAS scores, incidence of postoperative adverse reactions, and concentration of serum markers BDNP, 5-HT, TNF-α, and IL-6 in the experimental group will be lower than those in the control group. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR2200066303. Registered on November 30, 2022. PROTOCOL VERSION: 1.0.

Crosstalk Between Peripheral Innervation and Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.

The prediction of postoperative delirium with the preoperative bispectral index in older aged patients: a cohort study.

BACKGROUND: Postoperative delirium (POD) is the most common postoperative complication in elderly patients, especially in older aged patients (aged 75 years or over). The development of electroencephalography analysis could provide indicators for early detection, intervention, and evaluation. If there are pathophysiological changes in the brain, the BIS value will also change accordingly. In this study, we investigated the predictive value of the preoperative bispectral (BIS) index in POD for patients aged over 75 years. METHODS: In this prospective study, patients (≥ 75 years) undergoing elective non-neurosurgery and non-cardiac surgery under general anesthesia were included (n = 308). Informed consent was obtained from all involved patients. Before the operation and during the first 5 postoperative days, delirium was assessed with the confusion assessment method by trained researchers twice every day. Thereafter, the preoperative bedside BIS of each patient was dynamically acquired by the BIS VISTA monitoring system and the BIS monitoring of electrodes. A series of evaluation scales were assessed before and after surgery. A preoperative predictive score was generated according to the results of multivariable logistic regression. The receiver operating characteristic curves were drawn and the area under the curves was estimated to evaluate the perioperative diagnostic values of BIS and preoperative predictive score for POD. The specificity, sensitivity, positive predictive value (PPV), and negative predictive (NPV) value were calculated. RESULTS: Delirium occurred in 50 of 308 (16.2%) patients. The median BIS of delirious patients was 86.7 (interquartile range [IQR] 80.0-94.0), lower than that of the non-delirious 91.9 (IQR 89.7-95.4, P < 0.001). According to the ROC curve of the BIS index, the optimal cut-off value was 84, with a sensitivity of 48%, specificity of 87%, PPV 43%, NPV 89% for forecasting POD and the area under curves was 0.67. While integrating BIS, mini-mental state examination, anemia, activities of daily living, and blood urea nitrogen, the model had a sensitivity of 78%, specificity of 74%, PPV of 0.37%, and NPV of 95% for forecasting POD, and the area under curves was 0.83. CONCLUSIONS: Preoperative bedside BIS in delirium patients was lower than that in non-delirium patients when undergoing non-neurosurgery and non-cardiac surgery in patients aged over 75. The model of integrating BIS, mini-mental state examination, anemia, activities of daily living, and blood urea nitrogen is a promising tool for predicting postoperative delirium in patients aged over 75.

Dual roles of anesthetics in postoperative cognitive dysfunction: Regulation of microglial activation through inflammatory signaling pathways.

Postoperative cognitive dysfunction (POCD) is a prevalent clinical entity following surgery and is characterized by declined neurocognitive function. Neuroinflammation mediated by microglia is the essential mechanism of POCD. Anesthetics are thought to be a major contributor to the development of POCD, as they promote microglial activation and induce neuroinflammation. However, this claim remains controversial. Anesthetics can exert both anti- and pro-inflammatory effects by modulating microglial activation, suggesting that anesthetics may play dual roles in the pathogenesis of POCD. Here, we review the mechanisms by which the commonly used anesthetics regulate microglial activation via inflammatory signaling pathways, showing both anti- and pro-inflammatory properties of anesthetics, and indicating how perioperative administration of anesthetics might either relieve or worsen POCD development. The potential for anesthetics to enhance cognitive performance based on their anti-inflammatory properties is further discussed, emphasizing that the beneficial effects of anesthetics vary depending on dose, exposure time, and patients' characteristics. To minimize the incidence of POCD, we recommend considering these factors to select appropriate anesthetics.

Motilin and its receptor are expressed in the dorsal horn in a rat model of acute incisional pain: Intrathecal motilin injection alleviates pain behaviors.

Aims: To observe the effects of intrathecal administration of motilin on pain behavior and expression of motilin (MTL)/motilin receptor (MTLR) in the spinal cord of a rat model of acute incisional pain. Methods: An incisional pain model was established in rats using a unilateral plantar incision. The rats were also injected intrathecally with 1, 5, or 25 µg of motilin. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were determined. MTL/MTLR expression in the spinal cord was detected by western blotting and immunofluorescence. The expression of MTL in the spinal cord, stomach, duodenum, and plasma was determined by enzyme-linked immunosorbent assay (ELISA). Results: Motilin/motilin receptor were detected in the spinal cord. Spinal cord MTL/MTLR expression peaks at 2 h after modeling (P < 0.05) and start to decrease at 24 h (P < 0.05) to almost reach baseline levels at 72 h. The changes in gastric, duodenal, plasma, and spinal cord motilin levels correlated with MWT and TWL (all R 2 > 0.82). The intrathecal injection of 1, 5, or 25 µg of motilin could increase the pain threshold of rats with incisional pain within 72 h in a dose-dependent manner. Conclusion: This study showed for the first time that MTL/MTLR are expressed in rats' spinal dorsal horn. Acute pain increased MTL/MTLR expression in the spinal dorsal horn. Also, for the first time, this study showed that motilin intrathecal injection alleviates pain in rat models of acute incisional pain. These results suggest that MTL/MTLR could be a novel target for the management of acute pain.

ALKBH5 ALLEVIATES HYPOXIA POSTCONDITIONING INJURY IN d -GALACTOSE-INDUCED SENESCENT CARDIOMYOCYTES BY REGULATING STAT3.

ABSTRACT: Ischemic postconditioning (I/Post) reduces I/R injury by activating endogenous cardioprotection mechanisms, such as the JAK/signal transducer and activator of transcription 3 (STAT3) and PI3K/Akt pathways, which offer a traditional approach to myocardial protection. According to a previous study, cardioprotection by I/Post may be lost in aged mice, and in our previous research, hypoxic postconditioning (H/Post) lacked a protective effect in senescent cardiomyocytes, which was associated with low expression of long noncoding RNA H19. The N6-methyladenosine (m 6 A) modification is a dynamic and reversible process that has been confirmed to play a role in cardiovascular diseases. However, the mechanisms of m 6 A modification in myocardial I/Post remain to be explored. Neonatal cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats, and senescence was induced by d -galactose, followed by stimulation of hypoxia-reoxygenation and H/Post. Hypoxic injury was evaluated by cell viability and the Bcl-2/Bax protein ratio. Total m 6 A levels were measured using a colorimetric m 6 A RNA Methylation Quantification Kit, and the m 6 A modified and differentially expressed mRNA was determined by MeRIP (methylated RNA immunoprecipitation). We found that H/Post increased m 6 A methylation and decreased RNA mA demethylase alkB homolog 5 (ALKBH5) expression in aged cardiomyocytes. Furthermore, ALKBH5 knockdown exacerbated injury following H/Post in senescent cardiomyocytes. In addition, ALKBH5 regulated STAT3 expression by mediating its m 6 A modification and long noncoding RNA H19/miR-124-3p. ALKBH5 also alleviated the H/Post injury induced by the low expression of STAT3 in senescent cardiomyocytes.

Video-assisted thoracoscopic tracheal resection with only endobronchial intubation.

We report a case of video-assisted thoracoscopic surgery (VATS) tracheal resection and running suture anastomosis with only endobronchial intubation in a patient with adenoid cystic carcinoma (ACC). The tumor extended 3.2 × 1.9 cm in the distal trachea, and the distance to carina was 2 cm. Running suture anastomosis around the endobronchial tube was performed. No cross-field intubation was needed. The postoperative course was good and no complication occurred. VATS tracheal resection and running suture anastomosis with only endobronchial intubation is a feasible option for patients with distal tracheal tumor.

Myocardial protection of propofol on apoptosis induced by anthracycline by PI3K/AKT/Bcl-2 pathway in rats.

Background: The release of proinflammatory cytokines is inhibited by propofol, which could reduce oxidative stress and suggests that propofol could ameliorate the adverse effects of anthracyclines in myocardial cells as a promising cardioprotective agent. The aim of the study was to evaluate the protective effects of propofol on phosphatidylinositol 3 kinase/protein kinase B/B cell lymphoma 2 (PI3K/AKT/Bcl-2) pathway in cardiomyocyte apoptosis induced by doxorubicin [adriamycin (ADM)] of rat cardiomyocytes in vivo. Methods: The 40 F344 female rats were randomly divided into 4 groups (n=10): treatment control, ADM, Propofol (Prop) and ADM + Prop group. Blood samples were taken as baseline, before the 4th administration of the agents and before humane death. The serum levels of malondialdehyde (MDA), an oxidant factor, were detected by the thiobarbituric acid method. Superoxide dismutase (SOD) levels were analyzed by xanthine oxidase, and those of cardiac troponin I (cTnI), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) were analyzed by enzyme linked immunosorbent assay (ELISA). Apoptosis of cardiac myocytes was measured by flow cytometry. The expression levels of PI3K-110α and pAKT-Ser473 and Bcl-2 proteins in rat heart tissue were detected by western blot. Results: Apoptosis induced by ADM was significantly reduced by propofol. Compared with the ADM group, the serum levels of MDA, cTnI and BNP in the ADM + Prop group were significantly downregulated. In addition, the PI3K-110α and pAKT-Ser473 expressions in the ADM group were significantly higher than those in the ADM + Prop group, and the increases in Bcl-2 expression in the ADM + Prop group was statistically significant compared with the ADM group. Conclusions: We identified that the PI3K/AKT/Bcl-2 axis is involved in the regulation of cardiomyocyte apoptosis induced by ADM in vivo. In addition, our results elucidated that propofol had a protective role in cardiomyocyte apoptosis induced by ADM by suppressing the PI3K/AKT/Bcl-2 pathway.

The expression of HOXC10 is correlated with tumor-infiltrating immune cells in basal-like breast cancer and serves as a prognostic biomarker.

Background: Homeobox gene C10 (HOXC10) plays a vital role in the occurrence and development of several cancers, but its effects and underlying mechanism in the prognosis of different subtypes of breast cancer remain unclear. Methods: First, we evaluated and compared the expression levels of HOXC10 cancer to normal tissues in the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. Second, the correlation between HOXC10 and the survival of patients with different types of cancer, including breast cancer, was analyzed in the PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan-Meier plotter databases. Finally, the relationship between HOXC10 and immune-infiltration levels or gene marker sets of immune cells in basal-like breast cancer (BLBC) was investigated in the TIMER and GEPIA databases. Results: The expression of HOXC10 was elevated in breast cancer tissues. High HOXC10 expression indicated a poor prognosis for breast cancer patients, and expression affected the survival time of lymph-node positive or grade III breast cancer patients. In BLBC, the median overall survival (OS) of patients with high HOXC10 expression was significantly shorter than that of patients with low HOXC10 expression. HOXC10 was positively correlated with the immune infiltration of macrophages in BLBC. Breast cancer patients with low HOXC10 expression in different enriched immune-cell subgroups had a favorable prognosis. Conclusions: The level of HOXC10 expression increased significantly in breast cancer, and elevated HOXC10 was positively correlated with immune-cell infiltration and poor prognosis in BLBC. These findings shed light on the important role of HOXC10 in breast cancer. HOXC10 should be recognized as a prognostic biomarker for determining prognosis and immune infiltration in BLBC patients.

Diminazen Aceturate Protects Pulmonary Ischemia-Reperfusion Injury via Inhibition of ADAM17-Mediated Angiotensin-Converting Enzyme 2 Shedding.

Lung ischemia-reperfusion (IR) injury is induced by pulmonary artery occlusion and reperfusion. Lung IR injury commonly happens after weaning from extracorporeal circulation, lung transplantation, and pulmonary thromboendarterectomy; it is a lethal perioperative complication. A definite therapeutic intervention remains to be determined. It is known that the enzyme activity of angiotensin-converting enzyme 2 (ACE2) is critical in maintaining pulmonary vascular tone and epithelial integrity. In a noxious environment to the lungs, inactivation of ACE2 is mainly due to a disintegrin and metalloprotease 17 (ADAM17) protein-mediated ACE2 shedding. Thus, we assumed that protection of local ACE2 in the lung against ADAM17-mediated shedding would be a therapeutic target for lung IR injury. In this study, we established both in vivo and in vitro models to demonstrate that the damage degree of lung IR injury depends on the loss of ACE2 and ACE2 enzyme dysfunction in lung tissue. Treatment with ACE2 protectant diminazen aceturate (DIZE) maintained higher ACE2 enzyme activity and reduced angiotensin II, angiotensin type 1 receptor, and ADAM17 levels in the lung tissue. Concurrently, DIZE-inhibited oxidative stress and nitrosative stress via p38MAPK and NF-κB pathways consequently reduced release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ß. The underlying molecular mechanism of DIZE contributed to its protective effect against lung IR injury and resulted in the improvement of oxygenation index and ameliorating pulmonary pathological damage. We concluded that DIZE protects the lungs from IR injury via inhibition of ADAM17-mediated ACE2 shedding.

Intracranial electroencephalography features of young and old mice under midazolam administration.

Understanding the electroencephalography features of young and old patients treated with anesthetic drugs is important to allow accurate drug use in elderly patients. This study aimed to monitor the intracranial electroencephalography (in the cortex and hippocampus) in free-moving young and old mice under midazolam administration. Behavioral assessment revealed that compared with young mice, old mice had a longer immobility time with a similar midazolam dose. In both young and old mice, midazolam significantly suppressed the total, δ (0.5-4 Hz), θ (4-8 Hz), and α (8-12 Hz) power, and thus induced an increase in the relative ß (12-30 Hz) and γ (30-140 Hz) power. Age had a main effect on the γ frequency; specifically, under normal conditions, old mice had a lower γ power than young mice. After midazolam administration, the relative power of high γ frequency (50-140 Hz) remained lower in old mice than in young mice. Our findings suggest that a lower γ power is indicative of an aging brain.

Pain Mechanism in Rheumatoid Arthritis: From Cytokines to Central Sensitization.

Pain is the most common symptom in patients with rheumatoid arthritis (RA). Although in recent years, through the implementation of targeted treatment and the introduction of disease-modifying antirheumatic drugs (DMARDs), the treatment of RA patients has made a significant progress, a large proportion of patients still feel pain. Finding appropriate treatment to alleviate the pain is very important for RA patients. Current research showed that, in addition to inflammation, RA pain involves peripheral sensitization and abnormalities in the central nervous system (CNS) pain regulatory mechanisms. This review summarized the literature on pain mechanisms of RA published in recent years. A better understanding of pain mechanisms will help to develop new analgesic targets and deploy new and existing therapies.

The major causes and risk factors of total and cause-specific mortality during 5.4-year follow-up: the Shanghai Changfeng Study.

To investigate the major causes and predictive factors of death in a middle-aged and elderly Chinese population. A total of 6591 residents aged ≥ 45 years from Shanghai Changfeng community were followed up for an average of 5.4 years. The causes of death were coded according to the 10th Revision of International Classification of Diseases. The mortality rate was calculated by person-years of follow up and age-standardized according to the 2010 Chinese census data. Multivariable-adjusted Cox proportional hazards model was performed to investigate the predictors of all-cause and cause-specific mortality. During the total follow-up of 35,739 person-years, 370 deaths were documented (157 from malignant neoplasms, 70 from heart diseases, 68 from cerebrovascular diseases, 75 from other causes). The age-standardized all-cause mortality rate was 798.2 per 100,000 person-years (927.9 among men and 716.7 among women). Results from multivariable analyses showed that aging, diabetes, and osteoporosis at baseline were independent predictors of all-cause mortality, with hazard ratios (HR) of 1.11 (95% CI 1.10-1.13), 1.91 (1.51-2.42), and 1.71 (1.24-2.35), respectively. The population attributable risk percent of diabetes and osteoporosis was 19.7% and 11.7%, respectively. Cigarette smoking was associated with a higher risk of all-cause mortality in men (HR and 95%CI 1.44, 1.01-2.06). In women, diabetes and osteoporosis were related to a higher risk of cardiovascular mortality (3.27, 1.82-5.88 and 1.89, 1.04-3.46, respectively). While in men, osteoporosis was related to a higher risk of malignant neoplasms mortality (2.39, 1.07-5.33). Malignant neoplasms, heart diseases, and cerebrovascular diseases are the leading causes of death. Aging, smoking, underweight, diabetes, and osteoporosis are independent predictors of premature death among middle-aged and elderly Chinese community population. Moreover, there may have been some differences in the causes and predictors of premature death between men and women.

L-655,708 Does not Prevent Isoflurane-induced Memory Deficits in Old Mice.

BACKGROUND: General anesthesia and increasing age are two main risk factors for postoperative cognitive dysfunction (POCD). Effective agents for the prevention or treatment of POCD are urgently needed. L-655,708, an inverse agonist of α5 subunit-containing γ-aminobutyric acid subtype A (α5GABAA) receptors, can prevent anesthesia-induced memory deficits in young animals. However, there is a lack of evidence of its efficacy in old animals. METHODOLOGY: Young (3- to 5-month-old) and old (18- to 20-month-old) mice were given an inhalation of 1.33% isoflurane for 1 hour and their associative memory was evaluated 24 hours after anesthesia using fear-conditioning tests (FCTs). To evaluate the effect of L-655,708, mice received intraperitoneal injections of L-655,708 (0.7 mg/kg) or vehicle 30 minutes before anesthesia. RESULTS: Old mice exhibited impaired memory and lower hippocampal α5GABAA levels than young mice under physiological conditions. Pre-injections of L-655,708 significantly alleviated isoflurane-induced memory decline in young mice, but not in old mice. CONCLUSIONS: L-655,708 is not as effective for the prevention of POCD in old mice as it is in young mice. The use of inverse agonists of α5GABAA in preventing POCD in old patients should be carefully considered.

Inhibition of α5 GABAA receptors has preventive but not therapeutic effects on isoflurane-induced memory impairment in aged rats.

The α5 subunit-containing gamma-amino butyric acid type A receptors (α5 GABAARs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 GABAARs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose (1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young (3-month-old) and aged (24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia. The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reaction showed that low-dose isoflurane decreased the mRNA expression of α5 GABAARs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China (approval No. NBCDSER-IACUC-2015128) in December 2015.