Phosphorylated PKM2 regulates endothelium-dependent vasodilation in diabetes. / ç£·é ¸åŒ–PKM2è°ƒæŽ§ç³–å°¿ç— å† çš®ä¾èµ–æ€§è¡€ç®¡èˆ’å¼ åŠŸèƒ½.

OBJECTIVES: Endothelium-dependent vasodilation dysfunction is the pathological basis of diabetic macroangiopathy. The utilization and adaptation of endothelial cells to high glucose determine the functional status of endothelial cells. Glycolysis pathway is the major energy source for endothelial cells. Abnormal glycolysis plays an important role in endothelium-dependent vasodilation dysfunction induced by high glucose. Pyruvate kinase isozyme type M2 (PKM2) is one of key enzymes in glycolysis pathway, phosphorylation of PKM2 can reduce the activity of pyruvate kinase and affect the glycolysis process of glucose. TEPP-46 can stabilize PKM2 in its tetramer form, reducing its dimer formation and phosphorylation. Using TEPP-46 as a tool drug to inhibit PKM2 phosphorylation, this study aims to explore the impact and potential mechanism of phosphorylated PKM2 (p-PKM2) on endothelial dependent vasodilation function in high glucose, and to provide a theoretical basis for finding new intervention targets for diabetic macroangiopathy. METHODS: The mice were divided into 3 groups: a wild-type (WT) group (a control group, C57BL/6 mice) and a db/db group (a diabetic group, db/db mice), which were treated with the sodium carboxymethyl cellulose solution (solvent) by gavage once a day, and a TEPP-46 group (a treatment group, db/db mice+TEPP-46), which was gavaged with TEPP-46 (30 mg/kg) and sodium carboxymethyl cellulose solution once a day. After 12 weeks of treatment, the levels of p-PKM2 and PKM2 protein in thoracic aortas, plasma nitric oxide (NO) level and endothelium-dependent vasodilation function of thoracic aortas were detected. High glucose (30 mmol/L) with or without TEPP-46 (10 µmol/L), mannitol incubating human umbilical vein endothelial cells (HUVECs) for 72 hours, respectively. The level of NO in supernatant, the content of NO in cells, and the levels of p-PKM2 and PKM2 protein were detected. Finally, the effect of TEPP-46 on endothelial nitric oxide synthase (eNOS) phosphorylation was detected at the cellular and animal levels. RESULTS: Compared with the control group, the levels of p-PKM2 in thoracic aortas of the diabetic group increased (P<0.05). The responsiveness of thoracic aortas in the diabetic group to acetylcholine (ACh) was 47% lower than that in the control group (P<0.05), and that in TEPP-46 treatment group was 28% higher than that in the diabetic group (P<0.05), while there was no statistically significant difference in the responsiveness of thoracic aortas to sodium nitroprusside (SNP). Compared with the control group, the plasma NO level of mice decreased in the diabetic group, while compared with the diabetic group, the phosphorylation of PKM2 in thoracic aortas decreased and the plasma NO level increased in the TEPP-46 group (both P<0.05). High glucose instead of mannitol induced the increase of PKM2 phosphorylation in HUVECs and reduced the level of NO in supernatant (both P<0.05). HUVECs incubated with TEPP-46 and high glucose reversed the reduction of NO production and secretion induced by high glucose while inhibiting PKM2 phosphorylation (both P<0.05). At the cellular and animal levels, TEPP-46 reversed the decrease of eNOS (ser1177) phosphorylation induced by high glucose (both P<0.05). CONCLUSIONS: p-PKM2 may be involved in the process of endothelium-dependent vasodilation dysfunction in Type 2 diabetes by inhibiting p-eNOS (ser1177)/NO pathway.

Effect of remimazolam tosilate on early cognitive function in elderly patients undergoing upper gastrointestinal endoscopy.

BACKGROUND AND AIM: Remimazolam tosilate (RT) is under evaluation as a sedative for endoscopic procedures. Herein, we aimed to evaluate safety including cognition recovery of RT administered in elderly patients undergoing upper gastrointestinal endoscopy and assess its safety dosage. METHODS: Ninety-nine patients presenting for upper gastrointestinal endoscopy were randomized to receive 0.1 mg/kg RT (R1) or 0.2 mg/kg RT (R2), or propofol (P). Cognitive functions (memory, attention, and executive function) were measured via neuropsychological tests conducted before sedation and 5 min after recovery to full alertness. Adverse events were also assessed. RESULTS: There were no statistical differences between postoperative and baseline results for R1 group and P group, whereas those for R2 group revealed worsened postoperative cognitive functions (immediate recall and short delay recall) than baseline (P < 0.05). Compared with P group, Scores demonstrated worse restoration of immediate recall in R1 group, immediate recall, short-delayed recall, and attention function in R2 group (P < 0.05). Patients in R2 group had a longer sedation time (12.09 vs 8.27 vs 8.21 min; P < 0.001) and recovery time (6.85 vs 3.82 vs 4.33 min; P < 0.001) than that in R1 group and P group. Moreover, the incidence of hypotension was 3.0% in R1 group, whereas it was 21.2% in R2 group and 48.5% in P group (P < 0.05). CONCLUSION: The addition of 0.1 mg/kg RT as an adjunct to opiate sedation for upper gastrointestinal endoscopy not only achieves more stable perioperative hemodynamics but also achieves acceptable neuropsychiatric functions in elderly patients.

[Correlation between kynurenine metabolites and postpartum depression].

OBJECTIVE: To explore the correlation between kynurenine (KYN) metabolites and postpartum depression (PPD), and to provide new possible explanation for the pathogenesis of postpartum depression (PPD).
 Methods: A total of 726 Chinese women, who received cesarean section, were enrolled in this study. PPD was diagnosed with an Edinburgh Postnatal Depression Scale (EPDS) score ≥13. Twenty-four women with PPD and 48 matched women without PPD were randomly selected. The perinatal serum concentrations of KYN, quinolinic acid (QUIN) and kynurenic acid (KYNA) were measured. Subsequently, the puerperants were compared for the differences in the serum concentrations of KYN, QUIN and KYNA at the end of term, day 1 and day 3 after cesarean section, respectively.
 Results: The incidence of PPD was 7.99%. Of clinical characteristics, pressure during pregnancy was significantly different between subjects with or without PPD (P<0.01). Patients with PPD showed significantly increased serum KYN concentration (P<0.05) at the end of term, increased serum QUIN concentration (P<0.05) and decreased KYNA concentration (P<0.05) on the third day after cesarean section as compared with the control women. Furthermore, the KYNA/QUIN ratio was significantly higher in patients with PPD as compared to the control women on the third day after cesarean section (P<0.01).
 Conclusion: The contribution of alterations in plasma levels of KYN, QUIN and KYNA is closely related with the incidence of PPD, and correction of KYNA/QUIN ratio could be a new strategy for the prevention and treatment of postpartum depressive symptoms.

Renalase improves pressure overload-induced heart failure in rats by regulating extracellular signal-regulated protein kinase 1/2 signaling.

Renalase, a novel flavoprotein that is mainly expressed in the kidney and heart, plays a crucial role in hypertension. Recent studies have shown that renalase is expressed at low levels in the serum of patients with heart failure, while the role of renalase and its mechanism in cardiac failure is unclear. Adult Sprague-Dawley (SD) rats were used to investigate the role and function of renalase in the pathological process of transverse aortic constriction (TAC)-induced heart failure. Renalase-human protein chip analysis showed that renalase was directly associated with P38 and extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling. We further used lentivirus-mediated RNA interference to study the role of renalase in the progression of pathological ventricular hypertrophy and found that renalase inhibition attenuated the noradrenaline-induced hypertrophic response in vitro or the pressure overload-induced hypertrophic response in vivo. Recombinant renalase protein significantly alleviated pressure overload-induced cardiac failure and was associated with P38 and ERK1/2 signaling. These findings demonstrate that renalase is a potential biomarker of hypertrophy and that exogenous recombinant renalase is a potential and novel drug for heart failure.

The role of kynurenine pathway and kynurenic aminotransferase alleles in postpartum depression following cesarean section in Chinese women.

OBJECTIVES: A growing body of data indicates that the kynurenine pathway may play a role in the pathogenesis of postpartum depressive symptoms (PDS). Kynurenic aminotransferase (KAT) is an important kynurenine pathway enzyme, catalyzing kynurenine (KYN) into kynurenic acid (KYNA). This study investigated as to whether genetic variations in KAT are associated with PDS. METHODS: A cohort of 360 Chinese women scheduled to undergo cesarean delivery was enrolled into this study. PDS was determined by an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 13. A total of eight KAT single nucleotide polymorphisms (SNPs) were genotyped and their association with PDS investigated. Serum concentrations of KYN, KYNA, and quinolinic acid (QUIN) in women with or without PDS were also measured. This allowed the determination of the KYNA/KYN ratio, which is reflective of KAT activity. RESULTS: Postpartum depressive symptoms incidence was 7.2%. Advanced maternal age, lower education, antenatal depression, and postpartum blues were risk factors for PDS (p < .05). Women with PDS, versus non-PDS, had heightened KYN levels one day prior to surgery (ante-d1) (p < .05), as well as having significantly lower KYNA and higher QUIN levels at postnatal day three (post-d3) (p < .05). Women with, versus without, PDS also had a significantly higher QUIN/KYNA ratio at post-d3 (p < .05). KAT activity was significantly lower in women with, versus without, PDS at ante-d3 (p < .05). No significant association was evident between the KAT SNPs and PDS. CONCLUSION: Our data support a role for alterations in the kynurenine pathway in the pathogenesis of PDS, although no significant association was found for the eight tested KAT SNPs with PDS.

Insulin Resistance Predicts Postoperative Cognitive Dysfunction in Elderly Gastrointestinal Patients.

BACKGROUND: Members of the aging population who undergo surgery are at risk of postoperative cognitive dysfunction (POCD). Exploring an effective and reliable early predictor of POCD is essential to the identification of high-risk patients and to making prospective decisions. The purpose of this study was to examine whether preoperative insulin resistance is an independent predictor of POCD. METHODS: A total of 124 patients aged 60 years and older and who were scheduled for gastrointestinal surgery were enrolled in a prospective observational clinical study. All participants completed a battery of neuropsychological tests before surgery and 7 days later. POCD was defined as a decline of at least 1.5 SD on two or more of neuropsychological tests. Plasma concentration of the tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and S-100ß protein were measured. The status of insulin resistance was assessed by Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). The relationship between HOMA-IR and POCD was assessed by Multivariable logistic regression models and the receiver operating characteristic (ROC) curve. RESULTS: Fifty one patients (41.1%) were diagnosed with POCD at 7 days after surgery. Preoperative HOMA-IR values of the POCD group were significantly higher than the non-POCD group. Furthermore, CRP and TNF-α levels of the POCD group were significantly higher at each postoperative time point (P < 0.05). The preoperative HOMA-IR value was an independent predictor of POCD (adjusted OR 1.88, 95% CI, 1.18-2.99) even after adjust for confounding variables, and when dichotomized, individuals above the HOMA-IR threshold (HOMA-IR > 2.6) had a three-times higher risk of POCD (OR 3.26; 95% CI, 1.07-9.91) compared to individuals below the threshold. The areas under the ROC curve of HOMA-IR was 0.804 (95% CI, 0.725-0.883; P < 0.001). The optimal cut-off value was found to be 0.583, with a sensitivity of 84.3% and specificity of 74%. The HOMA-IR value was positively associated with the TNF-α concentration at baseline (R 2 = 0.43, P < 0.01) and 1 day after surgery (R 2 = 0.3861, P < 0.01). CONCLUSION: Preoperative insulin resistance is an effective predictor for the occurrence of POCD. Targeted prevention and treatment strategies of insulin resistance may be effective interventions of patients at risk for POCD.

Dexmedetomidine Alleviates Postpartum Depressive Symptoms following Cesarean Section in Chinese Women: A Randomized Placebo-Controlled Study.

OBJECTIVES: Few studies have investigated the prophylactic efficacy of dexmedetomidine (DEX) in postpartum depressive symptoms (PDS). A randomized double-blind placebo-controlled trial was conducted to investigate whether the administration of DEX, immediately after delivery and for patient-controlled intravenous analgesia (PCIA), can attenuate PDS. METHODS: A total of 600 parturients scheduled for elective cesarean delivery under spinal anesthesia were randomly allocated into the control group (infusion with 0.9% normal saline after delivery and PCIA with sufentanil) and the DEX group (DEX infusion 0.5 µg/kg after delivery and PCIA with DEX plus sufentanil). The prevalence of postpartum depressive disorders was indicated by the Edinburgh Postnatal Depression Scale (EPDS). Postoperative analgesia, sedation, and sleep quality of parturients were also assessed. RESULTS: Postpartum blues and PDS prevalence in the DEX, versus control, group were significantly lower (5.0% vs 14.1%, p<0.001; 5.7% vs 16.3%, p<0.001, respectively), especially in parturients with antenatal depression or moderate stress during pregnancy. Compared with the control group, the EPDS score at postpartum days 7 and 42 in the DEX group was significantly lower (4.23 ± 4.37 vs 1.93 ± 3.36, p<0.001; 4.68 ± 4.78 vs 1.99 ± 3.18, p<0.001, respectively), as was the incidence of postpartum self-harm ideation at postpartum days 7 and 42 in the DEX group versus the control group (1.1% vs 4.0%, p=0.03; 0.4% vs 2.9%, p=0.04, respectively). The pain score and the sleep quality in the DEX group were better than that in the control group (p<0.001). CONCLUSION: The application of DEX in the early postpartum period can significantly attenuate the incidence of postpartum depressive disorders.

BIS-guided deep anesthesia decreases short-term postoperative cognitive dysfunction and peripheral inflammation in elderly patients undergoing abdominal surgery.

OBJECTIVES: Postoperative cognitive dysfunction (POCD) is a common clinical complication, with an underlying pathophysiology linked to heightened levels of neuroinflammation. However, it requires clarification as to whether the depth of anesthesia modulates postoperative cognitive dysfunction. This study investigated the association between depth of anesthesia and POCD in elderly patients undergoing abdominal surgery. METHODS: A total of 120 patients aged 60 years or older who were planned for abdominal surgery under total intravenous anesthesia were included in this study. The depth of anesthesia was guided by monitoring Bispectral Index (BIS) data. All study participants completed a battery of nine neuropsychological tests before surgery and at 7 days and 3 months after surgery. POCD was calculated by using the reliable change index. Plasma concentration of C-reactive protein (CRP), interleukin (IL)-1ß, IL-10, S-100ß, and norepinephrine (NE) were measured. RESULTS: The incidence of POCD at 7 days after surgery in the deep anesthesia group was 19.2% (10/52), which was significantly lower (p = 0.032) than the light anesthesia group 39.6% (21/53). The depth of anesthesia had no effect on POCD at 3 months after surgery (10.3% vs 14.6%, respectively, p = 0.558). Similarly, plasma levels of CRP and IL-1ß in deep anesthesia group were lower than that in light anesthesia group at 7 days after surgery (p < 0.05), but not at 3 months after surgery (p > 0.05). There were no significant differences in the plasma concentration of IL-10, S-100ß, and NE between the groups (p > 0.05). CONCLUSIONS: Deep anesthesia under total intravenous anesthesia could decrease the occurrence of short-term POCD and inhibit postoperative peripheral inflammation in elderly patients undergoing abdominal surgery, compared with light anesthesia.

Inhibiting RIPK1 Limits Neuroinflammation and Alleviates Postoperative Cognitive Impairments in D-Galactose-Induced Aged Mice.

Neuroinflammation plays a critical role in the pathogenesis of postoperative cognitive dysfunction (POCD) of the elderly patients. Receptor-interacting protein kinase1 (RIPK1) is a key molecular switch modulating inflammation, apoptosis and necroptosis. Here, we investigated whether inhibiting RIPK1 by necrostatin-1 (Nec-1) could limit neuroinflammation and attenuate POCD in D-Galactose (D-Gal)-induced aged mice. The mice were subjected to anesthesia and partial hepatectomy, and necrostatin-1 was administered intraperitoneally 1 h prior to anesthesia and surgery. Cognitive function and movement were tested 24 h after surgery by open field, Barnes maze and puzzle box. The hippocampal tissues were collected to detect the following: neuroinflammation (Iba-1, IL-1α, IL-1ß, TNF-α), Necroptosis (Propidium Iodide (PI) labeling, RIPK1, nuclear transcription factor kappa B (NF-κB) and neuroplasticity (doublecortin (DCX), NR2B, GluA1, GluA2). We found that anesthesia and surgery induced a significant deficit in spatial memory acquisition and impairment of executive function and memory to simple task in D-Galactose-induced aged mice. Inhibiting RIPK1 by necrostatin-1 strikingly mitigated cognitive impairment and alleviated postoperative amplified neuroinflammation, necroptosis and GluA1 loss in hippocampus. These suggest that targeting RIPK1 by necrostatin-1 may serve as a promising therapeutics for prevention of POCD in elderly patients.

Inhibiting RIP1 Improves Chronic Stress-Induced Cognitive Impairments in D-Galactose-Induced Aging Mice.

Mounting evidence shows that chronic stress can affect both the structure and function of the brain resulting in decreased synaptic plasticity and cognitive dysfunction. Although several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown how to prevent stress-induced memory deficits in aged animals. Neuroinflammation plays an important role in the pathogenesis of chronic stress-related brain dysfunction. Receptor-interacting protein 1 (RIP1) is a key molecule that can modulate inflammation, apoptosis, and necroptosis. Here, we investigated whether inhibiting RIP1 using necrostatin-1 during chronic stress could improve chronic stress-related brain dysfunction in D-galactose-induced aging mice. The stressed mice underwent restraint stress for 14 days. Necrostatin-1 (6.25 mg/kg) or vehicle was administered intraperitoneally once every 3 days during the stress period. Locomotor activity was tested using the open field test and cognitive function was assessed using the novel object recognition and Barnes maze tests. The hippocampus was collected to assess neuroinflammation (Iba1, IL-1α, IL-1ß, TNF-α, and C1q), necroptosis [RIP1, RIP3, mixed lineage kinase domain-like (MLKL), and NF-κB], neuroplasticity (doublecortin, NR1, NR2A, NR2B, GluA1, and GluA2), and the expression of glucocorticoid and mineralocorticoid receptors. Blood samples were collected to quantify the levels of corticosterone. We found that chronic stress induced obvious memory impairment and neuroinflammation, decreased neurogenesis and GluA2 expression, and increased the expression of RIP1 and NF-κB. Inhibiting RIP1 by necrostatin-1 during chronic stress rescued the memory impairment and alleviated the pathological changes induced by stress. These suggest that inhibiting RIP1 using necrostatin-1 improves chronic stress-related brain dysfunction in D-galactose-induced aging mice. The potential mechanisms include limitation of neuroinflammation and the rescue of neurogenesis and GluA2 expression.

Tramadol combined with fentanyl in awake endotracheal intubation.

OBJECTIVE: To explore the feasibility and dosage of tramadol combined with fentanyl in awake endotracheal intubation. METHODS: Using Dixon's up-and-down sequential design, the study enrolled patients from each of the 20-49, 50-60 and 70-and-above age groups scheduled for elective surgery under general anesthesia. The feasibility and dosage of tramadol combined with fentanyl in awake endotracheal intubation, guided by fiberoptic bronchoscopy, were verified. RESULTS: After intravenous injection with fentanyl 2.2 µg/kg and tramadol 2.0 mg/kg in the 20-49 age group, fentanyl 1.6 µg/kg and tramadol 1.9 mg/kg in the 50-69 age group and fentanyl 1 µg/kg and tramadol 1.8 mg/kg in those at the age of 70 or above, the patients achieved conscious sedation without obvious respiratory depression. Meanwhile, under these dosages, the patients could easily tolerate the thyrocricocentesis airway surface anesthesia and fiberoptic bronchoscope guided tracheal intubation. Postoperative follow-up showed that most patients had memory of the intubation process but without significant discomfort. No awake endotracheal intubation-related side effect was noted. CONCLUSIONS: Fiberoptic bronchoscope guided nasotracheal intubation can be successfully completed with background administration of fentanyl and tramadol. However, the specific dosages need to be tailored in different age of patients.