Sirt7/HIC1 complex participates in hyperglycaemia-mediated EndMT via modulation of SDC1 expression in diabetic kidney disease and metabolic memory.

Diabetic kidney disease (DKD), a primary microvascular complication arising from diabetes, may result in end-stage renal disease. Epigenetic regulation of endothelial mesenchymal transition (EndMT) has been recently reported to exert function in metabolic memory and DKD. Here, we investigated the mechanism which Sirt7 modulated EndMT in human glomerular endothelial cells (HGECs) in the occurrence of metabolic memory in DKD. Lower levels of SDC1 and Sirt7 were noted in the glomeruli of both DKD patients and diabetes-induced renal injury rats, as well as in human glomerular endothelial cells (HGECs) with high blood sugar. Endothelial-to-mesenchymal transition (EndMT) was sustained despite the normalization of glycaemic control. We also found that Sirt7 overexpression associated with glucose normalization promoted the SDC1 expression and reversed EndMT in HGECs. Furthermore, the sh-Sirt7-mediated EndMT could be reversed by SDC1 overexpression. The ChIP assay revealed enrichment of Sirt7 and H3K18ac in the SDC1 promoter region. Furthermore, hypermethylated in cancer 1 (HIC1) was found to be associated with Sirt7. Overexpression of HIC1 with normoglycaemia reversed high glucose-mediated EndMT in HGECs. The knockdown of HIC1-mediated EndMT was reversed by SDC1 upregulation. In addition, the enrichment of HIC1 and Sirt7 was observed in the same promoter region of SDC1. The overexpressed Sirt7 reversed EndMT and improved renal function in insulin-treated diabetic models. This study demonstrated that the hyperglycaemia-mediated interaction between Sirt7 and HIC1 exerts a role in the metabolic memory in DKD by inactivating SDC1 transcription and mediating EndMT despite glucose normalization in HGECs.

GDPD3 Deficiency Alleviates Neuropathic Pain and Reprograms Macrophagic Polarization Through PGE2 and PPARγ Pathway.

The complex mechanism of neuropathic pain involves various aspects of both central and peripheral pain conduction pathways. An effective cure for neuropathic pain therefore remains elusive. We found that deficiency of the gene Gdpd3, encoding a lysophospholipase D enzyme, alleviates the inflammatory responses in dorsal root ganglia (DRG) of mice under neuropathic pain and reduces PE (20:4) and PGE2 in DRG. Gdpd3 deficiency had a stronger analgesic effect on neuropathic pain than Celecoxib, a nonsteroidal anti-inflammatory drug. Gdpd3 deficiency also interferes with the polarization of macrophages, switching from M1 towards M2 phenotype. The PPARγ/ FABP4 pathway was screened by RNA sequencing as functional related with Gdpd3 deficient BMDMs stimulated with LPS. Both protein and mRNA levels of PPARγ in GDPD3 deficient BMDMs were higher than those of the litter control mice. However, GW9962 (inhibitor of PPARγ) could reverse the reprogramming polarization of macrophages caused by GDPD3 deficiency. Therefore, our study suggests that GDPD3 deficiency exerts a relieving effect on neuropathic pain and alleviates neuroinflammation in DRG by switching the phenotype of macrophages from M1 to M2, which was mediated through PGE2 and PPARγ/ FABP4 pathway.

Resequencing of Rosa rugosa accessions revealed the history of population dynamics, breed origin, and domestication pathways.

BACKGROUND: Rosa rugosa is a shrub that originated in China and has economic and ecological value. However, during the development of R. rugosa, the genetic background was chaotic, and the genetic structure among different wild populations was unclear, as well as wild and cultivated accessions. Here, we report whole-genome resequencing of wild and cultivated R. rugosa accessions. RESULTS: A total of 19,041,284 SNPs were identified in 188 R. rugosa accessions and 3 R. chinensis accessions by resequencing. Population genetic analysis revealed that cultivated and wild groups were separated very early. All R. rugosa accessions were divided into 8 categories based on genetic structure: (1) Weihai, Yantai, and Liaoning category, (2) Jilin category, and (3) Hammonasset category (above three are wild); (4) traditional varieties, (5) hybrids between R. rugosa and R. chinensis, (6) Zizhi Rose, (7) Kushui Rose, (8) hybrids between R. rugosa and R. multiflora. We found that the heterozygosity and genetic diversity of wild accessions were generally lower than those of cultivated individuals. The genes that were selected during cultivation were identified, and it was found that these genes were mainly related to environmental adaptation and growth. CONCLUSIONS: The Jilin population was the oldest population and later migrated to Liaoning and then migrated to Yantai and Weihai by sea regression in the Bohai Basin. The Hammonasset naturalized population probably originated from the Jilin population and then experienced separate differentiation. The long-term asexual reproduction pattern of R. rugosa decreased genetic diversity in the wild population. During R. rugosa cultivation, the ancestors of the Jilin population were involved in breeding traditional varieties, after which almost no wild individuals were engaged in breeding. However, in recent decades, cross breeding of R. rugosa started the utilization of wild germplasms. In comparison, some other species play important roles in variety formation. Few genes related to economic traits were selected, suggesting no directional domestication in the R. rugosa cultivation process.

No smoking signs with strong smoking symbols induce weak cravings: an fMRI and EEG study.

No smoking signs (NSSs) that combine smoking symbols (SSs) and prohibition symbols (PSs) represent common examples of reward and prohibition competition. To evaluate how SSs within NSSs influence their effectiveness in guiding reward vs. prohibition, we studied 93 male smokers. We collected self-reported craving ratings (N=30), cue reactivity under fMRI/EEG (N=33), and smoking-behavior anticipation for paired NSSs and SSs (N=30). We found that NSS-induced cravings were negatively correlated with SS-induced cravings and PS-induced inhibition. fMRI indicated that both correlations were mediated by activation of the inferior frontal gyrus and precuneus, suggesting that the effects of SSs and PSs interact with each other. EEG revealed that the prohibition response occurs after the cigarette response, indicating that the cigarette response might be precluded by the prohibition, supporting the effect of SSs in discouraging smoking. Moreover, stronger SSs induced stronger slow positive waves and late positive potentials, and the stronger the late positive potentials, the stronger the late positive potentials. Both the amplitudes of late positive potentials and slow positive waves were positively correlated with the amplitude of N2, which was positively correlated with the attention grabbed score by the NSS. In addition, the weaker the NSS-induced craving, the greater the smoking behavior anticipation reduction, indicating the capability of NSSs to decrease smoking behavior. Our study provides empirical evidence for selecting the most effective NSSs: those combining strong SS and PS, offering insights about competition between cigarette reward and prohibition and providing neural evidence on how cigarette reward and prohibition interact.

Riluzole Promotes Neurite Growth in Rats after Spinal Cord Injury through the GSK-3ß/CRMP-2 Pathway.

Spinal cord injury (SCI) is a disastrous event that often leads to permanent neurological deficits involving motor, sensory, and autonomic dysfunctions in patients. Accumulating research has demonstrated that riluzole may play crucial roles in the process of spinal tissue repair, but the underlying mechanisms remain elusive. This study verified the effectiveness of riluzole and speculated that a riluzole-afforded protection mechanism may be associated with the glycogen synthase kinase-3 beta (GSK-3ß)/collapsin response mediator protein-2 (CRMP-2) pathway in rats after spinal cord injury. Here, a modified Allen's weight dropping model was generated and riluzole at 4 mg/kg was injected intraperitoneally after surgery and twice a day for 7 consecutive days. At 6 weeks after SCI, we found that riluzole treatment reduced the central cavity size of the spinal cord and improved neurological functions. Meanwhile, riluzole-treated rats exhibited shorter latency and larger amplitude in motor evoked potentials and somatosensory evoked potentials, compared with vehicle-treated rats. Furthermore, Western blotting and immunofluorescence data revealed that the expression levels of GSK-3ß and phosphorylated-GSK-3ß were lower in riluzole-treated SCI rats compared with vehicle-treated rats. We next detected the expression CRMP-2 and phosphorylated CRMP-2 and found that the expression of CRMP-2 showed no difference between the riluzole-treated and vehicle-treated groups; however, administration of riluzole downregulated phosphorylated CRMP-2 expression. The current findings suggest that after SCI, administration of riluzole promotes neurological functional restoration, which may be associated, in part, with its activation of the GSK-3ß/CRMP-2 signaling pathway.

The effects of smoking on clinical and structural outcomes after rotator cuff repair: a systematic review and meta-analysis.

BACKGROUND: Several factors have been reported to adversely affect clinical and structural outcomes after rotator cuff repair (RCR). However, the effects of smoking on rotator cuff healing and clinical outcomes remain controversial. The purpose of this study was to compare the clinical and structural outcomes after RCR between smokers and nonsmokers. We hypothesized that there would be no significant difference in the clinical scores after RCR and that smoking would be associated with a significantly increased risk of retear and reoperation. METHODS: This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines using the PubMed, Cochrane Library, and Embase databases. We included only articles in which patients underwent arthroscopic and open RCR, the clinical outcome scores were reported for smokers and nonsmokers, and the number of rotator cuff retears and reoperations were reported. Data relevant to this study were extracted and statistically analyzed. We used the Newcastle-Ottawa Scale to assess the risk of bias in each study and calculated the I2 value to quantify the effect of heterogeneity. RESULTS: Fourteen eligible articles were identified, with 73,817 participants (8553 smokers and 65,264 nonsmokers). The meta-analysis demonstrated that there were no significant differences in the American Shoulder and Elbow Surgeons score (P = .10), Simple Shoulder Test score (P = .19), University of California-Los Angeles score (P = .09), or visual analog scale score (P = .19) between smokers and nonsmokers after surgery, but the Constant score was significantly lower (P = .005) for smokers. Smoking was significantly associated with an increased risk of retear (P = .002; risk ratio, 2.06 [95% confidence interval, 1.30-3.28]; I2 = 31%) and reoperation (P < .001; risk ratio, 1.29 [95% confidence interval, 1.20-1.40]; I2 = 36%) in patients after RCR. CONCLUSION: Besides the Constant score, which was lower in smokers, there were no significant differences in the clinical scores after RCR between smokers and nonsmokers. However, smoking was associated with a significantly increased risk of retear and reoperation.

Radiographic adjacent segment degeneration and risk factors for osteoporotic vertebral compression fractures treated with percutaneous kyphoplasty.

PURPOSE: In this study, we aimed to clarify whether osteoporotic vertebral compression fracture (OVCF) following percutaneous kyphoplasty (PKP) was associated with a high risk for radiographic adjacent segment degeneration (ASD) and to identify the risk factors for radiographic ASD in these individuals. METHODS: We retrospectively reviewed consecutive patients with OVCFs who underwent PKP at our institution between November 2015 and January 2021. The incidence of radiographic ASD was calculated and specific subgroups of ASD were identified. Univariate and multivariate analyses of demographic, clinical baseline, and radiologic data were performed to identify risk factors associated with radiographic ASD. RESULTS: With a mean follow-up time of 27.3 months, a total of 95 eligible patients were enrolled. The incidence of radiographic ASD distinguished from natural degeneration was 52.6%. Patients with OVCFs who underwent PKP had a high risk of developing radiographic ASD, particularly disc degeneration. Intradiscal cement leakage (odds ratio [OR], 5.706; 95% confidence interval [CI], 2.039-15.970; P = 0.001) and preoperative disc height (OR, 0.681; 95% CI, 0.518-0.895; P = 0.006) were identified as independent risk factors. CONCLUSION: Patients with OVCFs who underwent PKP were more likely to develop radiographic ASD, and their progression was distinguished from natural degeneration. Disc degeneration was the most common type of degeneration. Intradiscal cement leakage and preoperative disc height were identified as independent risk factors for developing radiographic ASD in these patients. Further validation through prospective multicenter studies is required.

Bioaugmentation for low C/N ratio wastewater treatment by combining endogenous partial denitrification (EPD) and denitrifying phosphorous removal (DPR) in the continuous A2/O - MBBR system.

Endogenous partial denitrification (EPD) and denitrifying phosphorous removal (DPR) were combined in a novel A2/O - MBBR (Anaerobic Anoxic Oxic - Moving Bed Biofilm Reactor) system for low carbon/nitrogen (C/N) ratio wastewater treatment. The DPR performance was compared and the nutrient metabolism was elucidated based on the optimization of hydraulic retention time (HRT, 4-12 h) and nitrate recycling (R, 200%-600%). In the continuous-flow, the nitrate (NO3-) denitrification accompanied by nitrite (NO2-, via EPD) accumulation with the nitrate-to-nitrite transformation ratio (NTR) of 35.87%-43.31% in the anoxic zones. At HRT of 12 h with R of 500%, batch test initially revealed the DPR mechanism using both NO3- and NO2- as electron acceptor, where denitrifying phosphorus accumulation organisms (DPAOs) and denitrifying glycogen accumulation organisms (DGAOs) were the main contributors for EPD with incomplete denitrification (NO3- → NO2-). Furthermore, stoichiometry-based functional bacteria analysis displayed that higher bioactivity of DPAOs (NO2-→N2, 57.30%; NO3-→N2, 35.85%) over DGAOs (NO3-→N2, 6.85%) facilitated the anoxic NO3- reduction. Microbial community analysis suggested that Cluster I of Defluviicoccus-GAO group (∼4%) was responsible for stable NO2- accumulation performance via EPD, while increased Accumulibacter-PAO group (by ∼15%) contributed to the advanced nutrient removal. Based on the achievement of NO2- accumulation, the application feasibility of integrated EPD - DPR - Anammox for deep-level nutrient removal was discussed.

Encapsulation of a Core-Shell Porous Fe3O4@Carbon Material with Reduced Graphene Oxide for Li+ Battery Anodes with Long Cyclability.

Anode materials are critical for energy devices based on Li-ion batteries (LIBs). This work reports on a facile method to produce anodes based on carbon-coated Fe3O4 (CP-Fe3O4) that is encapsulated in reduced graphene oxide (rGO) layers forming a porous core-shell structure Fe3O4@carbon (rGO-CP-Fe3O4). First, Fe3O4 particles were coated with carbon by hydrothermal and carbothermal reduction methods leading to an intermediate product termed CP-Fe3O4. Next, CP-Fe3O4 was encapsulated by two-dimensional layered rGO to obtain CP-Fe3O4 composites with a three-dimensional structure. The Fe3O4 volume expansion during LIB cycling was inhibited by carbon and rGO and a three-dimensional electron transport network was generated by the introduction of rGO. The rGO-CP-Fe3O4 composite showed excellent electrochemical properties (839 mA h g-1 at 0.3 A g-1 after 200 cycles) and rate capacities (165 mA h g-1 at 6.0 A g-1). In addition, the rGO-CP-Fe3O4 pseudocapacitance was equal to 65% of the overall capacity at 5 mV s-1.

What is the impact of scoliotic correction on postoperative shoulder imbalance in severe and rigid scoliosis.

BACKGROUND: Although recent studies have investigated the risk factors for PSI, few studies have focused on the impact of scoliotic correction on postoperative shoulder imbalance (PSI), especially in severe and rigid scoliosis (SRS). The purpose of the study was to study the effect of scoliotic correction on PSI in SRS. METHODS: The preoperative, postoperative, and minimum 2-year follow-up radiographs of 48 consecutive patients with SRS who underwent posterior spinal fusion surgery were evaluated. We regarded radiographic shoulder height (RSH) as a shoulder balance parameter and divided the patients into improved and aggravated groups of PSI from pre- to post-operation and from post-operation to last follow-up, respectively. In addition, patients were divided into nine groups based on the observed changes in PSI after surgery and at follow-up, and the correction rate ratios were calculated among the groups. Independent samples T test and Chi-squared test were performed between the improved and aggravated groups of PSI. RESULTS: After surgery, the proximal thoracic curve (PTC) flexibility (P = 0.040), correction rate of the main thoracic curve (MTC) (P = 0.010), and Cobb angle of the lumbar curve (LC) (P = 0.037) were significantly higher, while the ratio of the correction rate of the PTC to the MTC (P = 0.042) was smaller in the aggravated group. At follow-up, the improved group had significantly larger PTC flexibility (P = 0.006), larger ratio of the correction rate of PTC to MTC (P = 0.046), a larger ratio correction rate of PTC to LC (P = 0.027), and a smaller correction rate of LC (P = 0.030). The correction rate ratios of the groups after surgery were as follows: negative to negative (N-N) (1.08) > negative to balance (N-B) (0.96) > negative to positive (N-P) (0.67), B-N (1.26) > B-B (0.94) > B-P (0.89), and P-N (0.34) > P-P (0.83). The order of the correction rate ratio at follow-up was as follows: N-N (0.96) > N-B (0.51), B-B (0.97) > B-P (0.90), and P-B (0.87) > P-P (0.84). CONCLUSION: Harmonizing the correction rate ratio of the PTC, MTC, and LC should be recommended for intraoperative correction and postoperative compensation of PSI. In addition, greater PTC flexibility plays an important role in the spontaneous correction and compensation of PSI in SRS.

Complications and risk factors of percutaneous endoscopic transforaminal discectomy in the treatment of lumbar spinal stenosis.

BACKGROUND: With the advancements in surgical methods, optical designs, and surgical instruments, percutaneous endoscopic transforaminal discectomy (PETD) has become an effective and minimally invasive procedure to treat lumbar spinal stenosis (LSS) in recent years. Few studies have focused on the complications associated with the treatment of LSS using percutaneous endoscopic lumbar discectomy (PELD). This study aimed to summarize the complications of PETD and identify the associated risk factors. METHODS: Complications in a total of 738 consecutive LSS patients who underwent single-level PETD were retrospectively recorded and analyzed between January 2016 and July 2020. In addition, a matched case-control study was designed, and according to the date of operation, the control group was matched with patients without complications, with a matching ratio of 1:3. Demographic parameters included age, sex, BMI, smoking and drinking status, comorbidity, and surgical level. The radiological parameters included grade of surgical-level disc degeneration, number of degenerative lumbar discs, grade of lumbar spinal stenosis, degenerative lumbar scoliosis, lumbar lordosis, disc angle, and disc height index. Univariate analysis was performed using independent samples t-test and chi-squared test. RESULTS: The incidence of different types of complications was 9.76% (72/738). The complications and occurrence rates were as follows: recurrence of LSS (rLSS), 2.30% (17/738); persistent lumbosacral or lower extremity pain, 3.79% (28/738); dural tear, 1.90% (14/738); incomplete decompression, 0.81% (6/738); surgical site infection, 0.41% (3/738); epidural hematoma, 0.27% (2/738); and intraoperative posterior neck pain, 0.27% (2/738). Univariate analysis demonstrated that age, the grade of surgical-level disc degeneration (P < 0.001) and the number of disc degeneration levels (P = 0.004) were significantly related to the complications. CONCLUSION: Complications in the treatment of LSS using PELD included rLSS, persistent pain of the lumbosacral or lower extremity, dural tear, incomplete decompression, surgical site infection, epidural hematoma, and intraoperative posterior neck pain. In addition, old age, severe grade of surgical-level disc degeneration and more disc degeneration levels significantly increased the incidence of complications.

High glucose inhibits vascular endothelial Keap1/Nrf2/ARE signal pathway via downregulation of monomethyltransferase SET8 expression.

Hyperglycemia-mediated reactive oxygen species (ROS) accumulation plays an important role in hyperglycemia-induced endothelial injury. Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway inhibition participates in hyperglycemia-induced ROS accumulation. Our previous study indicated that SET8 overexpression inhibits high glucose-mediated ROS accumulation in human umbilical vein endothelial cells (HUVECs). In the present study, we hypothesize that SET8 may play a major role in high glucose-induced ROS accumulation via modulation of Keap1/Nrf2/ARE pathway. Our data indicated that high glucose mediated cell viability reduction, ROS accumulation, and Nrf2/ARE signal pathway inhibition via upregulation of Keap1 expression in HUVECs. Moreover, high glucose inhibited the expressions of SET8 and H4K20me1 (a downstream target of SET8). SET8 overexpression improved high glucose-mediated Keap1/Nrf2/ARE pathway inhibition and endothelial oxidation. Consistently, the effects of sh-SET8 were similar to that of high glucose treatment and were reversed by si-Keap1. A mechanistic study found that H4K20me1 was enriched at the Keap1 promoter region. SET8 overexpression attenuated Keap1 promoter activity and its expression, while mutant SET8 R259G did not affect Keap1 promoter activity and expression. The results of this study demonstrated that SET8 negatively regulates Keap1 expression, thus participating in high glucose-mediated Nrf2/ARE signal pathway inhibition and oxidative injury in HUVECs.

Melatonin improves functional recovery in female rats after acute spinal cord injury by modulating polarization of spinal microglial/macrophages.

Spinal cord injury (SCI) is a devastating neurological disorder, but few drugs have proven to be effective for its treatment. Neuroinflammation exaggerates the secondary injury subsequent to trauma. Emerging evidence suggests that melatonin may help protect neural tissue against secondary injury after SCI, but the underlying mechanisms remain elusive. Microglial/macrophages polarization plays an important role in regulating immune responses. To examine whether melatonin exerts neuroprotective effects after acute SCI by regulating microglial/macrophages polarization in the spinal cord, we administered intraperitoneal injections of melatonin (50 mg/kg) in female rats immediately after SCI and then daily for seven consecutive days (n = 6). Compared with the vehicle-treated group (n = 6), the melatonin-treated group exhibited a greater Basso, Beattie, and Bresnahan locomotor rating score, smaller spinal cavity, and less cleaved caspase 3 immunofluorescence staining in the injured spinal segments. Real-time PCR data revealed decreases in the expression levels of M1 microglia phenotypic markers and increases in M2 markers in the spinal cord of melatonin-treated SCI rats, as compared to levels in the vehicle-treated group. Melatonin increased the number of CD206+ and Arg1+ cells, decreased the number of CD16+ and iNOS+ cells and reduced the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) in the spinal cord tissue of female SCI rats. Current findings suggest that melatonin may inhibit pro-inflammatory responses and promote M2 polarization of microglial/macrophages in the spinal cord in the early stage of SCI, facilitating functional recovery. Accordingly, melatonin may represent a promising therapeutic candidate for acute SCI.

Propofol attenuates the adhesion of tumor and endothelial cells through inhibiting glycolysis in human umbilical vein endothelial cells.

Propofol is one of the most commonly used intravenous anesthetics and plays an important role in tumor suppression. In the present study, we aimed to investigate the mechanism by which propofol attenuates tumor endothelial cells (TECs) and tumor cell adhesion to inhibit tumor metastasis in vitro. Human umbilical vein endothelial cells (HUVECs) cultured in Dulbecco's modified Eagle's medium were treated with tumor conditioned medium for 24 h, followed by 4 h of treatment with or without 25 µM of propofol, 10 µM of KN93, 500 µM of MK801, or 20 µM of rapastinel. It was found that propofol inhibited TEC adhesion and the glycolysis level of TECs. Consistently, propofol inhibited the expressions of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) and glycolysis proteins (GLUT1, HK2, and LDHA) in TECs. Moreover, propofol attenuated the expression of HIF-1α, the phosphorylation of AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the Ca2+ concentration in TECs. MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMKII, both inhibited the expressions of adhesion molecules and glycolysis proteins, in a manner similar to propofol. Additionally, rapastine, an activator of NMDA receptor, could counteract the effects of propofol. Our results indicated that propofol attenuates intracellular Ca2+ concentration, CaMKII and AKT phosphorylation, and HIF-1α expression, probably via inhibiting the NMDA receptor, thus inhibiting glycolysis and adhesion of tumor and endothelial cells.

Propofol attenuates high glucose-induced P66shc expression in human umbilical vein endothelial cells through Sirt1.

Perioperative hyperglycemia is a common metabolic disorder in clinic settings. Hyperglycemia leads to endothelial inflammation, endothelial cell apoptosis, and dysfunction, thus resulting in endothelial injury. Propofol (2,6-diisopropylphenol) is a widely used intravenous anesthetic in clinic settings. Our previous study indicated that propofol inhibits mitochondrial reactive oxygen species (ROS) production via down-regulation of phosphatase A2 (PP2A) expression, inhibition of Ser36-p66shc dephosphorylation and mitochondrial translocation, thus improving high glucose-induced endothelial injury. The expression of p66shc was inhibited by propofol in hyperglycemic human umbilical vein endothelial cells (HUVECs). However, the mechanism by which propofol inhibits p66shc expression in hyperglycemic HUVECs is still obscure. In the present study, we mainly examined how propofol inhibited high glucose-induced p66shc expression in HUVECs. Compared with 5 mM glucose treatment, high glucose increased p66shc expression and decreased sirt1 expression, which was inhibited by propofol treatment. Moreover, EX527 (a sirt1 inhibitor) reversed the effect of propofol against high glucose-induced p66shc expression. However, EX527 did not reverse the effects of propofol against high glucose-induced ROS accumulation, endothelial inflammation, and apoptosis. Furthermore, when cells were incubated with propofol, EX527, and FTY720 (a PP2A activator) simultaneously, the effects of propofol against high glucose-induced ROS accumulation, inflammation, and apoptosis were reversed. Our results suggested that propofol inhibited high glucose-induced p66shc expression via upregulation of sirt1 expression in hyperglycemic HUVECs. Moreover, propofol protects against high glucose-mediated ROS accumulation and endothelial injury via both inhibition of p66shc expression and dephosphorylation of Ser36-p66shc.

Propofol Disrupts Aerobic Glycolysis in Colorectal Cancer Cells via Inactivation of the NMDAR-CAMKII-ERK Pathway.

BACKGROUND/AIMS: To investigate the effect of propofol on glucose metabolism in colorectal cancer cells and in an in vivo xenograft model. METHODS: Glucose metabolism was assessed by measuring the extracellular acidification rate in HT29 and SW480 colorectal cancer cells. Quantitative real-time PCR and western blot analyses were used to detect mRNA and protein levels, respectively. Intracellular calcium was assessed by using a Fluo-3 AM fluorescence kit. Micro-positron emission tomography/computed tomography (microPET/CT) imaging was used to analyze glucose metabolism in the tumors of the xenograft model. RESULTS: Propofol exposure induced a dose-dependent decrease of aerobic glycolysis in HT29 and SW480 colorectal cancer cells. MicroPET/CT indicated that propofol also inhibited 18F-FDG uptake in the xenograft model. In addition, hypoxia-inducible factor 1α (HIF1α) was also reduced by propofol dose-dependently. Propofol repressed the NMDAR-CAMKII-ERK pathway to inactivate HIF1α and therefore reduced glycolysis. CONCLUSION: Propofol inhibited aerobic glycolysis in colorectal cancer cells through the inactivation of the NMDAR-CAMKII-ERK pathway, which may facilitate a better understanding of the use of propofol in the clinical setting.

Methylammonium Cation Dynamics in Methylammonium Lead Halide Perovskites: A Solid-State NMR Perspective.

In light of the intense recent interest in the methylammonium lead halides, CH3NH3PbX3 (X = Cl, Br, and I) as sensitizers for photovoltaic cells, the dynamics of the methylammonium (MA) cation in these perovskite salts has been reinvestigated as a function of temperature via 2H, 14N, and 207Pb NMR spectroscopy. In the cubic phase of all three salts, the MA cation undergoes pseudoisotropic tumbling (picosecond time scale). For example, the correlation time, τ2, for the C-N axis of the iodide salt is 0.85 ± 0.30 ps at 330 K. The dynamics of the MA cation are essentially continuous across the cubic ↔ tetragonal phase transition; however, 2H and 14N NMR line shapes indicate that subtle ordering of the MA cation occurs in the tetragonal phase. The temperature dependence of the cation ordering is rationalized using a six-site model, with two equivalent sites along the c-axis and four equivalent sites either perpendicular or approximately perpendicular to this axis. As the cubic ↔ tetragonal phase transition temperature is approached, the six sites are nearly equally populated. Below the tetragonal ↔ orthorhombic phase transition, 2H NMR line shapes indicate that the C-N axis is essentially frozen.

Propofol attenuates BV2 microglia inflammation via NMDA receptor inhibition.

Activated microglia, involved in the occurrence and improvement of sepsis-associated encephalopathy, can induce the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, resulting in inflammation-mediated neuronal cell death. It was reported that propofol could inhibit lipopolysaccharide (LPS) induced pro-inflammatory cytokine and pro-inflammatory enzyme expression in BV2 and primary microglial cells. However, the underlying mechanism is not well known. In the present study, we investigated whether and how propofol inhibited LPS-induced the expression of pro-inflammatory cytokines and pro-inflammatory enzymes in BV2 cells. LPS induced pro-inflammatory cytokine and pro-inflammatory enzyme expression, NF-κB, extracellular regulated kinase 1/2 (ERK), calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMK II) phosphorylation, and BV2 cell Ca2+ accumulation. Propofol could reverse these effects induced by LPS. MK801, an inhibitor of the NMDA receptor, could attenuate LPS-induced Ca2+ accumulation, the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, and phosphorylation of NF-κB, ERK, and CaMK II, which was similar to propofol. Moreover, these effects of propofol could be counteracted by rapastinel, an activator of the NMDA receptor. The present study suggested that propofol, via inhibiting the NMDA receptor, attenuating Ca2+ accumulation, and inhibiting CaMK II, ERK1/2, and NF-κB phosphorylation, down-regulated LPS-induced pro-inflammatory cytokine and pro-inflammatory enzyme expression.

SET8 is involved in the regulation of hyperglycemic memory in human umbilical endothelial cells.

Hyperglycemic memory occurs in diabetic cardiovascular complications, but the underlying mechanism remains to be elucidated. Although the depletion of SET8 leads to increased mitochondrial oxidative stress via increasing cellular reactive oxygen species (ROS) production, the role of SET8 in hyperglycemic memory-induced mitochondrial dysfunction is not well understood. Here, we investigated the role of SET8 in this setting. Our results showed that high glucose-induced vascular inflammation, ROS production and apoptosis remained at high levels even when glucose returned to normal level. Elevated glucose reduced SET8 expression, which also remained at low level after returning to normoglycemia. SET8 overexpression protected cells from elevated glucose and hyperglycemic memory-induced endothelial injury by blocking ROS accumulation, attenuating vascular inflammation, and restoring nitric oxide production. Thus, our results suggest that SET8 may be a key mediator in hyperglycemic memory.

Nalmefene attenuates malignant potential in colorectal cancer cell via inhibition of opioid receptor.

Morphine is postulated a risk factor in promoting tumor growth and metastasis during the preoperative period, and high glycolysis of tumor cells is proved to accelerate tumor progression. In this study, we investigated whether nalmefene, an opioid receptor inhibitor, could inhibit CT26 colon cancer cell growth through influencing cell glycolysis. CCK8 and transwell migration assays showed that nalmefene inhibited CT26 cells viability and migration in a concentration-dependent manner. Extracellular acidification rate and oxygen consumption rate showed that nalmefene inhibited glycolysis of CT26 cells. Moreover, western blot analysis and quantitative real-time PCR revealed that nalmefene decreased the expressions of enzymes related to glycolysis. Flow cytometry results revealed that intracellular calcium (Ca2+) level was changed by nalmefene, western blot analysis showed that nalmefene decreased calmodulin expression and calcium/calmodulin dependent protein kinases II (CaMK II) phosphorylation, thus inhibiting the serine/threonine kinase (AKT)-glycogen synthase kinase-3ß (GSK-3ß) pathway. Furthermore, the effects of KN93, an inhibitor of CaMK II, were similar to the effects of nalmefene, and the anti-tumor effect of nalmefene could be counteracted by morphine. In conclusion, the anti-tumor effect of nalmefene may be achieved by inhibiting opioid receptor and down-regulating calmodulin expression and CaMK II phosphorylation, thus inhibiting AKT-GSK-3ß pathway and the glycolysis of CT26 cells.