Remimazolam Attenuates LPS-Derived Cognitive Dysfunction via Subdiaphragmatic Vagus Nerve Target α7nAChR-Mediated Nrf2/HO-1 Signal Pathway.

Sepsis-induced neuroinflammation is significantly associated with sepsis-related brain dysfunction. Remimazolam is a novel ultra-short-acting benzodiazepine anesthetic with multiple organ protective effects. However, it is unknown whether remimazolam can ameliorate LPS-induced brain impairment. In this study, Lipopolysaccharide (5 mg/kg, LPS) severely impaired Sprague-Dawley rats spatial learning ability, memory, and cognitive function. However, remimazolam treatment showed a protective effect on LPS-induced cognitive dysfunction. Remimazolam partly reversed LPS-induced splenomegaly, decreased serum cytokine expression, suppressed hippocampal M1 microglial activation, and mitigated oxidative stress injury and neuroinflammation. Electroacupuncture (EA) or PNU282987 treatment improved LPS-induced cognitive dysfunction and also significantly inhibited neuroinflammation and systemic inflammation. However, MLA, ML385, or subdiaphragmatic vagus nerve (SDV) treatment abolished the protective effects of remimazolam. Further mechanistic studies showed that remimazolam induces protective effects by activating subdiaphragmatic vagus nerve target α7nAChR-mediated Nrf2/HO-1 signaling pathway. These results demonstrate that remimazolam can up-regulate α7nAChR, Cyto-Nrf2, HO-1, and cognitive-related (CREB, BDNF, PSD95) protein expressions, suppress M1 microglia, ameliorate neuroinflammation or systemic inflammation, and reverse cognitive dysfunction. Therefore, this study provides insight into a new therapeutic target for the treatment of sepsis-induced cerebral dysfunction.

Propofol-induced sleep ameliorates cognition impairment in sleep-deprived rats.

PURPOSE: Propofol has been shown to clear sleep debt in rats after sleep deprivation (SD). We examined whether or not propofol-assisted sleep can restore cognitive function in SD rats and explored the possible mechanisms. METHODS: A sleep deprivation model was established by housing 9 to 12 week-old rats to a multiplatform water tank for 96 h. Model rats were then intraperitoneally injected with different concentrations of propofol or 10% fat emulsion (vehicle control). All treatment groups were examined for spatial learning and memory ability in the Morris water maze (MWM). After euthanasia, morphological changes in the hippocampus, hippocampal neurons, and mitochondria were examined by hematoxylin-eosin staining and transmission electron microscopy. Serum and hippocampal levels of IL-1ß, TNF-α, and hippocampal concentrations of ATP and Cyt-c were measured by ELISA (enzyme-linked immunosorbent assay). Immunohistochemistry and Western blotting were performed to assess hippocampal expression of Bcl-2, Bax, and cleaved caspase-3. RESULTS: Results showed that escape latencies in MWM training trials were significantly shorter and target crossings in the memory probe trial significantly greater in propofol-treated SD model rats compared to vehicle-treated SD rats. Propofol also reduced the number of apoptotic bodies in the hippocampal CA1 region. Sleep deprivation reduced IL-1ß and ATP in hippocampus while increasing TNF-α and Cyt-c, and propofol treatment reversed all these changes. There was no significant difference in Bcl-2 expression between propofol- and vehicle-treated SD rats, but pro-apoptotic Bax and cleaved caspase-3 expression levels were significantly reduced by propofol in SD rats. CONCLUSIONS: Propofol-assisted sleep restored cognitive function in SD rats possibly by attenuating mitochondria-mediated neuronal apoptosis in the hippocampus.

Functional modular networks identify the pivotal genes associated with morphine addiction and potential drug therapies.

BACKGROUND: Chronic morphine usage induces lasting molecular and microcellular adaptations in distinct brain areas, resulting in addiction-related behavioural abnormalities, drug-seeking, and relapse. Nonetheless, the mechanisms of action of the genes responsible for morphine addiction have not been exhaustively studied. METHODS: We obtained morphine addiction-related datasets from the Gene Expression Omnibus (GEO) database and screened for Differentially Expressed Genes (DEGs). Weighted Gene Co-expression Network Analysis (WGCNA) functional modularity constructs were analyzed for genes associated with clinical traits. Venn diagrams were filtered for intersecting common DEGs (CDEGs). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for functional annotation. Protein-protein interaction network (PPI) and CytoHubba were used to screen for hub genes. Potential treatments for morphine addiction were figured out with the help of an online database. RESULTS: Sixty-five common differential genes linked to morphine addiction were identified, and functional enrichment analysis showed that they were primarily involved in ion channel activity, protein transport, the oxytocin signalling pathway, neuroactive ligand-receptor interactions, and other signalling pathways. Based on the PPI network, ten hub genes (CHN2, OLIG2, UGT8A, CACNB2, TIMP3, FKBP5, ZBTB16, TSC22D3, ISL1, and SLC2A1) were checked. In the data set GSE7762, all of the Area Under Curve (AUC) values for the hub gene Receiver Operating Characteristic (ROC) curves were greater than 0.8. We also used the DGIdb database to look for eight small-molecule drugs that might be useful for treating morphine addiction. CONCLUSIONS: The hub genes are crucial genes associated with morphine addiction in the mouse striatum. The oxytocin signalling pathway may play a vital role in developing morphine addiction.

Correlation and influencing factors of preoperative anxiety, postoperative pain, and delirium in elderly patients undergoing gastrointestinal cancer surgery.

BACKGROUND: The correlation and influencing factors of preoperative anxiety, postoperative pain, and delirium in elderly patients undergoing gastrointestinal cancer surgery were explored with the Beck Anxiety Inventory (BAI) scale, 10-point Visual Analogue Scale (VAS), and Confusion Assessment Method Chinese Reversion (CAM-CR) scale. METHODS: A total of 120 patients aged 65 years old who receiving gastrointestinal cancer surgery were enrolled in the study. Perioperative anxiety, pain, and delirium were assessed by the BAI scale, VAS scale, and CAM-CR scale, respectively. The correlation and influencing factors of preoperative high anxiety, postoperative high pain, and postoperative delirium were analyzed. RESULTS: Preoperative high anxiety had a moderate positive correlation with postoperative high pain (P < 0.001, r = 0.410), and had a weak positive correlation with postoperative delirium (P = 0.005, r = 0.281). postoperative high pain had a weak positive correlation with postoperative delirium (P = 0.017, r = 0.236). Type of cancer and surgical approach were considered to be independent risk factors of preoperative high anxiety (P = 0.006 and P = 0.021). Preoperative high anxiety was considered to be an independent risk factor of postoperative high pain (P< 0.001). Age and preoperative high anxiety were considered to be independent risk factors of postoperative delirium (P< 0.001 and P = 0.010). CONCLUSIONS: Elderly patients undergoing gastrointestinal cancer surgery had a higher incidence of preoperative anxiety, as well as first-day postoperative pain and first-day postoperative delirium. Factors such as type of cancer, surgical approach and preoperative anxiety had been identified as influencing preoperative anxiety levels; preoperative anxiety had been linked to postoperative pain; and age and preoperative anxiety have been identified as influencing factors of postoperative delirium. TRIAL REGISTRATION: hiCTR2000032008, 17/04/2020, Title: "Effects of different analgesic methods on postoperative recovery of elderly patients with digestive tract tumor". Website: https://www.chictr.ogr.cn .

Effects of penehyclidine hydrochloride combined with dexmedetomidine on pulmonary function in patients undergoing heart valve surgery: a double-blind, randomized trial.

AIM: To investigate the effects of penehyclidine hydrochloride combined with dexmedetomidine on pulmonary function in patients undergoing heart valve surgery with cardiopulmonary bypass (CPB). METHODS: A total of 180 patients undergoing elective heart valve surgery with CPB were randomly divided into four groups: 45 in group P (intravenous penehyclidine hydrochloride 0.02 mg/kg 10 min before anesthesia induction and at the beginning of CPB, total 0.04 mg/kg); 43 in group D (dexmedetomidine 0.5 µg/kg/h after induction of anesthesia until the end of anesthesia); 44 in group PD ( penehyclidine hydrochloride 0.04 mg/kg combined with dexmedetomidine 0.5 µg/kg/h intravenously during anesthesia); and 43 in group C (same amount of normal saline 10 min before and after anesthesia induction, to the end of anesthesia, and at the beginning of CPB). The main outcomes were the incidence and severity of postoperative pulmonary complications (PPCs). The secondary outcomes were: (1) extubation time, length of stay in intensive care, and postoperative hospital stay, and adverse events; and (2) pulmonary function evaluation indices (oxygenation index and respiratory index) and plasma inflammatory factor concentrations (tumor necrosis factor-α, interleukin-6, C-reactive protein and procalcitonin) during the perioperative period. RESULTS: The incidence of PPCs in groups P, D and PD after CPB was lower than that in group C (P < 0.05), and the incidence in group PD was significantly lower than that in groups P and D (P < 0.05). The scores for PPCs in groups P, D and PD were lower than those in group C (P < 0.05). CONCLUSION: Combined use of penehyclidine hydrochloride and dexmedetomidine during anesthesia reduced the occurrence of postoperative pulmonary dysfunction, and improved the prognosis of patients undergoing heart valve surgery with CPB. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry on 3/11/2020 (Registration No.: ChiCTR2000039610).

Optimal dose of perineural dexmedetomidine to prolong analgesia after brachial plexus blockade: a systematic review and Meta-analysis of 57 randomized clinical trials.

BACKGROUND AND OBJECTIVES: Peripheral injection of dexmedetomidine (DEX) has been widely used in regional anesthesia to prolong the duration of analgesia. However, the optimal perineural dose of DEX is still uncertain. It is important to elucidate this characteristic because DEX may cause dose-dependent complications. The aim of this meta-analysis was to determine the optimal dose of perineural DEX for prolonged analgesia after brachial plexus block (BPB) in adult patients undergoing upper limb surgery. METHOD: A search strategy was created to identify suitable randomized clinical trials (RCTs) in Embase, PubMed and The Cochrane Library from inception date to Jan, 2021. All adult patients undergoing upper limb surgery under BPB were eligible. The RCTs comparing DEX as an adjuvant to local anesthetic (LA) with LA alone for BPB were included. The primary outcome was duration of analgesia for perineural DEX. Secondary outcomes included visual analog scale (VAS) in 12 and 24 h, consumption of analgesics in 24 h, and adverse events. RESULTS: Fifty-seven RCTs, including 3332 patients, were identified. The subgroup analyses and regression analyses revealed that perineural DEX dose of 30-50 µg is an appropriate dosage. With short-/intermediate-acting LAs, the mean difference (95% confidence interval [CI]) of analgesia duration with less than and more than 60 µg doses was 220.31 (153.13-287.48) minutes and 68.01 (36.37-99.66) minutes, respectively. With long-acting LAs, the mean differences (95% CI) with less than and more than 60 µg doses were 332.45 (288.43-376.48) minutes and 284.85 (220.31-349.39) minutes. CONCLUSION: 30-50 µg DEX as adjuvant can provides a longer analgesic time compared to LA alone and it did not increase the risk of bradycardia and hypotension.

Crosstalk between Cdk5/p35 and ERK1/2 signalling mediates spinal astrocyte activity via the PPARγ pathway in a rat model of chronic constriction injury.

The specific mechanisms underlying cyclin-dependent kinase 5 (Cdk5)-mediated neuropathic pain at the spinal cord level remain elusive. The aim of the present study was to explore the role of crosstalk between Cdk5/p35 and extracellular signal-regulated kinase 1/2 (ERK1/2) signalling in mediating spinal astrocyte activity via the PPARγ pathway in a rat model of chronic constriction injury (CCI). Here, we quantified pain behaviour after CCI; detected the localization of p35, Cdk5, phosphorylated ERK1/2 (pERK1/2), phosphorylated peroxisome proliferator-activated receptor γ (pPPARγ), neuronal nuclei (a neuronal marker), glial fibrillary acidic protein (GFAP, an activated astrocyte marker) and ionized calcium binding adaptor molecule 1 (a microglial marker) in the dorsal horn using immunofluorescence; measured the protein levels of Cdk5, p35, pERK1/2, pPPARγ and GFAP using western blot analysis; and gauged the enzyme activity of Cdk5/p35 kinase using a Cdk5/p35 kinase activity assay kit. Tumour necrosis factor-α, interleukin (IL)-1ß and IL-6 levels were measured using enzyme-linked immunosorbent assay (ELISA). Ligation of the right sciatic nerve induced mechanical allodynia; thermal hyperalgesia; and the time-dependent upregulation of p35, pERK1/2 and GFAP and downregulation of pPPARγ. p35 colocalized with Cdk5, pERK1/2, pPPARγ, neurons and astrocytes but not microglia. Meanwhile, intrathecal injection of the Cdk5 inhibitor roscovitine, the mitogen-activated ERK kinase (MEK) inhibitor U0126 and the PPARγ agonist pioglitazone prevented or reversed behavioural allodynia, increased pPPARγ expression, inhibited astrocyte activation and alleviated proinflammatory cytokine (tumour necrosis factor-α, IL-1ß, and IL-6) release from activated astrocytes. Furthermore, crosstalk between the Cdk5/p35 and ERK1/2 pathways was observed with CCI. Blockade of either Cdk5/p35 or ERK1/2 inhibited Cdk5 activity. These findings indicate that spinal crosstalk between the Cdk5/p35 and ERK1/2 pathways mediates astrocyte activity via the PPARγ pathway in CCI rats and that targeting this crosstalk could be an effective strategy to attenuate CCI and astrocyte-derived neuroinflammation.

Morphine Can Inhibit the Growth of Breast Cancer MCF-7 Cells by Arresting the Cell Cycle and Inducing Apoptosis.

Morphine is widely used for relieving cancer pain in patients with advanced cancer. However, whether morphine can suppress or promote the progression of cancer in breast cancer patients receiving morphine analgesia remains unclear. Therefore, we used an in vitro model treated with morphine and naloxone to investigate the effects of morphine on breast cancer cell line MCF-7. MCF-7 cells were cultured with different concentrations (0.01 to 10 µM) of morphine at 12th, 24th, 36th, 48th, 60th and 72nd hours. Then, cell viability was measured through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell cycle and apoptosis assays were detected by flow cytometry (FCM). In addition, cell proliferation was conducted by colony formation assay. In this study, we have found that morphine (0.01 to 10 µM) could significantly reduce the cell vitality, growth and colony formation rate of MCF-7 cells, which has a certain relationship with cell cycle progression arrested at the G0/G1 and G2/M phase and MCF-7 cells apoptosis. Moreover, naloxone along with morphine could not reverse these effects, which indicates that the inhibition of MCF-7 breast cancer cell growth and proliferation by morphine could be its independent effect, not associated with opioid receptors. Morphine can inhibit cell growth by blocking the cell cycle and promote apoptosis in MCF-7 cells. Hence, morphine may be unable to promote the progression of cancer in breast cancer patients receiving morphine analgesia.

Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo.

Cisplatin-based therapy is one of the most important chemotherapy treatments for cancers. However, its efficacy is greatly limited by drug resistance and undesirable side effects. Therefore, it is of great importance to develop effective chemosensitization agents to cisplatin. In the present study, we demonstrated the strategy to use shikonin, a natural product from the root of Lithospermum erythrorhizon, as a synergistic agent of cisplatin and elucidated their action mechanisms. The combination of shikonin and cisplatin exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cells and normal cells. By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway. In addition, inhibition of ROS reversed the apoptosis induced by shikonin and cisplatin, and recovered the depletion of mitochondrial membrane potential, which revealed the vital role of ROS in the synergism. Moreover, HCT116 xenograft tumor growth in nude mice was more effectively inhibited by combined treatment with shikonin and cisplatin. Our findings suggest that the strategy to apply shikonin as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by inducing intracellular oxidative stress. Shikonin may be a promising candidate as a chemosensitizer to cisplatin-based therapy for cancer treatments.

Reversal of multidrug resistance in gastric cancer cells by E2F-1 downregulation in vitro and in vivo.

UNLABELLED: Transcription Factor E2F-1 plays a critical role in cell cycle regulation and other biological processes in cells. However whether or not it is involved in the multi-drug resistance (MDR) process of gastric cancer has not been fully elucidated yet. To explore the role of E2F-1 in the MDR process of gastric cancer in vitro and in vivo, a cisplatin-resistant gastric cancer cell line with stable downregulation of E2F-1 was established. E2F-1 shRNA led to downregulation of endogenous E2F-1 mRNA and protein. It significantly promoted the sensitivity of SGC7901/DDP cells to cisplatin, doxorubicin, and fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells increased after E2F-1 downregulation. This notion was further supported by the observation that downregulation of E2F-1 blocked entry into the S-phase of the cell cycle. Furthermore, downregulation of E2F-1 significantly increased intracellular accumulation of doxorubicin. In addition, we determined the in vivo effects of E2F-1 small interfering RNA (shRNA) on tumor size, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining. In molecular studies, semiquantitative RT-PCR and western blotting revealed that E2F-1 downregulation could inhibit expression of MDR1, MRP, Bcl-2/Bax, c-Myc, Skp2, Survivin, and Cyclin D1. IN CONCLUSION: E2F-1 may be involved in regulating multiple signaling pathways in reversing MDR, suggesting that E2F-1 may represent a novel target for gastric cancer therapy.

Amplified spontaneous emission via the coupling between Fabry-Perot cavity and surface plasmon polariton modes.

We demonstrated amplified spontaneous emission by embedding dye molecules within a dielectric layer of a metal-dielectric-metal subwavelength structure. It was reinforced when a strong coupling occurred between the Fabry-Perot mode supported by the dielectric layer and the surface plasmon polariton mode supported by the adjacent metallic grating. Here, we adjust the two mode interaction via tuning the depth of the metallic grating grooves. The stronger the interaction, the smaller the full width at half-maximum of the emission spectra and the lower the threshold of the amplified spontaneous emission.

Overexpression of E2F1 in human gastric carcinoma is involved in anti-cancer drug resistance.

BACKGROUND: Routine chemotherapy often cannot achieve good therapeutic effects because of multidrug resistance (MDR). MDR is frequently caused by the elevated expression of the MDR1 gene encoding P-glycoprotein (P-gp). E2F1 is a frequently overexpressed protein in human tumor cells that increases the activity of the MDR1 promoter, resulting in higher P-gp levels. The upregulation of P-gp might contribute to the survival of tumor cells during chemotherapy. E2F1 confers anticancer drug resistance; however, we speculate whether E2F1 affects MDR through other pathways. This study investigated the possible involvement of E2F1 in anticancer drug resistance of gastric carcinoma in vitro and in vivo. METHODS: A cisplatin-resistant SGC7901/DDP gastric cancer cell line with stable overexpression of E2F1 was established. Protein expression levels of E2F1, MDR1, MRP, TAp73, GAX, ZEB1, and ZEB2 were detected by western blotting. The influence of overexpression of E2F1 on anticancer drug resistance was assessed by measuring IC50 of SGC7901/DDP cells to cisplatin, doxorubicin, and 5-fluorouracil, as well as the rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. We determined the in vivo effects of E2F1-overexpression on tumor size in nude mice, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining. RESULTS: The SGC7901/DDP gastric cancer cell line stably overexpressing E2F1 exhibited significantly inhibited sensitivity to cisplatin, doxorubicin, and 5-fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells decreased after E2F1 upregulation, and that upregulation of E2F1 potentiated S phase arrest of the cell cycle. Furthermore, upregulation of E2F1 significantly decreased intracellular accumulation of doxorubicin. Western blot revealed that E2F1 upregulation suppressed expression of GAX, and increased the expression of MDR1, MRP, ZEB1, TAp73, and ZEB2. CONCLUSIONS: Overexpression of E2F1 promotes the development of MDR in gastric carcinoma, suggesting that E2F1 may represent an efficacious target for gastric cancer therapy.

Propofol inhibits proliferation and induces neuroapoptosis of hippocampal neurons in vitro via downregulation of NF-κB p65 and Bcl-2 and upregulation of caspase-3.

Propofol is widely used in paediatric anaesthesia and intensive care unit because of its essentially short-acting anaesthetic effect. Recent data have shown that propofol induced neurotoxicity in developing brain. However, the mechanisms are not extremely clear. To gain a better insight into the toxic effects of propofol on hippocampal neurons, we treated cells at the days in vitro 7 (DIV 7), which were prepared from Sprague-Dawley embryos at the 18th day of gestation, with propofol (0.1-1000 µM) for 3 h. A significant decrease in neuronal proliferation and a remarkable increase in neuroapoptosis were observed in DIV 7 hippocampal neurons as measured by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptosis assay respectively. Moreover, propofol treatment decreased the nuclear factor kappaB (NF-κB) p65 expression, which was accompanied by a reduction in B-cell lymphoma 2 (Bcl-2) mRNA and protein levels, increased caspase-3 mRNA and activation of caspase-3 protein. These results indicated that downregulation of NF-κB p65 and Bcl-2 were involved in the potential mechanisms of propofol-induced neurotoxicity. This likely led to the caspase-3 activation, triggered apoptosis and inhibited the neuronal growth and proliferation that we have observed in our in vitro systems.

[Reversion of multidrug resistance of human gastric cancer SGC7901/DDP cells by E2F-1 gene silencing].

OBJECTIVE: To investigate the effects of E2F-1 gene silencing on multidrug resistance of human gastric cancer SGC7901/DDP cells and its possible mechanisms. METHODS: Gastric cancer SGC7901/DDP cells were seeded in 6 well plates and divided into three groups: the experimental group, blank control and the negative control groups. For the experimental group, the SGC7901/DDP cells were transfected with recombinant lentivirus vector (Lv-shRNA-E2F-1), while the negative control with an control lentiviral vector (Lv-shRNA-NC) and the blank control with no treatment. The E2F-1 protein level was analyzed by Western blot. MTT assay was used to detect the half maximal inhibitory concentration (IC50) of three chemotherapy drugs including adriamycin, 5-fluorouracil (5-Fu) and cisplatine (DDP) of the three cell groups. Flow cytometry (FCM) was used to detect the pump-out rate of adriamycin and apoptosis rate of the three cell groups. Semi-quantitative RT-PCR and Western blot were also used to detect the protein and mRNA levels of multidrug resistance-associated genes (MDR1, MRP) and apoptosis-related genes (c-Myc, Skp2, cyclinD1). RESULTS: The expression of E2F-1 protein in the experimental group was significantly lower than that in the negative control and blank control groups (0.794 ± 0.033 vs. 1.487 ± 0.082 vs. 1.511 ± 0.084, P < 0.01). The IC50 of the three chemotherapy drugs (adriamycin, 5-Fu and cisplatine) in the experimental group was significantly lower than that of the negative control and blank control groups, respectively (P < 0.01). Compared with the negative control and blank control groups, the pump-out rate of adriamycin of the experimental group was significantly declined [(0.16 ± 0.01)% vs. (0.37 ± 0.01)% vs. (0.35 ± 0.02)%, P < 0.01]. However, the apoptosis rate of the experimental group was significantly higher than that of the negative control and blank control groups [(33.82 ± 1.26)% vs. (17.34 ± 0.81)% vs. (13.16 ± 1.06)%, P < 0.01]. The results of RT-PCR and Western blot assays showed that mRNA and protein expressions of five genes (MDR1, MRP, CyclinD1, c-Myc, Skp2) in the experimental group were significantly lower than that in the negative control and blank control groups, respectively (P < 0.01). CONCLUSIONS: E2F-1 gene silencing enhances the chemosensitivity of gastric cancer SGC7901/DDP cells to the chemotherapeutic drugs, directly or indirectly downregulated the expression of MDR1 and MRP, and finally reverses the multidrug resistance of the gastric cancer cells. The mechanism may be associated with the suppression of cyclinD1, c-Myc and Skp2.

Construction of a predictive model for blood transfusion in patients undergoing total hip arthroplasty and identification of clinical heterogeneity.

A precise forecast of the need for blood transfusions (BT) in patients undergoing total hip arthroplasty (THA) is a crucial step toward the implementation of precision medicine. To achieve this goal, we utilized supervised machine learning (SML) techniques to establish a predictive model for BT requirements in THA patients. Additionally, we employed unsupervised machine learning (UML) approaches to identify clinical heterogeneity among these patients. In this study, we recruited 224 patients undergoing THA. To identify factors predictive of BT during the perioperative period of THA, we employed LASSO regression and the random forest (RF) algorithm as part of supervised machine learning (SML). Using logistic regression, we developed a predictive model for BT in THA patients. Furthermore, we utilized unsupervised machine learning (UML) techniques to cluster THA patients who required BT based on similar clinical features. The resulting clusters were subsequently visualized and validated. We constructed a predictive model for THA patients who required BT based on six predictive factors: Age, Body Mass Index (BMI), Hemoglobin (HGB), Platelet (PLT), Bleeding Volume, and Urine Volume. Before surgery, 1 h after surgery, 1 day after surgery, and 1 week after surgery, significant differences were observed in HGB and PLT levels between patients who received BT and those who did not. The predictive model achieved an AUC of 0.899. Employing UML, we identified two distinct clusters with significantly heterogeneous clinical characteristics. Age, BMI, PLT, HGB, bleeding volume, and urine volume were found to be independent predictors of BT requirement in THA patients. The predictive model incorporating these six predictors demonstrated excellent predictive performance. Furthermore, employing UML enabled us to classify a heterogeneous cohort of THA patients who received BT in a meaningful and interpretable manner.

The Safety and Efficacy of Remimazolam Compared to Dexmedetomidine for Awake Tracheal Intubation by Flexible Bronchoscopy: A Randomized, Double-Blind, Controlled Trial.

Background: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that has the potential to be an alternative for procedural sedation due to its rapid sedation and recovery, no accumulation effect, stable hemodynamics, minimal respiratory depression, anterograde amnesia effect, and specific antagonist. Here, we aimed to compare the safety and efficacy of remimazolam with dexmedetomidine for awake tracheal intubation by flexible bronchoscopy (ATI-FB). Methods: Ninety patients scheduled for ATI-FB were randomly divided into three groups, each consisting of 30 cases: dexmedetomidine 0.6 µg/kg + sufentanil (group DS), remimazolam 0.073 mg/kg + sufentanil (group R1S), or remimazolam 0.093 mg/kg + sufentanil (group R2S). The primary outcome was the success rate of sedation. Secondary outcomes were MOAA/S scores, hemodynamic and respiratory parameters, intubation conditions, intubation time, tracheal intubation amnesia, and adverse events. Results: The success rates of sedation in groups R2S and DS were higher than that in group R1S (93.3%, 86.7%, respectively, vs 58.6%; P = 0.002), and intubation conditions were better than those in group R1S (P < 0.05). Group R2S had shorter intubation times than groups R1S and DS (P = 0.003), and a higher incidence of tracheal intubation amnesia than group DS (P = 0.006). No patient in the three groups developed hypoxemia or hypotension, and there were no significant differences in oligopnea, PetCO2, or bradycardia (P > 0.05). Conclusion: In conclusion, both DS and R2S had higher success rates of sedation, better intubation conditions, and minor respiratory depression, but R2S, with its shorter intubation time, higher incidence of anterograde amnesia, and ability to be antagonized by specific antagonists, may be a good alternative sedation regimen for patients undergoing ATI-FB.

The Influencing Factors of Frailty and Quality of Life in Elderly Patients After Spinal Surgery.

Background: To study the related factors of frailty and quality of life in elderly patients after spinal surgery. Methods: The anxiety, depression, frailty, and quality of life of all patients were assessed by the Anxiety screening scale (GAD-7), Depression screening scale (PHQ-9), Frailty screening scale (FRAIL), and European five-dimensional health scale (EQ-5D-5L) 1 day before surgery (DAY-0). A numeric rating scale (NRS) was used to evaluate patients' pain during activities on the 1st day (POD-1), 3rd day (POD-3), and 30th day (POD-30) after operation. FRAIL scale and EQ-5D-5L were used to evaluate patients' frailty and quality of life on POD-30 and 90th day (POD-90) after the operation. Results: There were significant differences in age, body mass index (BMI), preoperative serum albumin level (ALB), and NRS score on POD-1 between the two groups (P<0.05). Age and PHQ-9 score were positively correlated with EQ-5D-5L score (P<0.05, r Age=0.245, rPHQ-9=0.217), and preoperative ALB level was negatively correlated with EQ-5D-5L score (P<0.05, r ALB=-0.274). Conclusion: The older the age, the larger the BMI and the higher the NRS score on the first day after surgery, the more prone to frailty in elderly patients after spinal surgery; The older age and the lower the preoperative ALB level, the worse the quality of life in elderly patients after spinal surgery.

Transfer of massive mitochondria from astrocytes reduce propofol neurotoxicity.

Studies have shown that propofol-induced neurotoxicity is mediated by disruption of mitochondrial fission and fusion, leading to an imbalance in energy supply for developing neurons. Healthy mitochondria released from astrocytes migrate to compromised neurons to mitigate propofol-induced neurotoxicity, yet the precise mechanisms involved require further clarification. In our investigation, primary neurons were incubated with propofol, which decreased ATP synthesis and mitochondrial membrane potential, increased ROS generation and neuronal apoptosis. Notably, astrocytes did not respond to the deleterious effects of propofol. The culture medium of neurons or astrocytes incubated with propofol was collected. It was found that mitochondrial ratio was decreased and mitochondrial function was impaired. Non-contact co-culture of neuro-astrocytes facilitated transcellular mitochondrial transfer in both physiological and propofol interventions, but failed to reverse propofol-induced neurotoxicity. The more pronounced damage to neuronal mitochondria induced by propofol compared to that in astrocytes alludes to secondary injury. Damaged neurons incubated with large, functional extracellular mitochondria derived from astrocytes demonstrates transfer of mitochondria to neurons, effectively reversing propofol-induced neurotoxicity. This discovery presents a novel mitochondrial transfer of neuro-astrocytes crosstalk that contributes to neuroprotection and neurological recovery in neurotoxicity.

Association of peripheral B cells and delirium: combined single-cell sequencing and Mendelian randomization analysis.

Background: Delirium seriously affects the prognosis of patients and greatly reduces the ability to work and live. Peripheral inflammatory events may contribute to the development of delirium, the mechanism of which is still unclear. There is a lack of effective diagnostic and treatments for delirium in clinical practice. The study aims to investigate alterations in peripheral immune cell subsets under inflammatory stress and to explore causal associations with delirium. Methods: Single-cell transcriptional sequencing data of human peripheral blood mononuclear cells (PBMC) before and after lipopolysaccharide (LPS) intervention were processed by the Seurat package in R software. PBMC subsets and cellular markers were defined after downscaling and clustering by the Harmony algorithm to identify characteristic subsets in the context of inflammatory stress. Subsequently, a two-sample Mendelian randomization (MR) study was used to explore the causal associations of these inflammation-related PBMC subsets and their molecular phenotypes with delirium. Based on publicly available genetic data, the study incorporated 70 PBMC-associated immune traits, including 8 types of circulating immune cells, 33 B cell subsets and molecular phenotypes, 13 T cell subsets, and 16 B cell-associated cytokines. The results were also validated for robustness, heterogeneity, and horizontal pleiotropy. Results: Under LPS-induced inflammatory stress, B cells, T cells, monocytes, and dendritic cells in human PBMC showed significant activation and quantitative changes. Of these, only lymphocyte and B cell counts were causally associated with delirium risk. This risk link is also seen in the TNF pathway. Further studies of B cells and their subsets revealed that this association may be related to unswitched memory B cells and CD27 expressed on memory B cells. Annotation of the screened SNPs revealed significant polymorphisms in CD27 and CD40 annotated by rs25680 and rs9883798, respectively. The functions of the key annotated genes may be related to the regulation of immune responses, cell differentiation, proliferation, and intercellular interactions. Conclusion: The present study revealed the potential possibility that B cell, memory B cell subset, and TNF-related molecules may be involved in the development of delirium due to peripheral inflammation, which can provide clues for further investigation of delirium prevention and treatment strategies.