The role of perioperative sedative anesthetics in preventing postoperative delirium: a systematic review and network-meta analysis including 6679 patients.

OBJECTIVE: Postoperative delirium is a common and debilitating complication that significantly affects patients and their families. The purpose of this study is to investigate whether there is an effective sedative that can prevent postoperative delirium while also examining the safety of using sedatives during the perioperative period. METHODS: The net-meta analysis was used to compare the incidence of postoperative delirium among four sedatives: sevoflurane, propofol, dexmedetomidine, and midazolam. Interventions were ranked according to their surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 41 RCT studies involving 6679 patients were analyzed. Dexmedetomidine can effectively reduce the incidence of postoperative delirium than propofol (OR 0.47 95% CI 0.25-0.90), midazolam (OR 0.42 95% CI 0.17-1.00), normal saline (OR 0.42 95% CI 0.33-0.54) and sevoflurane (OR 0.39 95% CI 0.18-0.82). The saline group showed a significantly lower incidence of bradycardia compared to the group receiving dexmedetomidine (OR 0.55 95% CI 0.37-0.80). In cardiac surgery, midazolam (OR 3.34 95%CI 2.04-5.48) and normal saline (OR 2.27 95%CI 1.17-4.39) had a higher rate of postoperative delirium than dexmedetomidine, while in non-cardiac surgery, normal saline (OR 1.98 95%CI 1.44-2.71) was more susceptible to postoperative delirium than dexmedetomidine. CONCLUSION: Our analysis suggests that dexmedetomidine is an effective sedative in preventing postoperative delirium whether in cardiac surgery or non-cardiac surgery. The preventive effect of dexmedetomidine on postoperative delirium becomes more apparent with longer surgical and extubation times. However, it should be administered with caution as it was found to be associated with bradycardia.

Shen Yuan extract exerts a hypnotic effect via the tryptophan/5-hydroxytryptamine/melatonin pathway in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep plays a critical role in several physiologic processes, and sleep disorders increase the risk of depression, dementia, stroke, cancer, and other diseases. Stress is one of the main causes of sleep disorders. Ginseng Radix et Rhizoma and Polygalae Radix have been reported to have effects of calming the mind and intensifying intelligence in Chinese Pharmacopoeia. Traditional Chinese medicine prescriptions composed of Ginseng Radix et Rhizoma and Polygalae Radix (Shen Yuan, SY) are commonly used to treat insomnia, depression, and other psychiatric disorders in clinical practice. Unfortunately, the underlying mechanisms of the SY extract's effect on sleep are still unknown. AIM OF THE STUDY: This study aimed to investigate the hypnotic effect of the SY extract in normal mice and mice with chronic restraint stress (CRS)-induced sleep disorders and elucidate the underlying mechanisms. MATERIALS AND METHODS: The SY extract (0.5 and 1.0 g/kg) was intragastrically administered to normal mice for 1, 14, and 28 days and to CRS-treated mice for 28 days. The open field test (OFT) and pentobarbital sodium-induced sleep test (PST) were used to evaluate the hypnotic effect of the SY extract. Liquid chromatography-tandem mass spectrometry and enzyme-linked immunosorbent assay were utilized to detect the levels of neurotransmitters and hormones. Molecular changes at the mRNA and protein levels were determined using real-time quantitative polymerase chain reaction and Western blot analysis to identify the mechanisms by which SY improves sleep disorders. RESULTS: The SY extract decreased sleep latency and increased sleep duration in normal mice. Similarly, the sleep duration of mice subjected to CRS was increased by administering SY. The SY extract increased the levels of tryptophan (Trp) and 5-hydroxytryptamine (5-HT) and the expression of tryptophan hydroxylase 2 (TPH2) in the cortex of normal mice. The SY extract increased the Trp level, transcription and expression of estrogen receptor beta and TPH2 in the cortex in mice with sleep disorders by decreasing the serum corticosterone level, which promoted the synthesis of 5-HT. Additionally, the SY extract enhanced the expression of arylalkylamine N-acetyltransferase, which increased the melatonin level and upregulated the expressions of melatonin receptor-2 (MT2) and Cryptochrome 1 (Cry1) in the hypothalamus of mice with sleep disorders. CONCLUSIONS: The SY extract exerted a hypnotic effect via the Trp/5-HT/melatonin pathway, which augmented the synthesis of 5-HT and melatonin and further increased the expressions of MT2 and Cry1.

Plasma Metabonomics of Human Adenovirus-infected Patients with Pneumonia and Upper Respiratory Tract Infection.

OBJECTIVE: Human adenovirus (HAdV) infection is common and can develop to serious conditions with high mortality, yet the mechanism of HAdV infection remains unclear. In the present study, the serum metabolite profiles of HAdV-7-infected patients with pneumonia or upper respiratory tract infection (URTI) were explored. METHODS: In total, 35 patients were enrolled in the study following an outbreak of HAdV-7 in the army, of whom 14 had pneumonia and 21 had URTI. Blood samples were collected at the acute stage and at the recovery stage and were analyzed by untargeted metabolomics. RESULTS: Over 90% of the differential metabolites identified between the pneumonia patients and URTI patients were lipids and lipid-like molecules, including glycerophospholipids, fatty acyls, and sphingolipids. The metabolic pathways that were significantly enriched were primarily the lipid metabolism pathways, including sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism. The sphingolipid metabolism was identified as a significantly differential pathway between the pneumonia patients and URTI patients and between the acute and recovery stages for the pneumonia patients, but not between the acute and recovery stages for the URTI patients. Ceramide and lactosylceramide, involved in sphingolipid metabolism, were significantly higher in the pneumonia patients than in the URTI patients with good discrimination abilities [area under curve (AUC) 0.742 and 0.716, respectively; combination AUC 0.801]. CONCLUSION: Our results suggested that HAdV modulated lipid metabolism for both the patients with URTI and pneumonia, especially the sphingolipid metabolism involving ceramide and lactosylceramide, which might thus be a potential intervention target in the treatment of HAdV infection.

Metabolic alterations in urine among the patients with severe fever with thrombocytopenia syndrome.

BACKGROUND: The pathogenesis of severe fever with thrombocytopenia syndrome (SFTS) remained unclear. We aimed to profile the metabolic alterations in urine of SFTS patients and provide new evidence for its pathogenesis. METHODS: A case-control study was conducted in the 154th hospital in China. Totally 88 cases and 22 controls aged ≥ 18 years were enrolled. The cases were selected from laboratory-confirmed SFTS patients. The controls were selected among SFTSV-negative population. Those with diabetes, cancer, hepatitis and other sexually transmitted diseases were excluded in both groups. Fatal cases and survival cases were 1:1 matched. Inter-group differential metabolites and pathways were obtained, and the inter-group discrimination ability was evaluated. RESULTS: Tryptophan metabolism and phenylalanine metabolism were the top one important metabolism pathway in differentiating the control and case groups, and the survival and fatal groups, respectively. The significant increase of differential metabolites in tryptophan metabolism, including 5-hydroxyindoleacetate (5-HIAA), L-kynurenine (KYN), 5-hydroxy-L-tryptophan (5-HTP), 3-hydroxyanthranilic acid (3-HAA), and the increase of phenylpyruvic acid and decrease of hippuric acid in phenylalanine metabolism indicated the potential metabolic alterations in SFTSV infection. The increase of 5-HIAA, KYN, 5-HTP, phenylpyruvic acid and hippuric acid were involved in the fatal progress of SFTS patients. CONCLUSIONS: Tryptophan metabolism and phenylalanine metabolism might be involved in the pathogenesis of SFTSV infection. These findings provided new evidence for the pathogenesis and treatment of SFTS.

Development of an LC-MS/MS assay for quantification of intact INSL3 in rat plasma.

Background: Relatively large disulfide-linked polypeptides can serve as signaling molecules for a diverse array of biological processes and may be studied in animal models to investigate their function in vivo. The aim of this work was to develop an LC-MS/MS assay to measure a model peptide, INSL3, in rat plasma. Results: A dual enrichment strategy incorporating both protein precipitation and solid phase extraction was utilized to isolate INSL3 from rat plasma, followed by targeted LC-MS/MS detection. The method was able to measure full-length INSL3 (6.1 kDa) down to 0.2 ng/ml with acceptable accuracy and precision. Conclusion: The final assay was applied to support an exploratory pharmacokinetic study to evaluate steady-state concentrations of dosed INSL3 in rat plasma.

Corrigendum: A randomized controlled trial of a coping-focused family resilience intervention program for breast cancer patients: study protocol.

[This corrects the article DOI: 10.3389/fpsyg.2022.968154.].

Chrysomycin A Regulates Proliferation and Apoptosis of Neuroglioma Cells via the Akt/GSK-3ß Signaling Pathway In Vivo and In Vitro.

Glioblastoma (GBM) is a major type of primary brain tumor without ideal prognosis and it is therefore necessary to develop a novel compound possessing therapeutic effects. Chrysomycin A (Chr-A) has been reported to inhibit the proliferation, migration and invasion of U251 and U87-MG cells through the Akt/GSK-3ß signaling pathway, but the mechanism of Chr-A against glioblastoma in vivo and whether Chr-A modulates the apoptosis of neuroglioma cells is unclear. The present study aims to elucidate the potential of Chr-A against glioblastoma in vivo and how Chr-A modulates the apoptosis of neuroglioma cells. Briefly, the anti-glioblastoma activity was assessed in human glioma U87 xenografted hairless mice. Chr-A-related targets were identified via RNA-sequencing. Apoptotic ratio and caspase 3/7 activity of U251 and U87-MG cells were assayed via flow cytometry. Apoptosis-related proteins and possible molecular mechanisms were validated via Western blotting. The results showed that Chr-A treatment significantly inhibits glioblastoma progression in xenografted hairless mice, and enrichment analysis suggested that apoptosis, PI3K-Akt and Wnt signaling pathways were involved in the possible mechanisms. Chr-A increased the apoptotic ratio and the activity of caspase 3/7 in U251 and U87-MG cells. Western blotting revealed that Chr-A disturbed the balance between Bax and Bcl-2, activating a caspase cascade reaction and downregulating the expression of p-Akt and p-GSK-3ß, suggesting that Chr-A may contribute to glioblastoma regression modulating in the Akt/GSK-3ß signaling pathway to promote apoptosis of neuroglioma cells in vivo and in vitro. Therefore, Chr-A may hold therapeutic promise for glioblastoma.

Isolation and identification of 3,4-seco-labdane diterpenoids from Callicarpa nudiflora and investigation of their cytotoxicity against HepG2 cells.

Twenty-one previously undescribed compounds, including nineteen 3,4-seco-labdanes (nudiflopenes P-W, Y, AI-JI), one 3,4-seco-pimarane (nudiflopene X), and one labdane (nudiflopene Z), along with nine known compounds (one 3,4-seco-pimarane and eight 3,4-seco-labdanes) were isolated from the leaves of Callicarpa nudiflora Hook. Et Arn. The structures of these compounds were elucidated by high-resolution electrospray ionization mass spectrometry and one- and two-dimensional nuclear magnetic resonance spectroscopy. In addition, configurations of the isolated compounds were determined by electronic circular dichroism, DP4+ probability analysis, and single-crystal X-ray diffraction experiments. All undescribed compounds were evaluated for their cytotoxicity against HepG2 cells in vitro, among which compound 12 exhibited a moderate activity with an IC50 value of 27.8 µM.

The molecular mechanism of three novel peptides from C-phycocyanin alleviates MPTP-induced Parkinson's disease-like pathology in zebrafish.

Previous studies have shown that peptides isolated from C-phycocyanin (C-PC) possess various functions including antioxidant and anticancer activities. However, there is little research on C-PC peptides applied for the neuroprotective effect against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model. In this study, twelve novel peptides from C-PC were isolated, purified and identified, and the anti-PD effect of the synthesized peptides was evaluated in a zebrafish PD model. As a result, three of these peptides (MAAAHR, MPQPPAK, and MTAAAR) significantly reversed the loss of dopamine neurons and cerebral vessels, and reduced the locomotor impairment in PD zebrafish. In addition, three novel peptides could inhibit the MPTP-induced decrease of antioxidant enzymes (SOD, CAT, and GSH-Px) and increase the ROS and protein carbonylation content. In addition, they can also alleviate apoptosis of brain regions and acetylcholinesterase (AChE) activity in zebrafish. Further studies elucidated the potential molecular mechanism of peptides' anti-PD effects in the larvae. The results showed that C-PC peptides could modulate multiple genes associated with oxidative stress, autophagy and apoptosis signaling pathways, and thereby alleviate the occurrence of PD symptoms. Overall, our results highlight the neuroprotective effects of three novel peptides and provide valuable mechanistic insights and a promising drug target for the treatment of PD.

Kunxian Capsule Extract Inhibits Angiogenesis in Zebrafish Embryos via PI3K/AKT-MAPK-VEGF Pathway.

OBJECTIVE: To investigate the anti-angiogenic activity of Kunxian Capsule (KX) extract and explore the underlying molecular mechanism using zebrafish. METHODS: The KX extract was prepared with 5.0 g in 100 mL of 40% methanol followed by ultrasonication and freeze drying. Freeze dried KX extract of 10.00 mg was used as test stock solution. Triptolide and icariin, the key bioactive compounds of KX were analyzed using ultra-high performance liquid chromatography. The transgenic zebrafish Tg(flk1:GFP) embryos were dechorionated at 20-h post fertilization (hpf) and treated with PTK 787, and 3.5, 7, 14 and 21 µg/mL of KX extract, respectively. After 24-h post exposure (hpe), mortality and malformation (%), intersegmental vessels (ISV) formation, and mRNA expression level of angiogenic pathway genes including phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), mitogen-activated protein kinase (MAPK), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2) were determined. Further, the embryos at 72 hpf were treated with KX extract to observe the development of sub-intestinal vein (SIV) after 24 hpe. RESULTS: The chromatographic analysis of test stock solution of KX extract showed that triptolide and icariin was found as 0.089 mg/g and 48.74 mg/g, respectively, which met the requirements of the national drug standards. In zebrafish larvae experiment, KX extract significantly inhibited the ISV (P<0.01) and SIV formation (P<0.05). Besides, the mRNA expression analysis showed that KX extract could significantly suppress the expressions of PI3K and AKT, thereby inhibiting the mRNA levels of ERKs and MAPK. Moreover, the downstream signaling cascade affected the expression of VEGF and its receptors (VEGFR and VEGFR-2). FGF-2, a strong angiogenic factor, was also down-regulated by KX treatment in zebrafish larvae. CONCLUSION: KX extract exhibited anti-angiogenic effects in zebrafish embryos by regulating PI3K/AKT-MAPK-VEGF pathway and showed promising potential for RA treatment.

Pain Relief and Safety of Microwave Ablation Combined with Percutaneous Vertebroplasty for Vertebral Metastasis: A Pilot Study.

BACKGROUND: We investigate the pain relief and safety of microwave ablation (MWA) combined with percutaneous vertebroplasty (PVP) in the treatment of metastatic vertebral tumors. METHODS: This prospective pilot study enrolled patients with metastatic vertebral tumors treated between January 2018 and October 2019. The participants were randomized to the PVP and MWA + PVP groups. Clinical parameters, pain visual analog scale (VAS), analgesic use scores (AUS), and quality-of-life score (QLS) were compared between groups. RESULTS: Sixty-seven participants were enrolled (PVP: n = 35; MWA + PVP: n = 32). There were no differences in bone cement injection volume, extravasation, and X-ray exposure time between the two groups (p > 0.05), but treatment costs were higher for the MWA + PVP group (26,418 ± 194 vs. 15,606 ± 148 yuan; p < 0.05). There were no significant improvements in VAS from baseline to 24 hours, 72 hours, 7 days, 1 month, and 3 months in the two groups (p > 0.05); at 6 and 12 months after the operation, the improvement from baseline was significant in the two groups (p < 0.05). The VAS was lower at 6 months (2.7 ± 0.7 vs. 3.2 ± 0.7) and 12 months (3.5 ± 0.8 vs. 4.0 ± 0.7) in the MWA + PVP group (both p < 0.01 vs. PVP). The AUS and QLS were improved with PVP at 6 and 12 months (p < 0.05) and with MWA + PVP at 12 months (p < 0.05). The AUS was lower at 6 and 12 months in the MWA + PVP group (p < 0.05 vs. PVP). CONCLUSION: MWA combined with PVP might be a safe and effective palliative treatment for pain from metastatic vertebral tumors.

Chrysomycin A Inhibits the Proliferation, Migration and Invasion of U251 and U87-MG Glioblastoma Cells to Exert Its Anti-Cancer Effects.

Chrysomycin A (Chr-A), an antibiotic from Streptomyces, is reported to have anti-tumor and anti-tuberculous activities, but its anti-glioblastoma activity and possible mechanism are not clear. Therefore, the current study was to investigate the mechanism of Chr-A against glioblastoma using U251 and U87-MG human cells. CCK8 assays, EdU-DNA synthesis assays and LDH assays were carried out to detect cell viability, proliferation and cytotoxicity of U251 and U87-MG cells, respectively. Transwell assays were performed to detect the invasion and migration abilities of glioblastoma cells. Western blot was used to validate the potential proteins. Chr-A treatment significantly inhibited the growth of glioblastoma cells and weakened the ability of cell migration and invasion by down regulating the expression of slug, MMP2 and MMP9. Furthermore, Chr-A also down regulated Akt, p-Akt, GSK-3ß, p-GSK-3ß and their downstream proteins, such as ß-catenin and c-Myc in human glioblastoma cells. In conclusion, Chr-A may inhibit the proliferation, migration and invasion of glioblastoma cells through the Akt/GSK-3ß/ß-catenin signaling pathway.

A randomized controlled trial of a coping-focused family resilience intervention program for breast cancer patients: Study protocol.

Background: Breast cancer patients and their families are under various pressures in the process of disease diagnosis and treatment, which seriously threaten their physical and mental health. Findings from existing research suggest that good family resilience can help breast cancer families better adapt and cope with adversity and challenges. However, there are only a few intervention studies on family resilience and no intervention studies on resilience among the families of breast cancer patients. Therefore, this study aims to explore appropriate measures to improve the resilience level of breast cancer families and help them better cope with the disease. Objective: The purpose of this study protocol is to demonstrate a coping-focused family resilience intervention to increase the level of resilience in the families of breast cancer patients and help them better cope with adversity. Methods: The trial will recruit 80 breast cancer families and randomly assign them to experimental and control groups in a 1:1 ratio. The control group will receive routine care, and the intervention group will receive a 6-week one-on-one online family resilience intervention based on the control group. Two groups of subjects will be assessed at baseline and at 1 week, 1 month, and 3 months after the intervention. The primary outcome is family resilience, and the secondary outcomes are coping style, social support, family disease burden, and levels of anxiety and depression. Expected results: We hypothesized that after the intervention, the intervention group would have significantly higher levels of family resilience than the preintervention and control groups. In the intervention group, other aspects related to family resilience, such as family disease burden and anxiety and depression levels of patients and their families, were significantly alleviated, and disease coping and social support levels were improved accordingly. Discussion: If the program works, it can help breast cancer families identify family strengths and resources to proactively address challenges so that families can successfully navigate the crisis and patient and family recovery can be facilitated. It can also provide a practical path for clinical workers to help breast cancer families adjust rationally. Clinical Trial Registration: This study has been registered in the Chinese Clinical Trials Registry (Registration Number: http://www.chictr.org.cn/ChiCTR2100052108).

Network Pharmacology Analysis and Experimental Validation of Kaempferol in the Treatment of Ischemic Stroke by Inhibiting Apoptosis and Regulating Neuroinflammation Involving Neutrophils.

Kaempferol, a natural plant flavonoid compound, has a neuroprotective effect on ischemic stroke, while the specific mechanism remains unclear. In the current study, we applied the comprehensive strategy that combines network pharmacology and experimental evaluation to explore the potential mechanism of kaempferol in the treatment of cerebral ischemia. First, network pharmacology analysis identified the biological process of kaempferol, suggesting that kaempferol may partly help in treating ischemic stroke by regulating apoptosis and inflammatory response. Then, we evaluated the efficacy of kaempferol in the acute stage of ischemic stroke and elucidated its effects and possible mechanisms on cell apoptosis and neuroinflammation involved by neutrophils. The results showed that kaempferol could significantly reduce the modified neurological severity score (mNSS), and reduce the volume of cerebral infarction and the degree of cerebral edema. In terms of anti-apoptosis, kaempferol could significantly reduce the number of TUNEL-positive cells, inhibit the expression of pro-apoptotic proteins and promote the expression of anti-apoptotic proteins. Kaempferol may play an anti-apoptotic role by up-regulating the expression level of the BDNF-TrkB-PI3K/AKT signaling pathway. In addition, we found that kaempferol inhibited neuron loss and the activation of glial cells, as well as the expression level of the inflammatory protein COX-2 and the classic pro-inflammatory signaling pathway TLR4/MyD88/NF-κB in the ischemic brain, reduced MPO activity and neutrophil counts in peripheral blood, and down-regulated neutrophil aggregation and infiltration in the ischemic brain. Western blot revealed that kaempferol down-regulated the activation of the JAK1/STAT3 signaling pathway in neutrophils and ischemic brains. Our study showed that kaempferol inhibited the activation and number of neutrophils in the rat peripheral blood and brain, which may be related to the down-regulation of the JAK1/STAT3 pathway.

Effects of Sport Stacking on Neuropsychological, Neurobiological, and Brain Function Performances in Patients With Mild Alzheimer's Disease and Mild Cognitive Impairment: A Randomized Controlled Trial.

Objective: To investigate the effects of sport stacking on the overall cognition and brain function in patients with mild Alzheimer's disease (AD) and mild cognitive impairment (MCI). Methods: A single-blind randomized controlled design was performed using sport stacking for 30 min, 5 days/week for 12 weeks. Forty-eight subjects with mild AD or MCI were randomly divided into the sport stacking group (T-mAD = 12, T-MCI = 12) and the active control group (C-mAD = 11, C-MCI = 13). Auditory Verbal Learning Test (AVLT), Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL), Geriatric Depression Scale (GDS-30), and Pittsburgh Sleep Quality Index (PSQI) were performed, the level of amyloid ß-protein-40 (Aß-40), Aß-42, brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1(IGF-1), tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and soluble trigger receptor expressed on myeloid cells 2 (sTREM2) in plasma were tested, and brain functional connectivity in resting state and activation under finger movement task were analyzed by functional near-infrared spectroscopy (fNIRS). Results: Thirty-nine patients completed the trial. After 4 weeks, we found a significant increase in AVLT score in T-MCI (6.36 ± 5.08 vs. -1.11 ± 4.23, p = 0.004), and T-mAD group (4.60 ± 4.77 vs. -0.11 ± 2.89, p = 0.039). After 12 weeks, there was a significantly improved in AVLT (9.64 ± 4.90 vs. -0.33 ± 6.10, p = 0.002) and ADCS-ADL (3.36 ± 3.59 vs. -1.89 ± 2.71, p = 0.003) in T-MCI. There was a significant improvement in AVLT (5.30 ± 5.42 vs. 0.44 ± 2.40) in T-mAD (p < 0.05). Plasma levels of BDNF were upregulated in both T-MCI and T-mAD, and IGF-1 increased in T-MCI (P < 0.05) compared to the control groups. The functional connectivity in MCI patients between DLPFC.R and SCA.R, SMA.L, and SCA.R was decreased. In contrast, in mAD patients, the brain regional function connection was increased between DLPFC.R and Broca's.L. The activation of channel 36 located in the left primary somatosensory cortex was significantly increased after 12-week training, which was correlated with the improved AVLT and the increase of BDNF. Conclusion: Our findings suggested that sport stacking is effective for patients with MCI and mild AD, possibly through increasing the expression of neuroprotective growth factors and enhancing neural plasticity to improve neurocognitive performance. Clinical Trial Registration: https://www.ClinicalTrials.gov, ChiCTR.org.cn, identifier: ChiCTR-2100045980.

Extra Loading Dose of Dexmedetomidine Enhances Intestinal Function Recovery After Colorectal Resection: A Retrospective Cohort Study.

Importance: Postoperative gastrointestinal dysfunction (POGD) may be caused by postoperative vagus nerve tension inhibition and systemic inflammation. Dexmedetomidine (Dex) increases vagus nerve tone and affords an anti-inflammatory property, which may play a role in pathogenesis. Objective: To investigate whether a higher dose of Dex enhances gastrointestinal function recovery. Design: In this retrospective study, patients receiving colorectal surgery at the First Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2019 were included. We evaluated the postoperative flatus time between recipients who received loading plus maintenance dose of DEX (LMD group, 237 recipients) and those who recieved maintenance dose of DEX (MD group, 302 recipients). Data were analyzed by logical regression and stratified and interaction analyses. The simulated pharmacokinetics of two DEX regimens was compared using the Tivatrainer software. Thirty paired blood samples from patients whose propensity scores matched with POGD-related factors at 24 h postoperatively were randomly selected, and their tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), d-lactate (DLA), acetylcholine (Ach), interleukin (IL)-10, lipopolysaccharide (LPS), IL-6, and inducible nitric oxide synthase (iNOS) levels were measured. Setting: Operating rooms and general surgery wards. Participants: Among the 644 patients undergoing colorectal surgery, 12 who had a colostomy, 26 without Dex infusion, 20 whose Dex administration mode cannot be classified, and 47 with a history of intestinal surgery were excluded. A total of 539 patients were included. Result: Compared with the MD group, the LMD group had a shorter recovery time to flatus; lower incidences of nausea, vomiting, abdominal distension, and abdominal pain (p < 0.05); and a slightly decreased heart rate. The LMD group was the independent factor of POGD (OR = 0.59, 95% CI = 0.41-0.87, p = 0.007) without being reversed in stratified and interaction analyses and had higher Dex plasma concentration from skin incision to 8 h postoperatively. The LMD group had a 39% and 43% increase in Ach and IL-10 levels, respectively, and a 33%-77% decrease in TNF-α, IL-6, COX-2, iNOS, LPS, and DLA levels (p < 0.05). Conclusion: Adding an extra loading dose of Dex can increase parasympathetic tone and decrease inflammation; hence, it can enhance postoperative gastrointestinal function recovery following colorectal surgery.

ST2825, a Small Molecule Inhibitor of MyD88, Suppresses NF-κB Activation and the ROS/NLRP3/Cleaved Caspase-1 Signaling Pathway to Attenuate Lipopolysaccharide-Stimulated Neuroinflammation.

Neuroinflammation characterized by microglia activation is the mechanism of the occurrence and development of various central nervous system diseases. ST2825, as a peptide-mimetic MyD88 homodimerization inhibitor, has been identified as crucial molecule with an anti-inflammatory role in several immune cells, especially microglia. The purpose of the study was to investigate the anti-neuroinflammatory effects and the possible mechanism of ST2825. Methods: Lipopolysaccharide (LPS) was used to stimulate neuroinflammation in male BALB/c mice and BV2 microglia cells. The NO level was determined by Griess Reagents. The levels of pro-inflammatory cytokines and chemokines were determined by ELISA. The expressions of inflammatory proteins were determined by real-time PCR and Western blotting analysis. The level of ROS was detected by DCFH-DA staining. Results: In vivo, the improved levels of LPS-induced pro-inflammatory factors, including TNF-α, IL-6, IL-1ß, MCP-1 and ICAM-1 in the cortex and hippocampus, were reduced after ST2825 treatment. In vitro, the levels of LPS-induced pro-inflammatory factors, including NO, TNF-α, IL-6, IL-1ß, MCP-1, iNOS, COX2 and ROS, were remarkably decreased after ST2825 treatment. Further research found that the mechanism of its anti-neuroinflammatory effects appeared to be associated with inhibition of NF-κB activation and down-regulation of the NLRP3/cleaved caspase-1 signaling pathway. Conclusions: The current findings provide new insights into the activity and molecular mechanism of ST2825 for the treatment of neuroinflammation.

Triglyceride-glucose index and estimated 10-year risk of a first hard cardiovascular event.

Background: Whether Triglyceride-glucose (TyG) index is associated with 10-year risk of a first hard atherosclerotic cardiovascular disease (ASCVD) event in the United States remains unclear. Methods: In this cross-sectional study, the participants, ranged from 40 to 79 years old, were from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. TyG index was the independent variable and 10-year risk of a first hard ASCVD was the dependent variable. The other variables, such as age, gender, race, body mass index (BMI), hypertension treatment states, smoking states and low-density lipoprotein cholesterol (LDL-C) et al. were considered as the potential confounding factors. Multivariate linear regression models and smooth curve fittings were used to evaluate the association between TyG index and 10-year risk of a first hard ASCVD event. Results: A total of 2,142 participants were included in the analysis. The results showed that TyG index was associated with an increased 10-year risk of a first hard ASCVD event [ß = 2.208, 95% (1.716, 2.700), P < 0.00001]. The association had statistical significance in both men [ß = 3.862 95% CI (3.274, 4.450), P < 0.00001] and women [ß = 1.067, 95% CI (0.286, 1.849), P = 0.00756)] according to subgroup analysis. Smooth curve fittings revealed that TyG index was linearly associated with 10-year risk of ASCVD in both male and female. Conclusion: Triglyceride-glucose index was associated with an increased 10-year risk of a first hard ASCVD event in the United States, suggesting it is necessary to monitor and control an appropriate range of TyG index.

Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice.

Retinal angiogenesis is a critical process for normal retinal function. However, uncontrolled angiogenesis can lead to pathological neovascularization (NV), which is closely related to most irreversible blindness-causing retinal diseases. Understanding the molecular basis behind pathological NV is important for the treatment of related diseases. Twist-related protein 1 (TWIST1) is a well-known transcription factor and principal inducer of epithelial-mesenchymal transition (EMT) in many human cancers. Our previous study showed that Twist1 expression is elevated in pathological retinal NV. To date, however, the role of TWIST1 in retinal pathological angiogenesis remains to be elucidated. To study the role of TWIST1 in pathological retinal NV and identify specific molecular targets for antagonizing pathological NV, we generated an inducible vascular endothelial cell (EC)-specific Twist1 transgenic mouse model ( Tg-Twist1 iEC+ ). Whole-mount retinas from Tg-Twist1 iEC+ mice showed retarded vascular progression and increased vascular density in the front end of the growing retinal vasculature, as well as aneurysm-like pathological retinal NV. Furthermore, overexpression of Twist1 in the ECs promoted cell proliferation but disturbed cell polarity, thus leading to uncontrolled retinal angiogenesis. TWIST1 promoted pathological NV by activating the Wnt/ß-catenin signaling pathway and inducing the expression of NV formation-related genes, thereby acting as a 'valve' in the regulation of pathological angiogenesis. This study identified the critical role of TWIST1 in retinal pathological NV, thus providing a potential therapeutic target for pathological NV.

Case report: Fatal infantile hypertonic myofibrillar myopathy with compound heterozygous mutations in the CRYAB gene.

Background: Fatal infantile hypertonic myofibrillar myopathy (FIHMM) is an autosomal recessive hereditary disease characterized by amyotrophy, progressive flexion contracture and ankylosis of the trunk and limb muscles, apnea and respiratory failure, and increased creatine phosphate levels. It is caused by mutations in the CRYAB gene, and only around 18 cases including genetic mutations have been reported worldwide. All patients with FIHMM develop respiratory distress, progressive stiffness of the limbs, and have a poor prognosis. However, no effective treatment for CRYAB-associated respiratory failure has been reported. Here, we report a case of FIHMM with a novel heterozygous missense mutation. Case Presentation: A 2-year-old female developed scoliosis of the lumbar spine and restrictive ventilatory dysfunction in infancy. She was admitted to the hospital with labored breathing on the third day after the second injection of inactivated poliomyelitis vaccine. Acute respiratory failure, pneumothorax, and cardiac arrest arose in the patient during hospitalization, and progressive stiffness of the trunk and limb muscles appeared, accompanied by obvious abdominal distension and an increase in phosphocreatine kinase levels. Screenings for genetic metabolic diseases in the blood and urine were normal. Electromyography revealed mild myogenic damage. A muscle biopsy indicated the accumulation of desmin, α-crystallin, and myotilin in the musculus biceps brachii, and dense granules were observed in muscle fibers using electron microscopy. Mutation analysis of CRYAB revealed a novel heterozygous missense mutation in the proband, c.302A > C (p.His101Pro) and c.3G > A (p.Met1Ile), which inherited from her asymptomatic, heterozygous carrier parents, respectively. The proband was finally diagnosed as FIHMM. One month after the FIHMM diagnosis, the child died of respiratory failure. Conclusion: We report a case of FIHMM with a novel heterozygous missense mutation of CRYAB. This finding might improve our understanding of FIHMM and highlight a novel mutation in the Chinese population.