Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like.

OBJECTIVES: In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH). METHODS: Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH. RESULTS: The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression. CONCLUSIONS: NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.

Chronic Stress That Changed Intestinal Permeability and Induced Inflammation Was Restored by Estrogen.

Chronic psychological stress affects the health of humans and animals (especially females or pregnant bodies). In this study, a stress-induced model was established by placing eight-week-old female and pregnant mice in centrifuge tubes for 4 h to determine whether chronic stress affects the intestinal mucosal barrier and microbiota composition of pregnant mice. Compared with the control group, we found that norepinephrine (NE), corticosterone (CORT), and estradiol (E2) in plasma increased significantly in the stress group. We then observed a decreased down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, caspase-3, and expression of tight junction mRNA and protein. Moreover, the diversity and richness of the colonic microbiota decreased in pregnant mice. Bacteroidetes decreased, and pernicious bacteria were markedly increased. At last, we found E2 protects the intestinal epithelial cells after H2O2 treatment. Results suggested that 25 pg/mL E2 provides better protection for intestinal barrier after chronic stress, which greatly affected the intestinal mucosal barrier and altered the colonic microbiota composition.

A Tumor-Targeting Metal-Organic Nanoparticle Constructed by Dynamic Combinatorial Chemistry toward Accurately Redressing Carcinogenic Wnt Cascade.

Targeted and immunological therapy have revolutionized the malignancy treatment, but is suffering from the dose-limiting side effects and inadequate responsiveness. The emerging nanoscale infinite coordination polymers provide a feasible strategy for tumor targeting and immune sensitization. Herein, a "one-pot" self-assembled strategy based on dynamic combinatorial chemistry (DCC) principle is designed to construct a tumor-targeting metal-organic nanoparticle (MOICP) through a spontaneous co-assembling among three metal-organic coordination polymers tuned by a Wnt-inhibitor carnosic acid (CA). Responding to the tumor microenvironment, MOICP presents an optimized tumor-preferential accumulation and the satisfactory biosafety. MOICP is more active in vitro and in vivo than CA in suppressing of Wnt signaling pathway, and potently inhibits tumor growth in a patient-derived xenograft model of Wnt-activated pancreatic carcinoma. Moreover, MOICP reverses the lack of intratumoral infiltration of T lymphocytes, and hence augments the action of Anti-PD1 (programmed cell death protein 1) immunotherapy in B16F10 melanoma allograft mice model. This clinically viable MOICP can not only be applied to Wnt inhibition for cancer targeted therapy and immunotherapeutic sensitization, but also provides a de novo pattern for nanomedicine architecture with cargo-initiated co-self-assembly guided by DCC, thereby bringing new inspiration in general for disease intervention.

Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity.

Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy.

[Estimation of lung recruitment characteristics using the static pressure-volume curve of lungs].

Mechanical ventilation is an importmant life-sustaining treatment for patients with acute respiratory distress syndrome. Its clinical outcomes depend on patients' characteristics of lung recruitment. Estimation of lung recruitment characteristics is valuable for the determination of ventilatory maneurvers and ventilator parameters. There is no easily-used, bedside method to assess lung recruitment characteristics. The present paper proposed a method to estimate lung recruitment characteristics from the static pressure-volume curve of lungs. The method was evaluated by comparing with published experimental data. Results of lung recruitment derived from the presented method were in high agreement with the published data, suggesting that the proposed method is capable to estimate lung recruitment characteristics. Since some advanced ventilators are capable to measure the static pressure-volume curve automatedly, the presented method is potential to be used at bedside, and it is helpful for clinicians to individualize ventilatory manuevers and the correpsonding ventilator parameters.

Pellino1 regulates neuropathic pain as well as microglial activation through the regulation of MAPK/NF-κB signaling in the spinal cord.

BACKGROUND: Spinal cord microglia plays a crucial role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely determined. Here, we investigated the role of Pellino1 (Peli1) and its interplay with spinal microglial activation in neuropathic pain. METHODS: In this study, we examined the effects of Peli1 on pain hypersensitivity and spinal microglial activation after chronic constriction injury (CCI) of the sciatic nerve in mice. The molecular mechanisms involved in Peli1-mediated hyperalgesia were determined by western blot, immunofluorescence, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). We utilized immunoprecipitation to examine the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) following CCI. In addition, we explored the effect of Peli1 on BV2 microglial cells in response to lipopolysaccharide (LPS) challenge. RESULTS: We found that CCI induced a significant increase in the levels of Peli1, which was present in the great majority of microglia in the spinal dorsal horn. Our results showed that spinal Peli1 contributed to the induction and maintenance of CCI-induced neuropathic pain. The biochemical data revealed that CCI-induced Peli1 in the spinal cord significantly increased mitogen-activated protein kinase (MAPK) phosphorylation, activated nuclear factor kappa B (NF-κB), and enhanced the production of proinflammatory cytokines, accompanied by spinal microglial activation. Peli1 additionally was able to promote K63-linked ubiquitination of TRAF6 in the ipsilateral spinal cord following CCI. Furthermore, we demonstrated that Peli1 in microglial cells significantly enhanced inflammatory reactions after LPS treatment. CONCLUSION: These results suggest that the upregulation of spinal Peli1 is essential for the pathogenesis of neuropathic pain via Peli1-dependent mobilization of spinal cord microglia, activation of MAPK/NF-κB signaling, and production of proinflammatory cytokines. Modulation of Peli1 may serve as a potential approach for the treatment of neuropathic pain.

Pellino1 Contributes to Morphine Tolerance by Microglia Activation via MAPK Signaling in the Spinal Cord of Mice.

Chronic morphine-induced antinociceptive tolerance is a major unresolved issue in clinical practices, which is associated with microglia activation in the spinal cord. E3 ubiquitin ligase Pellino1 (Peli1) is known to be an important microglia-specific regulator. However, it is unclear whether Peli1 is involved in morphine tolerance. Here, we found that Peli1 levels in the spinal cord were significantly elevated in morphine tolerance mouse model. Notably, Peli1 was expressed in a great majority of microglia in the spinal dorsal horn, while downregulation of spinal Peli1 attenuated the development of morphine tolerance and associated hyperalgesia. Our biochemical data revealed that morphine tolerance-induced increase in Peli1 was accompanied by spinal microglia activation, activation of mitogen-activated protein kinase (MAPK) signaling, and production of proinflammatory cytokines. Peli1 additionally was found to promote K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) in the spinal cord after repeated morphine treatment. Furthermore, knocking down Peli1 in cultured BV2 microglial cells significantly attenuated inflammatory reactions in response to morphine challenge. Therefore, we conclude that the upregulation of Peli1 in the spinal cord plays a curial role in the development of morphine tolerance via Peli1-dependent mobilization of spinal microglia, activation of MAPK signaling, and production of proinflammatory cytokines. Modulation of Peli1 may be a potential strategy for the prevention of morphine tolerance.

[Simulation of spontaneous breathing for healthy adults using a nonlinear airway-segmented model of respiratory mechanics].

One-compartment lumped-parameter models of respiratory mechanics, representing the airflow resistance of the tracheobronchial tree with a linear or nonlinear resistor, are not able to describe the mechanical property of airways in different generations. Therefore, based on the anatomic structure of tracheobronchial tree and the mechanical property of airways in each generation, this study classified the human airways into three segments: the upper airway segment, the collapsible airway segment, and the small airway segment. Finally, a nonlinear, multi-compartment lumped-parameter model of respiratory mechanics with three airway segments was established. With the respiratory muscle effort as driving pressure, the model was used to simulate the tidal breathing of healthy adults. The results were consistent with the physiological data and the previously published results, suggesting that this model could be used for pathophysiological research of respiratory system.

Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell death.

Microglia-mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia-mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Nur77 over-expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase-2, IL-1ß, and tumor necrosis factor-α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS-induced NF-κB activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPS-activated NF-κB in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS-induced Nur77 reduction. Furthermore, in a microglia-conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that associated with microglia-mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease.

Effect of Zusanli Acupoint Injection with Anisodamine on Postoperative Recovery Quality of Patients Undergoing Bariatric Surgery.

PURPOSE: To evaluate the influence of anisodamine injection at the Zusanli (ST36) on early postoperative recovery quality in patients who have undergone laparoscopic sleeve gastrectomy. MATERIALS AND METHODS: 141 patients undergoing laparoscopic sleeve gastrectomy were randomly divided into the control group (group C), the normal saline group (group S) and the anisodamine group (group A). Acupuncture point injections were administered after induction of general anesthesia. The quality of recovery-40 questionnaire (QoR-40) scores were documented preoperatively (D0) and on the 1st (D1), 3rd (D3) and 7th (D7) days postoperatively. Additional metrics included: the numerical rating scale (NRS) for pain, postoperative nausea and vomiting (PONV), assessment and analgesic consumption 24-h post-extubation and the initial postoperative times for ambulation and anal exhaust. Substance P (SP), ß-endorphin (ß-EP), motilin (MTL) and gastrin (GAS) were quantified at 24-h post-surgery. RESULTS: Compared with group C, group A demonstrated an elevation in QoR-40 scores and physical comfort dimensions during D1-3, and an increased pain scores during D1-7; group S exhibited an augmentation in QoR-40 scores and pain scores on D1 (p < 0.05). Compared with group S, group A improved QoR-40 scores on D1 and pain scores during D1-3 (p < 0.05). SP, ß-EP, MTL and GAS presented significant variances among the groups 24-h post-surgery (p < 0.05). There were significant differences between the groups in NRS pain scores and PONV scores at 24-h postoperatively, dosage of dizocin on the first postoperative day, and time to first anal defecation (p < 0.05). CONCLUSION: The administration of anisodamine via ST36 acupoint injections has been demonstrated to facilitate the recuperation of gastrointestinal functionality, to alleviate postoperative pain and nausea, and substantially to enhance the quality of early postoperative recovery.

Modulating ß-catenin/BCL9 interaction with cell-membrane-camouflaged carnosic acid to inhibit Wnt pathway and enhance tumor immune response.

Introduction: Lung adenocarcinoma (LUAD) therapies are plagued by insufficient immune infiltration and suboptimal immune responses in patients, which are closely associated with the hyperactive Wnt/ß-catenin pathway. Suppressing this signaling holds considerable promise as a potential tumor therapy for LUAD, but Wnt suppressor development is hindered by concerns regarding toxicity and adverse effects due to insufficient targeting of tumors. Methods: We have synthesized a tumor-specific biomimetic Wnt pathway suppressor, namely CM-CA, by encapsulating carnosic acid within Lewis lung carcinoma (LLC) cell membranes. It possesses nano-size, allowing for a straightforward preparation process, and exhibits the ability to selectively target the Wnt/ß-catenin pathway in lung adenocarcinoma cells. To evaluate its in vivo efficacy, we utilized the LLC Lewis homograft model, and further validated its mechanism of action through immunohistochemistry staining and transcriptome sequencing analyses. Results: The findings from the animal experiments demonstrated that CM-CA effectively suppressed the Wnt/ß-catenin signaling pathway and impeded cellular proliferation, leading to notable tumor growth inhibition in a biologically benign manner. Transcriptome sequencing analyses revealed that CM-CA promoted T cell infiltration and bolstered the immune response within tumor tissues. Conclusion: The utilization of CM-CA presents a novel and auspicious approach to achieve tumor suppression and augment the therapeutic response rate in LUAD, while also offering a strategy for the development of Wnt/ß-catenin inhibitors with biosafety profile.

An innovative gene expression modulating strategy by converting nucleic acids into HNC therapeutics using carrier-free nanoparticles.

Background: Cell fate and microenvironmental changes resulting from aberrant expression of specific proteins in tumors are one of the major causes of inadequate anti-tumor immune response and poor prognosis in head and neck cancer (HNC). Eukaryotic initiation factor 3C (eIF3c) has emerged as a promising therapeutic target for HNC due to its ability to regulate protein expression levels in tumor cells, but its drug development is difficult to achieve by targeting traditional protein-protein interactions. siRNA has emerged as a highly promising modality for drug development targeting eIF3c, while its application is hindered by challenges pertaining to inadequate stability and insufficient concentration specifically within tumor sites. Method: We employed a method to convert flexible siRNAs into stable and biologically active infinite Auric-sulfhydryl coordination supramolecular siRNAs (IacsRNAs). Through coordinated self-assembly, we successfully transformed eIF3C siRNAs into the carrier-free HNC nanotherapeutic agent Iacs-eif3c-RNA. The efficacy of this agent was evaluated in vivo using HNC xenograft models, demonstrating promising antitumor effects. Results: Iacs-eif3c-RNA demonstrated the ability to overcome the pharmacological obstacle associated with targeting eIF3C, resulting in a significant reduction in eIF3C expression within tumor tissues, as well as effective tumor cell proliferating suppression and apoptosis promotion. In comparison to monotherapy utilizing the chemotherapeutic agent cisplatin, Iacs-eif3c-RNA exhibited superior anti-tumor efficacy and favorable biosafety. Conclusion: The utilization of Iacs-eif3c-RNA as a carrier-free nanotherapeutic agent presents a promising and innovative approach for addressing HNC treating challenges. Moreover, this strategy demonstrates potential for the translation of therapeutic siRNAs into clinical drugs, extending its applicability to the treatment of other cancers and various diseases.

Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma.

Introduction: Hypoxia is associated with unfavorable prognoses in melanoma patients, and the limited response rates of patients to PD-1/PD-L1 blockade could be attributed to the immunosuppressive tumor microenvironment induced by hypoxia. Exercise offers numerous benefits in the anti-tumor process and has the potential to alleviate hypoxia; however, the precise mechanisms through which it exerts its anti-tumor effects remain unclear, and the presence of synergistic effects with PD-1/PD-L1 immunotherapy is yet to be definitively established. Methods: We established a B16F10 homograft malignant melanoma model and implemented two distinct exercise treatments (low/moderate-intensity swim) based on the mice's exercise status. The specific function manner of exercise-induced anti-tumor effects was determined through RNA sequencing and analysis of changes in the tumor microenvironment. Furthermore, moderate-intensity swim that exhibited superior tumor suppression effects was combined with Anti-PD-1 treatment to evaluate its in vivo efficacy in mouse models. Results: Exercise intervention yielded a considerable effect in impeding tumor growth and promoting apoptosis. Immunohistochemistry and RNA sequencing revealed improvements in tumor hypoxia and down-regulation of hypoxia-related pathways. Cellular immunofluorescence and ELISA analyses demonstrated a notable increase of cytotoxic T cell amount and a decrease of regulatory T cells, indicating an improvement of tumor immune microenvironment. In comparison to Anti-PD-1 monotherapy, tumor suppressive efficacy of exercise combination therapy was found to be enhanced with improvements in both the hypoxic tumor microenvironment and T cell infiltration. Conclusion: Exercise has the potential to function as a hypoxia modulator improving the tumor immune microenvironment, resulting in the promotion of anti-tumor efficacy and the facilitation of biologically safe sensitization of PD-1/PD-L1 immunotherapy.

Postoperative serum CHI3L1 level is associated with postoperative cognitive dysfunction in elderly patients after hip fracture surgery: A prospective observational study.

Objectives: Postoperative cognitive dysfunction (POCD) is a common postoperative complication in older patients. Chitinase-3-like-1 protein (CHI3L1) is identified as a neuroinflammatory biomarker and impairs cognitive function. This study aimed to evaluate the association between serum levels of CHI3L1 and POCD and explore the levels of interleukin-6 (IL-6), IL-1ß and C-reactive protein (CRP) in the elderly after total hip arthroplasty (THA). Patients and methods: A total of 76 elderly patients undergoing THA were enrolled in the prospective observational study. Serum CHI3L1 levels were measured 1 day before and 1 day after surgery and other perioperative factors were also noted. The correlations between mediators of inflammation in the two groups were compared via Spearman correlation coefficients. The receiver operating characteristic (ROC) curves were implemented to analyze the predictive values of serum CHI3L1 and other inflammatory factors for POCD. And factors associated with POCD were analyzed by univariate and multivariate logistics. Results: POCD was observed in 31.6% of patients 1 week after surgery. Postoperative serum CHI3L1 levels were higher in POCD patients than in non-POCD patients [1348.26(778.46-1889.77) VS 2322.86(1686.88-2517.35) ng/ml, P < 0.001]. Postoperative serum CHI3L1 level was positively correlated with postoperative IL-6 level (r = 0.284, P = 0.013). Compared with IL-6, IL-1ß, and CRP, postoperative CHI3L1 level has the highest predictive value for POCD with the area under the curve (AUC) value of 0.779 according to the ROC curve. By the multivariate logistic regression analysis, elevated postoperative serum CHI3L1 level was found to be an independent risk factor for POCD 1 week after surgery (odds ratio = 1.204, 95% confidence interval = 1.087-1.332, P = 0.001). Conclusion: Postoperative elevated serum CHI3L1 level was significantly associated with the incident of POCD, and positively correlated with postoperative IL-6 level in the elderly after THA. This biomarker may have potential utility for further elucidating the etiology of POCD.

Perioperative lidocaine and dexmedetomidine intravenous infusion reduce the serum levels of NETs and biomarkers of tumor metastasis in lung cancer patients: A prospective, single-center, double-blinded, randomized clinical trial.

Background: Neutrophil extracellular traps (NETs) can enhance the metastasis of non-small cell lung cancer (NSCLC). As biomarkers of tumor metastasis, metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) together with NETs are essential to endothelial-to-mesenchymal transition (EMT). We hypothesized that intravenous infusion of lidocaine and dexmedetomidine could reduce the production of NETs and biomarkers of tumor metastasis after video-assisted thoracic surgery (VATS) in NSCLC patients. Method: The trial included 132 NSCLC patients undergoing VATS. The patients were equally randomized to a placebo group (Group C), a lidocaine group (Group L, intravenous lidocaine 8 mg/kg/h for 15 minutes before anesthesia, 2 mg/kg/h during surgery, and 1 mg/kg/h until 24 hours after surgery), a dexmedetomidine group (Group D, intravenous dexmedetomidine 2 µg/kg/h for 15 minutes before anesthesia, 0.5 µg/kg/h during surgery, and 0.25 µg/kg/h until 24 hours after surgery), and a dexmedetomidine plus lidocaine group (Group LD, combination use of lidocaine and dexmedetomidine). The primary outcome was the production of myeloperoxidase (MPO) and citrullinated histone-3 (H3Cit), biomarkers of NETs, on postoperative day (POD) 1. MMP-3, MMP-9, and VEGF-α, as biomarkers of tumor metastasis, were also evaluated on POD 1. Results: The baseline patient characteristics and perioperative data did not differ between the study groups. MPO was significantly decreased in Groups L, D, and LD (-197.08 ± 34.01, -137.37 ± 32.41, and -189.45 ± 33.73 U/ml, P<0.001, respectively) compared with Group C (-106.51 ± 25.44 U/ml). H3Cit was also lessened in Groups L, D, and LD (-49.51 ± 9.11, -34.80 ± 10.37, and -51.82 ± 8.98 ng/ml, P<0.001, respectively) compared with Group C (-24.73 ± 7.65 ng/ml). Lidocaine and dexmedetomidine also reduced MMP-3 (-69.08 ± 13.22, -52.84 ± 13.78, -85.34 ± 12.59 vs. -40.55 ± 10.71 ng/ml in Group L, D, LD vs. Group C, P<0.001, respectively), MMP-9 (-8.46 ± 1.68, -6.07 ± 1.82, -9.67 ± 1.43 vs. -4.28 ± 1.29 ng/ml in Group L, D, LD vs. Group C, P<0.001, respectively), and VEGF-α (-95.55 ± 22.53, -71.65 ± 18.77, -104.89 ± 15.49 vs. -51.73 ± 16.27 pg/ml in Group L, D, LD vs. Group C, P<0.001, respectively) on POD 1. Conclusion: In NSCLC patients, continuous perioperative intravenous infusion of lidocaine and dexmedetomidine significantly reduced the production of NETs and tumor metastasis biomarkers on POD 1. Meanwhile, it also decreased inflammation, protected cellular immune function, reduced pain and opioid consumption, and improved the quality of postoperative recovery. Clinical trial registration: chictr.org.cn, identifier: 187049.

Effect of Intraoperative Infusion of Esketamine on Quality of Postoperative Recovery in Patients Undergoing Laparoscopic Bariatric Surgery: A Randomized Controlled Trial.

INTRODUCTION: This study aims to evaluate the efficacy of esketamine on postoperative recovery quality after laparoscopic bariatric surgery. METHODS: Patients (n = 74) scheduled for laparoscopic bariatric surgery were randomly divided into two groups: the esketamine group (group E: 0.5 mg/kg/h infusion, i.e., 0.2 mL/kg/h) or the control group (group C: 0.2 mL/kg/h normal saline infusion). The infusions were stopped 20 min before the end of the procedure. The primary outcome was the Quality of Recovery-40 (QoR-40) score on postoperative day 1 (POD 1). The secondary outcomes included QoR-40 scores on PODs 2 and 7, Numeric Rating Scale (NRS) on PODs 1, 2, and 7, time to extubation, additional postoperative analgesic use, length of hospital stay, and time to first exhaust. Additonally, the safety indices were also recorded, including hemodynamic profile, perioperative anesthesia index (Ai), utilization of vasoactive drugs or urapidil, and side effects. RESULTS: All in all, 70 of the 74 patients completed the study, 35 in each group. The difference of QoR-40 scores on POD 1 was both statistically and clinically significant [difference 7.21, 95% confidence interval (CI) 5.17, 9.25, p < 0.001]. The difference of QoR-40 on POD 2 was statistically significant but clinically insignificant (difference 4.81, 95% CI 2.69, 6.92, p < 0.001). The difference of NRS scores on POD 1 was statistically significant (difference -1.23, 95% CI -2.36, -0.10, p = 0.033). Compared with group C, group E had a lower utilization rate of phenylephrine and higher Ai values (p < 0.05). There was no statistical difference between the two groups on other measures. CONCLUSION: Continuous ketamine infusion seems to be safe and well tolerated in laparoscopic bariatric surgery. It improved the quality of postoperative recovery and reduced pain on POD 1. In spite of the increased Ai value during the surgery, it also provided better hemodynamics with less usage of phenylephrine.

Cocktail hepatocarcinoma therapy by a super-assembled nano-pill targeting XPO1 and ATR synergistically.

Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents. To overcome it, the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier. Herein, a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound. In this proof-of-concept study, the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1 (XPO1) and ataxia telangiectasia mutated-Rad3-related (ATR), and then a super-assembled nano-pill (gold nano drug carrier loaded AZD6738 and 97-110 amino acids of apoptin (AP) (AA@G)) was constructed through camouflaging AZD6738 (ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle. As expected, both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest, promoting DNA damage and inhibiting DNA repair of hepatoma cell. This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential, but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds, thereby extending the scope of drugs for developing the advanced combination therapy.

The coupling mechanism of mammalian mitochondrial complex I.

Mammalian respiratory complex I (CI) is a 45-subunit, redox-driven proton pump that generates an electrochemical gradient across the mitochondrial inner membrane to power ATP synthesis in mitochondria. In the present study, we report cryo-electron microscopy structures of CI from Sus scrofa in six treatment conditions at a resolution of 2.4-3.5 Å, in which CI structures of each condition can be classified into two biochemical classes (active or deactive), with a notably higher proportion of active CI particles. These structures illuminate how hydrophobic ubiquinone-10 (Q10) with its long isoprenoid tail is bound and reduced in a narrow Q chamber comprising four different Q10-binding sites. Structural comparisons of active CI structures from our decylubiquinone-NADH and rotenone-NADH datasets reveal that Q10 reduction at site 1 is not coupled to proton pumping in the membrane arm, which might instead be coupled to Q10 oxidation at site 2. Our data overturn the widely accepted previous proposal about the coupling mechanism of CI.

Flavonoids from Scutellaria barbata D. Don exert antitumor activity in colorectal cancer through inhibited autophagy and promoted apoptosis via ATF4/sestrin2 pathway.

PURPOSE: Scutellaria barbata D. Don (SB), mainly containing flavonoids, has been frequently used for cancer treatment. However, little research has investigated the antitumor activity of flavonoids from SB (FSB). The current study aimed to assess the antitumor effect of TFSB and elucidate the probable underlying mechanism in vivo and in vitro. STUDY DESIGN: FSB was prepared, and its chemical composition was characterized by HPLC-MS. Colorectal HCT116 cells were treated with various concentration of FSB. The viability, proliferation, apoptosis, migration, and autophagy of HCT116 cells were studied, as were further confirmed in tumor xenografts. METHODS: Cell viability and proliferation were respectively examined by MTT and EdU staining. ROS was determined with DCFH-DA, and cell apoptosis was detected using flow cytometry. Transwell and wound-healing assays were performed to evaluate cell migration. Immunofluorescence was employed to evaluate sestrin2 and ATF4 level. The protein expressions of p-AMPK, p-ULK1, p-mTOR, 4E-BP1, LC3-I/II, cleaved-caspase-3, Bax, and bcl-2 were investigated by western blot. ATF4 was overexpressed in experiments to explore the role of ATF4/sestrin2 pathway in FSB-mediated efficacy. RESULTS: FSB clearly reduced the cell viability, promoted ROS generation, and induced apoptosis in HCT116 cells by down-regulated Bcl-2, and increased cleaved-caspase-3 and Bax. Furthermore, FSB significantly inhibited migration of colorectal cells in a dose-dependent manner. Further mechanistic study indicated that FSB upregulated p-mTOR protein level, and reduced p-AMPK, p-ULK1, p-mTOR, p-4E-BP1 and LC3-I/II expression, which were major autophagy-related genes. In addition, FSB could cause downregulation of endogenous mTOR inhibitor sestrin2 and ATF4 expression. Transient overexpression of ATF4 resulted in mTOR and sestrin2 inhibition, and significantly compromised the effects of FSB on apoptosis and autophagy in HCT116 cells. CONCLUSION: Our results reveal, for the first time, that FSB exerts antitumor activity through autophagy inhibition and apoptosis induction via ATF4/sestrin2 pathway in colorectal cancer cells. Scutellaria barbata D. Don may have great potential in the application for the prevention and treatment of human colorectal cancer.

Variations of human cerebral and ocular blood flow during exposure to multi-axial accelerations : A mathematical modeling study.

Human hemodynamic responses during exposure to multi-axial acceleration was a relatively new topic in the fields of acceleration physiology. This study aimed to focus on these responses, especially variations of blood perfusion to brain and eyes, through mathematical modeling. A mathematical model was established using lumped parameter methods, containing compartments of four heart chambers, systemic arteries and veins, circulation of typical systemic organs, and some compartments for pulmonary circulation, together with autonomic regulation considered. This model was firstly validated by using experimental data from experiment of posture change and centrifuge tests of +Gz accelerations, and then applied to analyze human hemodynamic responses to typical multi-axial accelerations. Validation results demonstrated the mathematical model could generate reasonable responses of human cardiovascular system during posture change and exposure to +Gz accelerations. Simulation results of hemodynamic responses to multi-axial accelerations depicted Gy induced significant differences of blood flow to the left and right eyes. And some contour maps were generated based on these results, which provided a quick way to estimate blood flow variations in brain and eyes during exposure to different accelerations. Graphical Abstract This study aimed to focus on variations of blood perfusion to brain and eyes during exposure to typical multi-axial accelerations through mathematical modeling. This model was firstly validated by using experimental data from experiment of posture change and centrifuge tests of +Gz accelerations, and then applied to analyze human hemodynamic responses to typical multi-axial accelerations. Simulation results of hemodynamic responses to multi-axial accelerations depicted Gy induced significant differences of blood flow to the left and right eyes. And contour maps that generated based on these results provided a quick way to estimate blood flow variations in brain and eyes during exposure to different accelerations.