In-situ noncovalent interaction of ammonium ion enabled C-H bond functionalization of polyethylene glycols.

The noncovalent interactions of ammonium ion with multidentate oxygen-based host has never been reported as a reacting center in catalytic reactions. In this work, we report a reactivity enhancement process enabled by non-covalent interaction of ammonium ion, achieving the C-H functionalization of polyethylene glycols with acrylates by utilizing photoinduced co-catalysis of iridium and quinuclidine. A broad scope of alkenes can be tolerated without observing significant degradation. Moreover, this cyano-free condition respectively allows the incorporation of bioactive molecules and the PEGylation of dithiothreitol-treated bovine serum albumin, showing great potentials in drug delivery and protein modification. DFT calculations disclose that the formed α-carbon radical adjacent to oxygen-atom is reduced directly by iridium before acrylate addition. And preliminary mechanistic experiments reveal that the noncovalent interaction of PEG chain with the formed quinuclidinium species plays a unique role as a catalytic site by facilitating the proton transfer and ultimately enabling the transformation efficiently.

P(III)-Directed Asymmetric C-H Arylation toward Planar Chiral Ferrocenes by Palladium Catalysis.

Planar chiral ferrocenyl phosphines have been employed as highly valuable ligands in metal-catalyzed asymmetric reactions. However, their preparation remains a formidable challenge due to the requirement for intricate, multistep synthetic sequences. In addressing this issue, we have developed a groundbreaking enantioselective C-H activation strategy facilitated by P(III) directing groups, enabling the efficient construction of planar chiral ferrocenyl phosphines in a single step. Our innovative approach entails the combination of a palladium catalyst, a parent ferrocenyl phosphine, and a chiral phosphoramidite ligand, leading to exceptional reactivity and enantioselectivity. Remarkably, these novel ligands exhibit remarkable efficacy in silver-catalyzed asymmetric 1,3-dipolar cycloadditions. We carried out a combination of experimental and computational studies to obtain a more comprehensive understanding of the reaction pathway and the factors contributing to enantioselectivity.

Enantioselective Reductive (Hetero)Arylation of Cyclic N-Sulfonyl Imines by Cobalt Catalysis.

Transition-metal-catalyzed enantioselective addition of aryl organometallic reagents to imines has emerged as one of the most powerful tools for the formation of optically active diarylmethylamines. Here, we report the first asymmetric reductive (hetero)arylations of imines using aryl and heteroaryl halides enabled by a chiral cobalt-bisphosphine catalyst. This approach shows good functional group compatibility and complements the reported strategy without use of organometallic reagents. Mechanistic investigations supported that aryl-cobalt, instead of an arylzinc reagent, was formed in situ in this reductive aryl-addition event.

CircGOT1 promotes cell proliferation, mobility, and glycolysis-mediated cisplatin resistance via inhibiting its host gene GOT1 in esophageal squamous cell cancer.

Esophageal squamous cell cancer (ESCC) is a prevalent malignant cancer with high incidence and fatality rate. Surging evidences have revealed that circular RNAs (circRNAs) act key role in ESCC tumorigenesis and progression. Therefore, the purpose of this study is to explore the role and regulatory mechanism of a novel circGOT1 in ESCC. In the present study, the transcriptional expression of circGOT1, miR-606 and GOT1, and the epithelial-mesenchymal transition (EMT) and apoptosis-related markers were examined by quantitative PCR. The protein levels of GOT1 and glycolysis-related proteins were detected by Western blotting. In addition, the glycolytic levels were determined via measuring glucose uptake, lactate production, and ATP levels. Then, the function experiments and rescue experiments were used to investigate the function and mechanism of circGOT1 in ESCC. In addition, RNA immunoprecipitation, pull-down, and luciferase activity reporter gene assays were used to analyze the circGOT1/miR-606/GOT1 axis. The xenograft mouse mode was used to determine the function of circGOT1 in vivo. Here, we identified that circGOT1 and GOT1 upregulate, whereas miR-606 was reduced in ESCC tissues and cell lines. High circGOT1 and GOT1 expression associated with poor survival and worse prognosis of ESCC patients, but miR-606 revealed opposite traits. Mechanically, circGOT1 sponged miR-606 to promote GOT1, which induced cell proliferation, migration, aerobic glycolysis, and cisplatin resistance. The tumor growth was reduced by circGOT1 inhibition in xenograft mouse. Our results indicate the oncogene role of circGOT1 in ESCC via an endogenous competition RNA (ceRNA) mechanism to promote GOT1 expression via sponging miR-606.

Effects of Systemic Lidocaine on Postoperative Recovery Quality and Immune Function in Patients Undergoing Laparoscopic Radical Gastrectomy.

OBJECTIVE: This study aimed to explore the effects of lidocaine on postoperative quality of recovery (QoR) and immune function in patients undergoing laparoscopic radical gastrectomy. METHODS: In total, 135 patients were enrolled and were equally randomized to receive low-dose lidocaine (Group LL: 1.5 mg/kg bolus followed by an infusion at 1.0 mg/kg/hour) or high-dose lidocaine (Group HL: 1.5 mg/kg bolus followed by an infusion at 2.0 mg/kg/hour) or Controls (Group C: received a volume-matched normal saline at the same rate). The primary outcome was a QoR-40 score on postoperative day (POD) 1. Secondary outcomes were a QoR-40 score on POD 3, levels of inflammatory factors (IL-6, IL-10, TNF-α) and CD4+T cells, CD8+T cells proportions, and CD4+/CD8+ cell ratios and postoperative recovery of bowel function. RESULTS: There were no statistically significant differences in patient characteristics at baseline. The total QoR-40 scores on POD 1 in Group HL (171.4±3.89) were higher than those in Group LL (166.20±4.05) and in Group C (163.40±4.38) (adjusted P<0.001). Differences in the dimension scores of QoR-40 for pain, physical comfort, and emotional state were significant across the three groups. Lidocaine administration significantly reduced the release of IL-6, IL-10, TNF-α, and attenuated immune changes induced by trauma. Kaplan-Meier curves showed that the median time to the first exhaust and defecation were shorter in the Group HL than in Groups LL and C (1.55 days vs 2.4 days vs 2.6 days, log rank P<0.0001; and 2.86 days vs 3.22 days vs 3.46 days, log rank P=0.002, respectively). Additionally, patients in lidocaine groups required less remifentanil consumption and experienced lower pain intensity, compared with the control group. CONCLUSION: Systemic lidocaine improved postoperative recovery, alleviated inflammation and immunosuppression, and accelerated the return of bowel function, and is thus, worthy of clinical application. CLINICAL TRIALS REGISTRATION: ChiCTR2000028934.

A mussel-inspired supramolecular hydrogel with robust tissue anchor for rapid hemostasis of arterial and visceral bleedings.

In recent years, the developed hemostatic technologies are still difficult to be applied to the hemostasis of massive arterial and visceral hemorrhage, owing to their weak hemostatic function, inferior wet tissue adhesion, and low mechanical properties. Herein, a mussel-inspired supramolecular interaction-cross-linked hydrogel with robust mechanical property (308.47 ± 29.20 kPa) and excellent hemostatic efficiency (96.5% ± 2.1%) was constructed as a hemostatic sealant. Typically, we combined chitosan (CS) with silk fibroin (SF) by cross-linking them through tannic acid (TA) to maintain the structural stability of the hydrogel, especially for wet tissue adhesion ability (shear adhesive strength = 29.66 ± 0.36 kPa). Compared with other materials reported previously, the obtained CS/TA/SF hydrogel yielded a lower amount of blood loss and shorter time to hemostasis in various arterial and visceral bleeding models, which could be ascribed to the synergistic effect of wound closure under wet state as well as intrinsic hemostatic activity of CS. As a superior hemostatic sealant, the unique hydrogel proposed in this work can be exploited to offer significant advantages in the acute wound and massive hemorrhage with the restrictive access of therapeutic moieties.

Incidence of postoperative sore throat after using a new technique of insertion of a second generation Laryngeal Mask Airway: A randomised controlled trial.

BACKGROUND: Sore throat is a common complication after Laryngeal Mask Airway Supreme (SLMA) insertion. OBJECTIVE: The aim of this study was to determine whether a new SLMA insertion technique (not removing the pilot tube blocker before insertion) lowers the incidence of sore throat in the postanaesthesia care unit (PACU). DESIGN: A prospective, single-centre, parallel randomised controlled trial. SETTING: Operating room and PACU at a hospital in China from June to September 2019. PATIENTS: Four hundred and eight patients aged 18 to 65 years with American Society of Anaesthesiologists physical status class I or II who were scheduled for elective surgery requiring anaesthesia and SLMA insertion. INTERVENTIONS: Leaving the blocker at the end of the pilot tube in situ (this blocker keeps the valve open and the balloon remains partially inflated but will deflate with pressure) or removing the blocker and actively deflating the cuff before SLMA insertion. MAIN OUTCOME MEASURES: The primary outcome was the incidence of postoperative sore throat in the PACU. The secondary outcomes included sore throat severity (Prince Henry Hospital Pain Score), first-attempt success rate, ease of insertion, time to successful SLMA insertion, oropharyngeal leak pressure, grade of view on fibreoptic bronchoscopy (indicating the accuracy of SLMA positioning) and adverse events. RESULTS: The incidence of sore throat was 33/204 (16.2%) in the nonremoval group, and 65/204 (31.9%) in the removal group (P < 0.001). The first-attempt success rate was 174/204 (85.3%) in the nonremoval group and 150/204 (73.76%) in the removal group (P = 0.003; relative risk 1.160, 95% CI 1.049 to 1.282). The Kaplan--Meier curves showed that the insertion time in the nonremoval group was shorter (log-rank P = 0.01). CONCLUSION: The new insertion technique, leaving the blocker attached to the end of the pilot balloon, resulted in a reduced incidence and severity of postoperative sore throat in the PACU, and an improved first-attempt success rate and the accuracy of SLMA positioning. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR1900023022.

Application of Intravenous Lidocaine in Obese Patients Undergoing Painless Colonoscopy: A Prospective, Randomized, Double-Blind, Controlled Study.

OBJECTIVE: Propofol for procedural sedation and analgesia (PSA) for colonoscopy can result in a high prevalence of severe respiratory depression. Studies have shown that intravenous (IV) infusion of lidocaine can reduce propofol requirements significantly and increase the ventilatory response to carbon dioxide in humans. We tested the hypothesis that IV lidocaine could improve propofol-induced respiratory depression in obese patients during colonoscopy. METHODS: Ninety obese patients scheduled for painless colonoscopy were randomized to receive lidocaine (1.5 mg/kg, then 2 mg/kg/h, IV) or the same volume of 0.9% saline. Intraoperative sedation was provided by propofol. The primary outcome was the number of oxygen-desaturation episodes. Secondary outcomes were: the number of apnea episodes; total propofol consumption; time to the first hypoxia episode; time to consciousness loss; intraoperative hemodynamic parameters; awakening time; adverse events; duration of post-anesthesia care unit (PACU) stay; satisfaction of endoscopists and patients. RESULTS: Demographic characteristics between the two groups were comparable. The number of oxygen-desaturation episodes in group L (1.49±1.12) decreased by 0.622 (P=0.018) compared with that in group N (2.11±1.32), and the number of apnea episodes in group L decreased by 0.533 (P<0.001). Kaplan-Meier curves showed that the median time to the first hypoxia episode was longer in group L (86.78 s) than that in group N (63.83 s) (Log rank P=0.0008). The total propofol consumption, awakening time, and duration of PACU stay were reduced in group L. There was no significant difference in the prevalence of adverse events (P>0.05 for all). Satisfaction scores for endoscopists and patients in group L were higher than that in group N (P<0.001). CONCLUSION: Intravenous infusion of lidocaine could significantly reduce the number of oxygen-desaturation and apnea episodes in obese patients during painless colonoscopy. This method is worthy of clinical promotion. CLINICAL TRIALS REGISTRATION: ChiCTR2000028937.

Neighborhood greenness associated with chronic obstructive pulmonary disease: A nationwide cross-sectional study in China.

Differential findings have been reported on the association between neighborhood greenness and chronic obstructive pulmonary disease (COPD). The underlying reasons might be the different types of vegetation and the diagnosis methods used in different studies. In this nationwide cross-sectional study in China, we examined the linkage between neighborhood greenness and COPD prevalence among 66,752 adults aged 40 years and above. Neighborhood greenness was estimated using the normalized difference vegetation index (NDVI) based on satellite imagery within buffers of 100, 300, 500, 1000, 2000, 3000 and 5000 m of residential community of the participants. COPD was defined according to the 2017 Global Initiative for Chronic Obstructive Lung Disease lung function criteria. A two-level logistic regression model was applied to estimate the associations. Finally, 9134 adults were classified as COPD. We observed significant positive associations between neighborhood greenness and COPD prevalence. The odds ratio for each interquartile range increase in NDVI within 100 m buffer was 1.08 (95% CI: 1.01, 1.15) after adjustment for potential confounders. Consistent associations were observed across all other NDVI buffer sizes. Stratified analyses revealed that younger adults (40-65 years) and urban residents might be the vulnerable subpopulations. Further regional analyses found that residents from the Northeastern and Northern China were more likely to have this association. Our results indicated that neighborhood greenness might be one risk factor of COPD prevalence. Our study have important public health implications for allocating the surrounding green spaces among living areas, especially for those with respiratory illness; however, the findings and the underlying mechanisms warrant further examinations in longitudinal settings.

The efficacy and safety of intrathecal dexmedetomidine for parturients undergoing cesarean section: a double-blind randomized controlled trial.

BACKGROUND: The efficacy and safety of spinal anesthesia by intrathecal dexmedetomidine (DEX) for parturients undergoing cesarean section are still lack of evidence. This aim of our study was to evaluate the efficacy and safety of intrathecal DEX for parturients undergoing cesarean section to provide more data evidence for intrathecal applications. METHODS: Three hundred parturients undergoing cesarean section under spinal anesthesia were randomly assigned into three groups: group B: 9.0 mg (1.2 ml) of 0.75% bupivacaine with saline (1 ml); group FB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 20 µg of fentanyl (1 ml); group DB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 5 µg of DEX (1 ml). Intraoperative block characteristics, parturients' postoperative quality of recovery, maternal and neonatal outcomes and the plasma concentration of DEX were measured. All parturients were followed up for 30 days to determine whether nerve injury occurred. RESULTS: Compared with group B, the duration of sensory block in group FB and group DB were significantly prolonged (108.4 min [95% Confidence Interval (CI) = 104.6-112.3] in group B, and 122.0 min [95% CI = 116.8-127.3] in group FB, 148.2 min [95% CI = 145.3-151.1] in group DB). The overall score of quality recovery in group DB (71.6 [95% CI = 71.0-72.2]) was significantly higher than that in group FB (61.5 [95% CI = 60.8-62.2]) and group B (61.7 [95% CI = 61.0-62.4]). There was no statistically significant difference among the three groups for PH, PaO2, and PaCO2 of newborn. The plasma concentration of DEX in umbilical artery and umbilical vein was low and cannot be detected. The 30-days follow-up of parturients did not show any new onset of back, buttock or leg pain or paresthesia. CONCLUSIONS: DEX is a potential local anesthetic adjuvant that the intrathecal combination of 5 µg DEX can safely exhibit a facilitatory block effect and improve parturients' recovery quality. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Registration number # ChiCTR1900022019 ; Date of Registration on March 20th, 2019).

Glycyrrhizin improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway to prevent Doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is one of the most effective and irreplaceable chemotherapeutic agents but its clinical use is limited due to its cardiotoxicity. Glycyrrhizin(GL) has been applied to liver disorders for long. However, little is known that if GL could be meaningful in attenuating cardiotoxicity. The aim of this study is to investigate the cardioprotective effects of GL in DOX-induced cardiotoxicity (DIC) and the underlying mechanism. Here, H9c2 cardiomyoblasts, Neonatal rat cardiomyocytes (NRCMs), and Rats were introduced as test models. A single dose of 20 mg/kg DOX (i.p.) was applied to induce acute cardiotoxicity in vivo, as reflected by growth inhibition, increased levels of AST and CK-MB, and reduction of SOD activity, while GL (25 or 50 mg/kg/d, 14 d, i.p.) could counteract these effects. Moreover, pre-incubation with GL (0.8 mM for 12 h) in H9c2 cells protected against DOX-induced cytotoxicity, oxidative stress and depolarization of mitochondrial membrane potential (MMP). Besides, Western blot analysis showed that DOX upregulated the expression of LC3 II and p62 whereas GL reversed that both in vitro and in vivo and improved the obstructed autophagy flux in DOX-treated H9c2 cells with an autophagy inhibitor Bafilomycin A1 (Baf A1, 50 nM, 2 h). It has been previously documented that High-mobility group box 1 (HMGB1) was involved in DIC. In our work, knockdown of HMGB1 significantly increased cell viability and LC3 II level in H9c2, suggesting HMGB1 was crucial in DOX-induced autophagy-triggering cell death. Intriguingly, GL is a direct inhibitor of HMGB1. We found that GL downregulated Akt/mTOR autophagy signaling pathway in DOX-treated H9c2 cells. More importantly, in non-silencing H9c2 cells (transfected with negative control siRNA) cells, the expression of phospho-Akt, phospho-mTOR, p62, and LC3 II was significantly decreased with GL pretreament compared to DOX alone. However, in H9c2/HMGB1－(transfected with HMGB1 siRNA) cells exposed to DOX, the expression of p-Akt, p-mTOR, p62, LC3 II had no statistical difference with or without GL, revealing that HMGB1 mediated the cardioprotective action of GL in DIC. Taken together, our findings demonstrate that improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway might contribute to attenuate DIC and go a novel insight into the underlying mechanisms of GL's cardioprotective action. GL could be a potential candidate for the prevention of DIC.

Influenza vaccination rate and its association with chronic diseases in China: Results of a national cross-sectional study.

INTRODUCTION: Influenza vaccination is the most effective way to prevent influenza. Few studies on its rate were reported throughout China and for populations with chronic diseases. An estimation of the rates in China was accomplished. METHODS: All data were from a national cross-sectional survey of a sample representing the population aged 40 years or older in mainland China in 2014-15. A total of 74,484 individuals with complete self-reported influenza vaccination status were analyzed in 2018-19. RESULTS: The overall influenza vaccination rate was 2.4% (95% CI 1.4-3.3) with 1.7% (95% CI 1.2-2.2) for the age group 40-59 years and 3.8% (95% CI 1.6-5.9) for the group ≥60 years. The rate was 4.0% (95% CI 2.0-5.9) among people with a chronic disease. People with asthma and people with emphysema had the highest rates (7.1%, 95% CI 3.2-11.0 and 6.6%, 95% CI 3.6-9.7) while people with chronic obstructive pulmonary disease (COPD) and people with chronic bronchitis had the lower rates (3.6%, 95% CI 2.0-5.2 and 4.8%, 95% CI 2.6-7.0). The rate was the highest among former smokers (3.3%, 95% CI 2.3-4.4) compared to current smokers (1.8%, 95% CI 0.9-2.7) and never smokers (2.5%, 95% CI 1.4-3.6). People living with finance-reimbursed vaccination policy, a positive factor for vaccination, had a higher vaccination rate (11.5%, 95% CI 10.8-12.2) (p < 0.05). People with older age, higher education level, occupation of professionals or technical personnel, living in rural areas or Northern China, former/never smoking were more likely to be vaccinated (p < 0.05). CONCLUSIONS: The influenza vaccination rate is low among adults aged ≥40 years, those ≥60 years and those with chronic diseases in China. Reimbursement policy targeting the elderly should be implemented widely and strategies towards patients with chronic diseases need urgent attention to increase the influenza vaccination coverage.

Formulation of injectable glycyrrhizic acid-hydroxycamptothecin micelles as new generation of DNA topoisomerase I inhibitor for enhanced antitumor activity.

To develop a new drug delivery system is one of the useful approaches to break through the limitation of hydroxycamptothecin (HCPT), a typical DNA topoisomerase I (Topo I) inhibitor in clinical appliance. Injectable glycyrrhizic acid-hydroxycamptothecin (GL-HCPT) micelles that were able to dramatically improve the solubility and stability of HCPT were prepared through self-assembly process and evaluated both in vitro and in vivo. With a mean particle size (PS) of 105.7 ±â€¯9.7 nm and a drug loading (DL) of 9.0 ±â€¯1.5%, GL-HCPT micelles were rapidly internalized by HepG2 cells after 1 h, significantly increasing the intracellular accumulation of HCPT. Compared with the current used HCPT injection and HCPT/GL physical mixture, GL-HCPT micelles showed enhanced antitumor activity against liver cancer cells (HepG2 and Huh7) as well as a superior suppression on the tumor growth of HepG2 tumor bearing mice. Interestingly, GL-HCPT micelles gathered in liver and simultaneously reduced the drug accumulation in normal tissues, thereby exhibiting minimal cytotoxicity to human normal liver cells (LO2). Therefore, we offered a convenient and cost-effective strategy to construct an intravenous drug delivery system (GL-HCPT micelles) as new generation of DNA Topo I inhibitor for enhanced cancer chemotherapy.

Novobiocin, a Newly Found TRPV1 Inhibitor, Attenuates the Expression of TRPV1 in Rat Intestine and Intestinal Epithelial Cell Line IEC-6.

Background and Purpose: Novobiocin (NOVO), an ABC transporter inhibitor, decreases intestinal wall permeability of capsaicin (CAP), an ABC transporter substrate. However, the mechanism of this effect is not consistent with the action of NOVO as an ABC transporter inhibitor. We previously found that CAP can also be transported via TRPV1, which was site-specific in the permeability of CAP across the intestine. We explored the regulation by NOVO of TRPV1 in the present study. Methods: Rats and transfected IEC-6 cells were used as the models to assess intestinal permeability and expression of TRPV1. Ussing chamber and intracellular accumulation were used to evaluate the influence of NOVO on the transport of CAP in vitro. The expression of TRPV1 was detected after administration of NOVO by qRT-PCR, western blot and immunofluorescent imaging. In addition, MTT and lactate dehydrogenase (LDH) were used to evaluate the cytotoxicity of NOVO in both rat and cell models. Finally, the effect of NOVO on the absorption of CAP in vivo was studied by LC-MS/MS. Results: In vitro data showed that there existed a dose-dependent relationship in the range of concentration between 5 and 50 µM, and even 5 µM NOVO could decrease intestinal permeability of CAP across the intestine. Meanwhile, cytosolic accumulation of CAP decreased when NOVO was used simultaneously or 24 h in advance. NOVO exhibited an inhibition level similar to that of ruthenium red (RR) or SB-705498, a TRPV1-specific inhibitor. NOVO down-regulated TRPV1 expression in the intestine and in transfected cells in a concentration-dependent fashion, hinting that its inhibition of the permeability of CAP is due to its inhibition of TRPV1 expression. Immunofluorescent imaging data showed that the fluorescence intensity of TRPV1 was reduced after pre-treatment with NOVO and SB-705498. In vivo data further demonstrated that oral co-administration of NOVO decreased Cmax and AUC of CAP in dosage-dependent ways, consistent with its role as a TRPV1 inhibitor. Conclusion: NOVO could be a potential TRPV1 inhibitor by attenuating the expression of TRPV1 and may be used to attenuate permeability of TRPV1 substrates.

Photoredox-Mediated Direct Cross-Dehydrogenative Coupling of Heteroarenes and Amines.

A photoredox-mediated direct cross-dehydrogenative coupling reaction to accomplish α-aminoalkylation of N-heteroarenes is reported. This mild reaction has a broad substrate scope, offers the first general method for synthesis of aminoalkylated N-heteroarenes without the need for substrate prefunctionalization, and is scalable to the gram level. Furthermore, the reaction was found to be applicable to other hydrogen donors besides amines (i.e., ethers, an aldehyde, a formamide, p-xylene, and alkanes), thus enabling the preparation of N-heteroarenes bearing various types of substituents.