Enhancing the Stability, Solubility, and Antioxidant Activity of Cinchonine through Pharmaceutical Cocrystallization.

PURPOSE: Cinchoninze hydrochloride solves the problem of the low solubility of cinchonine, but it is unstable and susceptible to deliquescence. In this study, we designed and prepared cinchonine cocrystal salts or cinchonine salts with better stability, solubility and antioxidant activity than cinchonine. METHOD: We successfully synthesized and characterized three cinchonine salts, namely, cinchonine-fumaric acid, cinchonine-isoferulic acid, and cinchonine-malic acid. The high humidity (92.5% RH) and high temperature (60°C) tests were conducted to determine the physical stability and hygroscopicity of cinchonine hydrochloride, cinchonine and three cinchonine salts. And the ultraviolet spectrophotometry was conducted to determine the equilibrium solubility and intrinsic dissolution rate of cinchonine and salts. Moreover, the DPPH, ABTS, and FRAP assays determined the antioxidant activity of cinchonine and salts. RESULT: Compared with cinchonine hydrochloride and cinchonine, all three cinchonine salts exhibited good physical stability over 15 days under high humidity (92.5% RH) and high temperature (60°C) conditions. While cinchonine and cinchonine hydrochloride are categorized as hygroscopic and deliquescent, respectively, three cinchonine salts are classified as slightly hygroscopic, meaning that they have a lower hygroscopicity than cinchonine and cinchonine hydrochloride. And three cinchonine salts had higher equilibrium solubility, faster intrinsic dissolution rates, and higher antioxidant activity in comparison to cinchonine. Moreover, they showed a "spring and parachute" pattern in the phosphate buffer (pH = 6.8). CONCLUSION: Cocrystallization technology is a viable option for improving cinchonine's poor physicochemical qualities.

Wearable Tin-Based Perovskite Solar Cells Achieved by a Crystallographic Size Effect.

Tin-based perovskite solar cells (PSCs) demonstrate a potential application in wearable electronics due to its hypotoxicity. However, poor crystal quality is still the bottleneck for achieving high-performance flexible devices. In this work, graphite phase-C3 N4 (g-C3 N4 ) is applied into tin-based perovskite as a crystalline template, which delays crystallization via a size-effect and passivates defects simultaneously. The double hydrogen bond between g-C3 N4 and formamidine cation can optimize lattice matching and passivation. Moreover, the two-dimensional network structure of g-C3 N4 can fit on the crystals, resulting an enhanced hydrophobicity and oxidation resistance. Therefore, the flexible tin-based PSCs with g-C3 N4 realize a stabilized power conversion efficiency (PCE) of 8.56 % with negligible hysteresis. In addition, the PSCs can maintain 91 % of the initial PCE after 1000 h under N2 environment and keep 92 % of their original PCE after 600 cycles at a curvature radius of 3 mm.

The propofol-sparing effect of intravenous lidocaine in elderly patients undergoing colonoscopy: a randomized, double-blinded, controlled study.

BACKGROUND: Propofol provides a prominent sedation effect in colonoscopy. However, anesthesia and sedation induced with propofol in the elderly might result in cardiopulmonary complications, especially when it is combined with opoids in the regimen. This study aimed to test the hypothesis that the addition of intravenous lidocaine to propofol-based sedation could decrease the overall propofol requirement in elderly patients during colonoscopy while the procedural sedation satisfaction and the hemodynamic stability were not compromised. METHODS: Ninety-two patients undergoing colonoscopy were randomly enrolled into lidocaine+propofol (L + P) group or normal saline+propofol (NS + P) groups. Subjects received intravenous bolus of 1.5 mg/kg lidocaine followed by 4 mg kg- 1 h- 1 lidocaine continuous infusion in L + P group or equivalent volumes of normal saline for boluses and infusion in NS + P group. Anesthesia was induced with 2.5 µg sufentanil followed by injection of 1.2 mg kg- 1 propofol in all patients. A single supplemental bolus of 0.6 mg kg- 1 propofol was administered whenever MOAA/S score > 1 or had body movement during the colonoscopy. The recorded primary endpoints included: the total amount of propofol administered during entire procedure, the supplemental amount of propofol after induction, and the frequencies of boluses of supplemental propofol. RESULTS: A total of 79 patients were included in the final analysis. Compared with NS + P group, the total amounts of propofol (induction plus supplemental) were no significant differences in L + P group; however, the required supplemental propofol was less (69.9 ± 39.2 mg vs. 51.5 ± 38.6 mg) (P = 0.039); the average frequencies of boluses of supplemental propofol given after induction were lower (2.1 ± 1.1 vs. 1.4 ± 0.9) (P = 0.003); the calculated "unit propofol" infusion rate was lower (0.18 ± 0.05 vs. 0.14 ± 0.04 mg kg- 1 min- 1) (P = 0.002). CONCLUSIONS: The addition of intravenous lidocaine to propofol-based sedation resulted in a remarked reduction of supplemental propofol in the elderly during colonoscopy. TRIAL REGISTRATION: The present clinical trial was registered at http://www.chictr.org.cn on 11th March 2019 (registration No. ChiCTR1900021818).

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin.

The continuous rise of multidrug-resistant (MDR) Gram-negative bacteria poses a severe threat to public health worldwide. Colistin(COL), employed as the last-line antibiotic against MDR pathogens, is now at risk due to the emergence of colistin-resistant (COL-R) bacteria, potentially leading to adverse patient outcomes. In this study, synergistic activity was observed when colistin and diclofenac sodium (DS) were combined and used against clinical COL-R strains of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa) both in vitro and in vivo. The checkerboard method and time-killing assay showed that DS, when combined with COL, exhibited enhanced antibacterial activity compared to DS and COL monotherapies. Crystal violet staining and scanning electron microscopy showed that COL-DS inhibited biofilm formation compared with monotherapy. The in vivo experiment showed that the combination of DS and COL reduced bacterial loads in infected mouse thighs. Synergistic activity was observed when COL and DS were use in combination against clinical COL-R strains of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa both in vitro and in vivo. The synergistic antibacterial effect of the COL-DS combination has been confirmed by performing various in vitro and in vivo experiments, which provides a new treatment strategy for infections caused by MDR bacteria.

Antibacterial and Anticancer Activity, Acute Toxicity, and Solubility of Co-crystals of 5-Fluorouracil and Trimethoprim.

5-Fluorouracil is mainly used for the treatment of tumors and has relatively high toxicity. Trimethoprim is a common broad-spectrum antibiotic agent with extremely poor water solubility. We hoped to solve these problems by synthesizing co-crystals (compound 1) of 5-fluorouracil and trimethoprim. Solubility tests showed that the solubility of compound 1 was improved compared to that of trimethoprim. In vitro anticancer activity tests of compound 1 showed higher activity against human breast cancer cells than 5-fluorouracil. Acute toxicity showed that its toxicity was much lower than that of 5-fluorouracil. In the test of anti-Shigella dysenteriae activity, compound 1 showed much stronger antibacterial activity than trimethoprim.

Effects of propofol on the proliferation and migration of liver cancer cells.

Liver cancer is a malignant cancer with worldwide prevalence. It has been reported that cancer cells are usually exposed to a hypoxic microenvironment, which is associated with a poor prognosis in patients with cancer. Propofol is an intravenous anesthetic that is widely used in cancer surgery. The present study aimed to determine the effects of propofol stimulation on the viability, proliferation and migration of liver cancer cells under normoxia and cobalt chloride (CoCl2)-induced hypoxia. Under normoxia, HepG2 and HCCLM3 cells were randomly divided into six groups as follows: i) Control group; ii) 10 µM propofol group; iii) 25 µM propofol group; iv) 50 µM propofol group; v) 100 µM propofol group; and vi) DMSO group. Cell viability and proliferation were analyzed using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, respectively, following 24 or 48 h of propofol treatment. In addition, wound healing and Transwell migration assays were used to determine the changes in cell migration. Under CoCl2-induced hypoxia, the protein levels of hypoxia inducible factor-1α (HIF-1α) of HepG2 cells were analyzed using western blotting. Subsequently, CCK-8 and wound healing assays were used to determine the effect of propofol on cell viability and migration. The results of the present study revealed that propofol stimulation had no significant effect on the viability, proliferation and migration of HepG2 and HCCLM3 cells under normoxia. The protein levels of HIF-1α were significantly upregulated following the treatment with 200 µM CoCl2 for 12 h. However, no significant differences were found in the viability and migration of HepG2 cells following the stimulation with propofol in the presence of CoCl2. In conclusion, the findings of the present study revealed that propofol exerted no effect on the viability, proliferation and migration of HepG2 and HCCLM3 cells under normoxic and hypoxic conditions.

Genome-Wide Identification of CBL-CIPK Gene Family in Honeysuckle (Lonicera japonica Thunb.) and Their Regulated Expression Under Salt Stress.

In plants, calcineurin B-like proteins (CBLs) are a unique group of Ca2+ sensors that decode Ca2+ signals by activating a family of plant-specific protein kinases known as CBL-interacting protein kinases (CIPKs). CBL-CIPK gene families and their interacting complexes are involved in regulating plant responses to various environmental stimuli. To gain insight into the functional divergence of CBL-CIPK genes in honeysuckle, a total of six LjCBL and 17 LjCIPK genes were identified. The phylogenetic analysis along with the gene structure analysis divided both CBL and CBL-interacting protein kinase genes into four subgroups and validated by the distribution of conserved protein motifs. The 3-D structure prediction of proteins shown that most LjCBLs shared the same Protein Data Bank hit 1uhnA and most LjCIPKs shared the 6c9Da. Analysis of cis-acting elements and gene ontology implied that both LjCBL and LjCIPK genes could be involved in hormone signal responsiveness and stress adaptation. Protein-protein interaction prediction suggested that LjCBL4 is hypothesized to interact with LjCIPK7/9/15/16 and SOS1/NHX1. Gene expression analysis in response to salinity stress revealed that LjCBL2/4, LjCIPK1/15/17 under all treatments gradually increased over time until peak expression at 72 h. These results demonstrated the conservation of salt overly sensitive pathway genes in honeysuckle and a model of Ca2+-LjCBL4/LjSOS3-LjCIPK16/LjSOS2 module-mediated salt stress signaling in honeysuckle is proposed. This study provides insight into the characteristics of the CBL-CIPK gene families involved in honeysuckle salt stress responses, which could serve as a foundation for gene transformation technology, to obtain highly salt-tolerant medicinal plants in the context of the global reduction of cultivated land.

Chemo-immune synergetic therapy of esophageal carcinoma: trastuzumab modified, cisplatin and fluorouracil co-delivered lipid-polymer hybrid nanoparticles.

Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Peptide modified nanoparticles have been engineered as novel strategies to improve esophageal adenocarcinoma (EAC) therapy. This study aimed to develop a trastuzumab (TAB) modified system for the delivery of cisplatin (CIS) and fluoropyrimidine (5-FU). In the present study, CIS and 5-FU co-encapsulated lipid-polymer hybrid nanoparticles (CIS/5-FU LPHNs) were prepared. TAB was conjugated to the surface of CIS/5-FU LPHNs to achieve TAB decorated CIS/5-FU LPHNs (TAB-CIS/5-FU LPHNs). After the in vitro assessment, a subcutaneous model was used for the in vivo study. The mean diameter of LPNHs was around 100 nm, with higher encapsulation efficacy (EE) of about 90%. The LPNHs was stable and able to release drugs in sustained manners. 63.9% of cell uptake was achieved by TAB-CIS/5-FU LPHNs, with the best in vivo antitumor ability. The best synergistic effect with the lowest CI value (0.68) was achieved at the ratio of 1/1, which was determined for the dosage of drugs in the LPHNs preparation. TAB-CIS/5-FU LPHNs provide a new strategy for synergistic treating of EAC with higher efficacy and reduced side effects, introducing this system as a candidate for EAC therapy.

Modified paediatric preoperative risk prediction score to predict postoperative ICU admission in children: a retrospective cohort study.

OBJECTIVE: To integrate intrinsic surgical risk into the paediatric preoperative risk prediction score (PRPS) model to construct a more comprehensive risk scoring system (modified PRPS) and improve the prediction accuracy of postoperative intensive care unit (ICU) admission in paediatric patients. DESIGN: This was a retrospective study conducted between 1 January and 30 December 2016. Data on age, American Society of Anaesthesiology physical status (ASA-PS), oxygen saturation, prematurity, non-fasted status, severity of surgery and immediate transfer to the ICU after surgery were collected. The modified PRPS was developed by logistic regression in the derivation cohort; it was tested and compared with the paediatric PRPS and ASA-PS by the Hosmer-Lemeshow test, the receiver operating characteristic (ROC) curve and Kappa analysis in the validation cohort. SETTING: Hospital-based study in China. PARTICIPANTS: Paediatric patients (≤14 years) who underwent surgery under general anaesthesia were included, and those who needed reoperation due to surgical complications or stayed in the ICU preoperatively were excluded. MAIN OUTCOME MEASURE: ICU admission rate, defined as any patients' direct disposition from the operating room to the ICU immediately after the surgery. RESULTS: A total of 9261 paediatric patients were included in this study, with 418 patients admitted to the ICU. In the validation cohort, the modified PRPS model fit the test data well (deciles of risk goodness-of-fit χ2=6.84, p=0.077). The area under the ROC curve of the modified PRPS, paediatric PRPS and ASA-PS were 0.963, 0.941 and 0.870, respectively (p<0.05), and the Kappa values were 0.620, 0.286 and 0.267. Analyses in the cohort indicated that the modified PRPS was superior to the paediatric PRPS and ASA-PS. CONCLUSIONS: The modified PRPS integrating intrinsic surgical risk shows better prediction accuracy than the previous PRPS.

Polyolefin Elastomer as the Anode Interfacial Layer for Improved Mechanical and Air Stabilities in Nonfullerene Solar Cells.

Despite the breakthroughs in power conversion efficiency (PCE) values of organic solar cells (OSCs), the other important issue concerns stability, which is urgently needed to be resolved for potential commercialization. A commercial and chemically stable polyolefin elastomer (POE) was incorporated into high-performance PBDB-T:ITIC, PM6:IT-4F, and PM6:Y6 nonfullerene systems to serve as the anode interfacial layer, affording remarkably improved mechanical and air stabilities when compared with those of the most studied MoO3 interfacial layer. The POE was found to selectively transport holes rather than electrons due to the upshifted surface contact potential of the active layer and the better ohmic contact between the active layer and the electrode. The POE serving as an encapsulating layer is supposed to suppress the penetration of water and oxygen in addition to the diffusion of Ag atoms into the active layer. After storing in an air environment with a humidity of approximately 70% for 150 days, the PCE of the device based on PM6:IT-4F with the POE anode interfacial layer decreased from 11.88 to 9.60%, retaining 80.8% of its original PCE value. The device using MoO3 as the anode interfacial layer showed a PCE value that was sharply reduced from 12.31 to 2.98% after storing for only 30 days. The POE could be potentially useful for flexible and large-scale device fabrication, accelerating the commercialization of OSCs.

Amphiphilic Fullerenes Employed to Improve the Quality of Perovskite Films and the Stability of Perovskite Solar Cells.

Fullerene end-capped polyethylene glycol (C60-PEG) was introduced via an antisolvent method to fabricate the perovskite films. C60-PEG could enlarge the perovskite crystal size and passivate the defects of perovskite films, facilitating the carrier transport and hindering the carrier recombination. In consequence, the superior optoelectronic properties were attained with an improved power conversion efficiency of 17.71% for the perovskite device with C60-PEG treatment. Meanwhile, amphiphilic C60-PEG enhanced the resistance of perovskite films to moisture. After 40 days, the C60-PEG-based devices without encapsulation remained 93 and 86% of the original power conversion efficiency value under nitrogen and ambient conditions (25 °C temperature, 60% humidity), respectively.

Recent Progress on the Long-Term Stability of Perovskite Solar Cells.

As rapid progress has been achieved in emerging thin film solar cell technology, organic-inorganic hybrid perovskite solar cells (PVSCs) have aroused many concerns with several desired properties for photovoltaic applications, including large absorption coefficients, excellent carrier mobility, long charge carrier diffusion lengths, low-cost, and unbelievable progress. Power conversion efficiencies increased from 3.8% in 2009 up to the current world record of 22.1%. However, poor long-term stability of PVSCs limits the future commercial application. Here, the degradation mechanisms for unstable perovskite materials and their corresponding solar cells are discussed. The strategies for enhancing the stability of perovskite materials and PVSCs are also summarized. This review is expected to provide helpful insights for further enhancing the stability of perovskite materials and PVSCs in this exciting field.

Enhancing the grain size of organic halide perovskites by sulfonate-carbon nanotube incorporation in high performance perovskite solar cells.

The grain size of perovskites was enhanced and the grain boundary was filled with sulfonate carbon nanotubes (s-CNTs) during the CH3NH3PbI3 perovskite precursor solution spin-coating process with the incorporation of s-CNTs. The performance of s-CNT incorporated perovskite solar cells remarkably increased from 10.3% to 15.1% (best) compared with pristine CNT incorporated perovskite solar cells.

Fish consumption doesn't reduce the risk of hepatocellular carcinoma.

BACKGROUND: Several observational studies have investigated the association between fish consumption and the risk of hepatocellular carcinoma (HCC), however, the results were inconsistent. Hence, we performed a meta-analysis of observational studies to evaluate the effect of fish consumption on HCC risk. METHODS: A systematic search was performed using the Pubmed, Embase, and Cochrane Library Central database for case-control and coshort studies that assessed fish intake and HCC risk. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Subgroup analyses and sensitivity analysis were also performed. RESULTS: Nine case-control studies and three cohort studies were included, involving a total of 1,071,458 participants and 2,627 HCC cases. Meta-analysis showed that there was no association between fish consumption and a significant reduction in HCC incidence (RR = 0.85, 95% CI [0.62, 1.17]). In our subgroup analyses, the result was substantially affected by adjustment for hepatic viruses' infection status. Sensitivity analysis confirmed the stability of results. Furthermore, there was no evidence of publication bias as suggested by Begg's P value (P = 0.411) and Egger's (P = 0.596) test. CONCLUSIONS: In conclusion, our results do not support a significant inverse association of fish consumption with HCC risk. More in-depth studies are warranted to report more detailed results, including stratified results by fish types, preparation methods, and gender.