Effect of remote ischemic preconditioning on postoperative cognitive dysfunction in adult patients with general anesthesia: a meta-analysis.

BACKGROUND: Remote ischemic preconditioning (RIPC) is proven to have neuroprotective protective effects. Nevertheless, the impact of RIPC on postoperative cognitive dysfunction (POCD) in patients undergoing general anesthesia is controversial. This meta-analysis of randomized controlled trials (RCTs) aimed to assess the effect of RIPC on POCD in adults after general anesthesia. METHODS: Relevant literature was obtained by searching Embase, PubMed, Web of Science, Cochrane Library, Wanfang, and China National Knowledge Infrastructure (CNKI) databases in July 2022. RCTs were included to assess the influences of RIPC on POCD in adults following general anesthesia. Two investigators independently performed literature screening, data extraction, and quality assessment based on the inclusion and exclusion criteria. The incidence of POCD, operation time, and hospital stay were analyzed by Review manager5.4 software. RESULTS: Thirteen RCTs with 1122 participants were selected for this meta-analysis. Compared to the control group, RIPC decreased the incidence of POCD (OR = 0.50, 95% CI 0.31-0.82), as well as reduced the duration of hospitalization (MD = - 0.98, 95% CI - 1.69 to - 0.27), but did not prolong operative time (MD = - 2.65, 95% CI - 7.68 to 2.37). CONCLUSION: RIPC reduced the incidence of POCD in adult patients after general anesthesia and accelerated their discharge.

Preparation of polyhydroxyalkanoate-based magnetic microspheres for carbonyl reductase purification and immobilization.

A polyhydroxyalkanoate (PHA) magnetic microsphere was designed for one-step purification and immobilization of a novel carbonyl reductase (RLSR5) from recombinant Escherichia coli lysate. The hydrophobic core of this microsphere was composed of a highly biocompatible polymer, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), in which magnetic Fe3O4 particles were embedded during solvent evaporation. The hydrophilic shell of the fusion protein formed by PHA particle-binding protein (PhaP) and RLSR5 (PR) was expressed in recombinant E. coli. The magnetic core of Fe3O4@PHBHHx directly purified the hydrophilic shell from the E. coli lysate, and the two self-assembled to form Fe3O4@PHBHHx-PR through hydrophobic and hydrophilic interactions, eliminating the separation of the fusion protein. The microstructure, magnetic properties, morphology, size, and dispersion of Fe3O4@PHBHHx-PR were investigated by XRD, VSM, SEM, TEM, elemental mapping and DLS. It was found that Fe3O4@PHBHHx-PR correctly assembled, with a well dispersed spherical structure at the nanoscale and superparamagnetism properties. The amount of RLSR5 immobilized on PHA microspheres reached 121.9 mg/g. The Fe3O4@PHBHHx-PR was employed to synthesize (R)-tolvaptan with 99 % enantiomeric excess and 97 % bioconversion efficiency, and the catalyst maintained 78.6 % activity after 10 recovery cycles. These PHA magnetic microspheres are versatile carriers for enzyme immobilization and demonstrate improved stability and reusability of the free enzyme.

Characterization and Application of a Novel Glucose Dehydrogenase with Excellent Organic Solvent Tolerance for Cofactor Regeneration in Carbonyl Reduction.

An efficient cofactor regeneration system has been developed to provide a hydride source for the preparation of optically pure alcohols by carbonyl reductase-catalyzed asymmetric reduction. This system employed a novel glucose dehydrogenase (BcGDH90) from Bacillus cereus HBL-AI. The gene encoding BcGDH90 was found through the genome-wide functional annotation. Homology-built model study revealed that BcGDH90 was a homo-tetramer, and each subunit was composed of ßD-αE-αF-αG-ßG motif, which was responsible for substrate binding and tetramer formation. The gene of BcGDH90 was cloned and expressed in Escherichia coli. The recombinant BcGDH90 exhibited maximum activity of 45.3 U/mg at pH 9.0 and 40 °C. BcGDH90 showed high stability in a wide pH range of 4.0-10.0 and was stable after the incubation at 55 °C for 5 h. BcGDH90 was not a metal ion-dependent enzyme, but Zn2+ could seriously inhibit its activity. BcGDH90 displayed excellent tolerance to 90% of acetone, methanol, ethanol, n-propanol, and isopropanol. Furthermore, BcGDH90 was applied to regenerate NADPH for the asymmetric biosynthesis of (S)-(+)-1-phenyl-1,2-ethanediol ((S)-PED) from hydroxyacetophenone (2-HAP) with high concentration, which increased the final efficiency by 59.4%. These results suggest that BcGDH90 is potentially useful for coenzyme regeneration in the biological reduction.

Effects of Remote Ischemic Preconditioning on Postoperative Cognitive Dysfunction in Elderly Patients with Laparoscopic Cholecystectomy.

Purpose: We hypothesized that remote ischemic preconditioning (RIPC) could improve postoperative cognitive dysfunction (POCD) in elderly patients following laparoscopic cholecystectomy (LC). Patients and Methods: Eighty-eight patients were randomly assigned to either the control or the RIPC group. The RIPC was applied on the right upper limb using a blood pressure cuff inflating 200 mmHg, consisting of 3 cycles of 5 min ischemia and 5 min reperfusion. Serum concentrations of Neuron-specific Enolase (NSE) and Brain-Derived Neurotrophic Factor (BDNF) were collected at one-day preoperative (T0), at the end of the operation (T4) and one-day postoperative (T5). Z score was tested at T0 and 3 days after the operation (T6). POCD was determined if there were two Z scores ≥1.96 at the same time or an average Z score ≥1.96. Results: There was no significant difference in the Z score of each test between the two groups at T0 (P > 0.05). Notably, the duration of Stroop test C was significantly shorter in the RIPC group than that in the Control group at T6 (P = 0.01). POCD occurred in 1/44 (2.3%) patients in the RIPC group and 8/44 (18.2%) patients in the control group at T6 (P=0.035). In addition, serum NSE concentration was significantly decreased, but serum BDNF concentration was increased compared with the control group at T4 and T5 (P<0.001). Conclusion: RIPC could reduce the incidence of POCD in elderly patients after laparoscopic cholecystectomy.

Amphiphilic Cationic Peptide-Coated PHA Nanosphere as an Efficient Vector for Multiple-Drug Delivery.

Amphiphilic core-shell (ACS) nanoparticles are gaining increasing research interest for multi-drug delivery in cancer therapy. In this work, a new cationic peptide-coated PHA nanosphere was prepared by self-assembly of a hydrophobic core of biodegradable poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) and a hydrophilic shell of fusion proteins of PHA granule-associated protein (PhaP) and cationic peptide RALA through a strong hydrophobic effect. The hydrophobic drug curcumin (Cur) was encapsulated in PHBHHx nanoparticles. The chemotherapy drug 5-fluorouracil (5-FU) was administered in the form of its metabolite oligomeric 5-fluorodeoxyuridine (FUdR). Fifteen consecutive FUdR (FUdR15S) were adsorbed on the surface of PHBHHx nanoparticles by electrostatic interaction with RALA to form Cur@PHBX-PR/FUdR15S. Such amphiphilic cationic nanospheres had 88.3% EE of Cur and the drug loading of Cur and FUdR were 7.8% and 12.1%. The dual-drug-loaded nanospheres showed a time-differential release of Cur and FUdR. In addition, Cur@PHBX-PR/FUdR15S exhibited excellent anticancer activity and played a vital role in promoting the synergistic effect of FUdR and Cur in gastric cancer cells. The exploration of antitumor mechanisms demonstrated that Cur improved the activity of apoptosis-related proteins and cancer cells sensitized to FUdR. This amphiphilic core-shell system can serve as a general platform for sequential delivery of multiple drugs to treat several cancer cells.

Affibody Modified G-quadruplex DNA Micelles Incorporating Polymeric 5-Fluorodeoxyuridine for Targeted Delivery of Curcumin to Enhance Synergetic Therapy of HER2 Positive Gastric Cancer.

Combination chemotherapy is emerging as an important strategy for cancer treatment with decreased side effects. However, chemotherapeutic drugs with different solubility are not easy to realize co-delivery in traditional nanocarriers. Herein, an affibody modified G-quadruplex DNA micellar prodrug (affi-F/GQs) of hydrophilic 5-fluorodeoxyuridine (FUdR) by integrating polymeric FUdRs into DNA strands is developed for the first time. To achieve synergistic efficacy with hydrophobic drugs, curcumin (Cur) is co-loaded into affi-F/GQs micelles to prepare the dual drug-loaded DNA micelles (Cur@affi-F/GQs), in which affibody is employed as a targeting moiety to facilitate HER2 receptor-mediated uptake. Cur@affi-F/GQs have a small size of approximately 130 nm and exhibit excellent stability. The system co-delivers FUdR and Cur in a ratiometric manner, and the drug loading rates are 21.1% and 5.6%, respectively. Compared with the physical combination of FUdR and Cur, Cur@affi-F/GQs show higher cytotoxicity and greater synergistic effect on HER2 positive gastric cancer N87 cells. Surprisingly, Cur@affi-F/GQs significantly enhance the expression and activity of apoptosis-associated proteins in Bcl-2/Bax-caspase 8, 9-caspase 3 apoptotic pathway, which is the main factor in the death of tumor cells induced by FUdR. Overall, this nanoencapsulation is a promising candidate for the targeted co-delivery of drugs with significant differences in solubility.

Green and scalable synthesis of chiral aromatic alcohols through an efficient biocatalytic system.

Chiral aromatic alcohols have received much attention due to their widespread use in pharmaceutical industries. In the asymmetric synthesis processes, the excellent performance of alcohol dehydrogenase makes it a good choice for biocatalysts. In this study, a novel and robust medium-chain alcohol dehydrogenase RhADH from Rhodococcus R6 was discovered and used to catalyse the asymmetric reduction of aromatic ketones to chiral aromatic alcohols. The reduction of 2-hydroxyacetophenone (2-HAP) to (R)-(-)-1-phenyl-1,2-ethanediol ((R)-PED) was chosen as a template to evaluate its catalytic activity. A specific activity of 110 U mg-1 and a 99% purity of e.e. was achieved in the presence of NADH. An efficient bienzyme-coupled catalytic system (RhADH and formate dehydrogenase, CpFDH) was established using a two-phase strategy (dibutyl phthalate and buffer), which highly raised the tolerated substrate concentration (60 g l-1 ). Besides, a broad range of aromatic ketones were enantioselectively reduced to the corresponding chiral alcohols by this enzyme system with highly enantioselectivity. This system is of the potential to be applied at a commercial scale.

Co-delivery of 5-fluorodeoxyuridine and doxorubicin via gold nanoparticle equipped with affibody-DNA hybrid strands for targeted synergistic chemotherapy of HER2 overexpressing breast cancer.

Combination chemotherapy is still of great importance as part of the standard clinical care for patients with HER2 positive breast cancer. As an attractive component, gold nanoparticles (AuNPs) have been extensively studied as biosafety nanomaterials, but they are rarely explored as drug nanocarriers for targeted co-delivery of multiple chemotherapeutics. Herein, a novel affibody-DNA hybrid strands modified AuNPs were fabricated for co-loading nucleoside analogue (5-fluorodeoxyuridine, FUdR) and anthracycline (doxorubicin, Dox). FUdRs were integrated into DNA hybrid strands decorated on AuNPs by DNA solid phase synthesis, and Dox molecules were intercalated into their duplex regions. Affibody molecules coupled to the DNA hybrid strands were distributed the surface of AuNPs, giving them targeting for HER2. The new dual-drug-containing affibody-DNA-AuNPs (Dox@affi-F/AuNPs) owned compact and stable spherical nanostructures, and precise drug loading. Cytotoxicity tests demonstrated that these nanoparticles caused a higher inhibition in HER2 overexpressing breast cancer cells, and showed better synergistic antitumor activity than simple mixture of the two drugs. The related mechanistic studies proved that Dox@affi-F/AuNPs achieved a remarkable combined antitumor activity of Dox and FUdR by promoting more cells to enter apoptosis pathway. Our work provided a nanomedicine platform for targeted co-delivery of nucleoside analog therapeutics and anthracycline anticancer drugs to achieve synergistic treatment of HER2+ cancer.

Affibody-Conjugated RALA Polymers Delivering Oligomeric 5-Fluorodeoxyuridine for Targeted Therapy of HER2 Overexpressing Gastric Cancer.

Affibody-conjugated RALA (affi-RA) are designed for delivering oligomeric 5-fluorodeoxyuridine (FUdR, metabolite of 5-FU) strand to raise the selectivity of 5-fluorouracil (5-FU), decrease its toxicity and improve its suboptimal therapeutic efficacy. The nanodrugs, FUdR@affi-RA, are spontaneously assembled by electrostatic interaction between positively charged affi-RA and negatively charged FUdR15 -strands (15 consecutive FUdR). FUdR@affi-RA exhibits excellent stability under simulated physiological conditions. Compared with free FUdR, FUdR@affi-RA shows excellent targeting and higher cytotoxicity in human epidermal growth factor receptor 2 (HER2) overexpressing gastric cancer N87 cells. Moreover, the anticancer mechanism studies reveal that FUdR@affi-RA enhances the expression and activity of apoptosis-associated proteins in the Bcl-2/Bax-caspase 8,9-caspase 3 apoptotic pathway induced by FUdR. This study indicates that the fusion vector, affi-RA, presents a promising delivery system platform for nucleoside analogue drugs and provides a new strategy for the development of therapeutics of cancer treatment.

Enhancing Antitumor Efficacy of Nucleoside Analog 5-Fluorodeoxyuridine on HER2-Overexpressing Breast Cancer by Affibody-Engineered DNA Nanoparticle.

BACKGROUND: Chemotherapy, as an adjuvant treatment strategy for HER2-positive breast cancer, can effectively improve clinical symptoms and overcome the drug resistance of therapeutic monoclonal antibodies. Nucleoside analogues are a class of traditional chemotherapeutic drugs that are widely applied in adjuvant therapy. However, there are many critical issues that limit their clinical efficiency, including poor selectivity and stability, severe side effects and suboptimal therapeutic efficacy. Hence, this work aims to develop a new DNA nanocarrier for targeted drug delivery to solve the above problems. METHODS: Four 41-mer DNA strands were synthesized and 10 FUdR molecules were attached to 5' end of each DNA strand by DNA solid-phase synthesis. An affibody molecule was connected to the end of polymeric FUdR through a linker in one of the four strands. The affibody-FUdR-tetrahedral DNA nanostructures (affi-F/TDNs) were self-assembled through four DNA strands, in which one vertex was connected to an affibody at the end of a polymeric FUdR tail and three vertices were only polymeric FUdR tails. In vitro cellular uptake of affi-F/TDNs was examined visually with confocal fluorescence microscopy and flow cytometry, and the cytotoxicity of affi-F/TDNs against cancer cells was investigated with MTT assay. Cell apoptosis was detected by Annexin V-FITC/PI double staining method. Using NOD/SCID (Mus Musculus) mice model, the targeted killing efficacy of affi-F/TDNs was also evaluated. RESULTS: The drug-loading of FUdR in affi-TDNs was 19.6% in mole ratio. The in vitro results showed that affi-F/TDNs had high selectivity and inhibition (81.2%) for breast cancer BT474 cells overexpressing HER2 and low toxicity in MCF-7 cells with low HER2 expression. During the in vivo application, affi-F/TDNs displayed good stability in the blood circulation, achieved specific accumulation in tumor region and the best antitumor efficacy (inhibition ratio of 58.1%), and showed excellent biocompatibility. CONCLUSIONS: The affibody-DNA tetrahedrons, as a simple and effective active targeting delivery nanocarrier, provided a new avenue for the transport of nucleoside antitumor drugs.

A new "turn-on" fluorescence probe based on hydrazine-triggered tandem reaction.

Hydrazine is extremely harmful to the human body. The leakage of hydrazine is liable to cause potential safety hazards. Here, we reported a new fluorescence probe based on the tandem reaction. The hydrazine-triggered hydrazinolysis-cyclization resulted in the formation of the iminocoumarin. The fluorescence intensity at 522 nm of the probe increased after the reaction with hydrazine. There was a linear relationship between the fluorescence intensity and the concentration of hydrazine (0.14-120.00 µM). The LOD of the probe to N2H4 was 1.36 ppb. Notably, the probe could detect hydrazine in BT474 cells and tap water.

DNA-affibody nanoparticle delivery system for cisplatin-based breast cancer chemotherapy.

Cisplatin is the most widely used anticancer drug, but its side effects limit the maximum systemic dose. To circumvent the side effects, a DNA tetrahedron-affibody nanoparticle was prepared by combination of a DNA chain with cisplatin via interstrand crosslinks or adducts. Each nanocarrier can bind ∼68 molecules of cisplatin. This cisplatin nanoparticle exhibited high selectivity and inhibition for breast cancer HER2 overexpressing cells BT474 and lower toxicity in MCF-7 cells with low HER2 expression. The nano-drug inhibited the growth of BT474 cells by 94.57% at 512 nM (containing 33.3 µM cisplatin), which was higher than that of cisplatin (82.9%, 33.3 µM).

Copper-Catalyzed Diamination of Alkenes of Unsaturated Ketohydrazones with Amines.

A convenient copper-catalyzed intra-/intermolecular diamination of ß,γ-unsaturated hydrazones has been developed with simple amines as external amine sources. The protocol enables efficient access to various nitrogen-containing pyrazolines under mild reaction conditions.