A mix & act liposomes of phospholipase A2-phosphatidylserine for acute brain detoxification by blood‒brain barrier selective-opening.

In the treatment of central nervous system disease, the blood-brain barrier (BBB) is a major obstruction to drug delivery that must be overcome. In this study, we propose a brain-targeted delivery strategy based on selective opening of the BBB. This strategy allows some simple bare nanoparticles to enter the brain when mixed with special opening material; however, the BBB still maintains the ability to completely block molecules from passing through. Based on the screening of BBB opening and matrix delivery materials, we determined that phospholipase A2-catalyzed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine liposomes can efficiently carry drugs into the brain immediately. At an effective dose, this delivery system is safe, especially with its effect on the BBB being reversible. This mix & act delivery system has a simple structure and rapid preparation, making it a strong potential candidate for drug delivery across the BBB.

Gelation Behavior and Drug Sustained-Release Properties of a Helix Peptide Organohydrogel with pH Responsiveness.

Based on the typical similar repeat units (abcdefg)n of α-helical structure, the peptide H was designed to self-assemble into an organohydrogel in response to pH. Depending on the different pH, the proportions of secondary structure, microstructure, and mechanical properties of the gel were investigated. Circular dichroism (CD) and Fourier transform infrared (FT-IR) showed that the proportion of α-helical structure gradually increased to become dominant with the increase of pH. Combining transmission electron microscopy (TEM) and atomic force microscopy (AFM), it was found that the increase of the ordered α-helix structure promoted fiber formation. The further increase in pH changed the intermolecular forces, resulting in an increase in the α-helix content and the enhancement of helix-helix interaction, causing the gel fibers to converge into thicker and more dense ones. The temperature test showed the stable rheological properties of the organohydrogel between 20-60 °C. Drug release and cytotoxicity showed that the DOX-loaded organohydrogel could have a better release in an acidic environment, indicating its potential application as a drug local delivery carrier.

Double pyramid stacked CoO nano-crystals induced by graphene at low temperatures as highly efficient Fenton-like catalysts.

Transition metal oxides are widely used as Fenton-like catalysts in the treatment of organic pollutants, but their synthesis usually requires a high temperature. Herein, an all-solid-state synthesis method controlled by graphene was used to prepare a double pyramid stacked CoO nano-crystal at a low temperature. The preparation temperature decreased by 200 °C (over 30% reduction) due to the introduction of graphene, largely reducing the reaction energy barrier. Interestingly, the corresponding degradation rate constants (kobs) of this graphene-supported pyramid CoO nano-crystals for organic molecules after their adsorption were over 2.5 and 35 times higher than that before adsorption and that of free CoO, respectively. This high catalytic efficiency is attributed to the adsorption of pollutants at the surface by supporting graphene layers, while free radicals activated by CoO can directly and rapidly contact and degrade them. These findings provide a new strategy to prepare low carbon-consuming transition metal oxides for highly efficient Fenton-like catalysts.

Immune persistence after different polio sequential immunization schedules in Chinese infants.

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody.

Copper-catalyzed thiocyanation of cyclobutanone oxime esters using ammonium thiocyanate.

A copper-catalyzed thiocyanation of cycloketone oxime esters with ammonium thiocyanate has been developed for the first time. This innovative approach allows access to cyano and thiocyano bifunctionally substituted alkanes, which can be further transformed into their respective trifluoromethylthiol-substituted or difluoromethylthiol-substituted alkylnitriles, alkynyl sulfides, and phosphorothioate esters. The readily available nature of ammonium thiocyanate and the cost-effectiveness of the copper catalyst make this method a promising strategy for the synthesis of sulfur-containing alkylnitriles.

Interaction of Cecropin A (1-7) Analogs with DNA Analyzed by Multi-spectroscopic Methods.

Cecropin A (1-7) is a cationic antimicrobial peptide which contain lots of basic amino acids. To understand the effect of basic amino acids on cecropin A (1-7), analogues CA2, CA3 and CA4 which have more arginine or lysine at the N-terminal or C-terminal were designed and synthesized. The interaction of cecropin A (1-7) and its analogs with DNA was studied using ultraviolet-visible spectroscopy, fluorescence spectroscopy and circular dichroism spectroscopy. Multispectral analysis showed that basic amino acids improved the interaction between the analogues and DNA. The interaction between CA4 and DNA is most pronounced. Fluorescence spectrum indicated that Ksv value of CA4 is 1.19 × 105  L mol-1 compared to original peptide cecropin A (1-7) of 3.73 × 104  L mol-1. The results of antimicrobial experiments with cecropin A (1-7) and its analogues showed that basic amino acids enhanced the antimicrobial effect of the analogues. The antimicrobial activity of CA4 against E. coli was eightfold higher than that of cecropin A (1-7). The importance of basic amino acid in peptides is revealed and provides useful information for subsequent studies of antimicrobial peptides.

Photochemical Difluoromethylation of Quinoxalin-2(1H)-ones with Difluoroacetic Anhydride and Pyridine N-Oxide.

A novel photochemical difluoromethylation of quinoxalin-2(1H)-ones under catalyst-free conditions was achieved with difluoroacetic anhydride and pyridine N-oxide. The green and mild reaction conditions as well as readily attainable difluoroacetic anhydride provide a useful protocol to prepare C3-difluoromethylated quinoxalin-2(1H)-ones.

Comparison of clinical outcomes in patients with acute ischemic stroke who underwent endovascular treatment using different perfusion modalities: a real-world multicenter study.

Background: Advanced perfusion modalities are increasingly popular for various diseases. However, few studies have focused on contrasting perfusion patterns. Objective: This study aimed to compare the time efficiency and clinical outcomes of patients with acute ischemic stroke (AIS) who underwent endovascular treatment (EVT) before one-stop arterial spin labeling (ASL) and computed tomography perfusion (CTP) protocols. Methods: This study retrospectively included 326 patients with AIS who had accepted EVT within 24 h of onset from four comprehensive stroke centers between October 2017 and September 2022. After 1:1 matching of the propensity scores, 202 patients were separated into two groups: the ASL group (n = 101) and the CTP group (n = 101). Results: Functional independence at 90 days (modified Rankin Scale [mRS] 0-2; p = 0.574), onset-to-puncture time (p = 0.231), door-to-puncture time (p = 0.136), and door-to-perfusion time (p = 0.646) were not significantly different between the two groups. The proportion of EVT complications (31.7% in the ASL group vs. 14.9% in the CTP group, p = 0.005) and symptomatic intracranial hemorrhage (sICH) at 24 h (23.8% in the ASL group vs. 9.9% in the CTP group, p = 0.008) in the CTP group were lower than the ASL group. The ischemic core volume was a common predictor of favorable outcomes in both ASL (p < 0.001) and CTP (p < 0.001) groups. Conclusion: There were no significant differences in time efficiency and efficacy outcomes between the two groups of patients receiving one-stop ASL and CTP. The proportion of sICH at 24 h and EVT complications of patients in the CTP group was lower than the ASL group. The ischemic core volume was an independent predictor for favorable outcomes.

Mechanisms and influencing factors of peptide hydrogel formation and biomedicine applications of hydrogels.

Self-assembled peptide-based hydrogels have shown great potential in bio-related applications due to their porous structure, strong mechanical stability, high biocompatibility, and easy functionalization. Herein, the structure and characteristics of hydrogels and the mechanism of action of several regular secondary structures during gelation are investigated. The factors influencing the formation of peptide hydrogels, especially the pH responsiveness and salt ion induction are analyzed and summarized. Finally, the biomedical applications of peptide hydrogels, such as bone tissue engineering, cell culture, antigen presentation, antibacterial materials, and drug delivery are reviewed.

Synthesis and mechanism of action of new purine derivatives against triple negative breast cancer.

Triple negative breast cancer (TNBC) is considered to be the most difficult subtype of breast cancer to treat because of its extremely prone to metastasis and the lack of targeted therapy drugs. New purine derivatives were synthesized and evaluated in a series of kinases and cell lines. The most active compounds 3g and 3j were selected based on their antiproliferative activities, then their pharmaceutical activity and mechanism in MDA-MB-231 cells were analyzed. The results in vitro indicated that compounds 3g and 3j can induce MDA-MB-231 cells apoptosis, and inhibit its migration and angiogenesis through influencing protein expression such as Bcl-2, Bax, Bcl-xl, P38, MMP2, MMP9, AKT and EGFR. In vivo results indicate that compounds 3g and 3j can inhibit tumor growth and metastasis and reduce the expression of Ki67 and CD31 protein in TNBC xenograft models. These findings not only broaden our understanding of the anti-TNBC effects and mechanisms of compounds 3g and 3j, but also provide new ideas and reference directions for the treatment of TNBC.

Recent advances in the development of inhibitors targeting KRAS-G12C and its related pathways.

The RAS gene, also known as the mouse sarcoma virus, includes three genes (KRAS, HRAS, and NRAS) that are associated with human tumors. Among them, KRAS has the highest incidence of mutations in cancer, accounting for around 80% of cases. At the molecular level, the RAS gene plays a regulatory role in transcription and translation, while at the cellular level, it affects cell proliferation and migration, making it crucial for cancer development. In 2021, the FDA approved AMG510, the first direct inhibitor targeting the KRAS-G12C mutation, which has shown tumor regression, prolonged survival, and low off-target activity. However, with the increase of drug resistance, a single inhibitor is no longer sufficient to achieve the desired effect on tumors. Therefore, a large number of other highly efficient inhibitors are being developed at different stages. This article provides an overview of the mechanism of action targeting KRAS-G12C in the KRASGTP-KRASGDP cycle pathway, as well as the structure-activity relationship, structure optimization, and biological activity effects of inhibitors that target the upstream and downstream pathways, or combination therapy.

The predictive value of CD4, CD8, and C-reactive protein in the prognosis of schistosomal and non-schistosomal colorectal cancer.

BACKGROUND: Although schistosomiasis has been basically eliminated, it has not been completely extinction in China and occasional outbreaks occur in Europe in recent years. The relationship between inflammation caused by Schistosoma japonicum and colorectal cancer (CRC) is still obscure, and the inflammation based prognostic systems of schistosomal colorectal (SCRC) has rarely been reported. AIM: To explore the different roles of tumor infiltrating lymphocytes (TILs) and C-reactive protein (CRP) in SCRC and in Non-schistosomal CRC (NSCRC), providing a possible predictive system to evaluate outcomes and to improve the risk stratification for CRC patients, especially for CRC patients with schistosomiasis. METHODS: Three hundred fifty-one CRC tumors were evaluated for density of CD4 + , CD8 + T cells and CRP in intratumoral and stromal compartments by immunohistochemical using tissue microarray. RESULTS: There were no association between TILs and CRP and schistosomiasis. Multivariate analysis identified stromal CD4 (sCD4) (p = 0.038), intratumoral CD8 (iCD8) (p = 0.003), schistosomiasis (p = 0.045) as independent prognostic factors for overall survival (OS) in the whole cohort; and sCD4 (p = 0.006) and iCD8 (p = 0.020) were independent prognostic factors for OS in the NSCRC and SCRC set, respectively. Besides, we found that there were no differences of TILs and CRP, which were distributed in different areas of tumor tissue, between CRC patients with and without schistosomiasis. CONCLUSION: The results remind us that different subtypes of TILs have distinguished biological behavior and prognosis value in the immune microenvironment of NSCRC and SCRC patients. Meanwhile, the findings require us to stratify patients with schistosomiasis and this might facilitate patient counseling and management.

Visible-light promoted cascade cyanoalkylsulfonylation/ipso-cyclization of N-arylpropiolamides toward sulfonated spiro[4,5]trienones via SO2 insertion.

A novel visible-light induced sulfonylation/ipso-cyclization of N-arylpropiolamides with cyclobutanone oxime esters and Na2S2O5 was reported. This protocol proceeded via a radical process. The wide substrate scope, sustainable metal-free conditions and readily accessible reagents make this protocol an efficient and green strategy for the synthesis of cyanoalkyl sulfonated spiro[4,5]trienones.

Copper-catalyzed ring-opening trifluoromethylthiolation/trifluoromethylselenolation of cyclopropanols with TsSCF3 or Se-(trifluoromethyl) 4-methoxybenzenesulfonoselenoate.

We report a ring-opening trifluoromethylthiolation of cyclopropanols with TsSCF3 by using Cu(OAc)2 as the catalyst. Moreover, by using this strategy, the trifluoromethylselenolation of cyclopropanols with Se-(trifluoromethyl) 4-methoxybenzenesulfonoselenoate to access ß-SeCF3-substituted carbonyl compounds is achieved for the first time. The broad substrate scope, readily accessible reagents and cheap catalyst make this protocol an alternative and efficient method for the synthesis of ß-SCF3-substituted or ß-SeCF3-substituted carbonyl compounds.

Interaction of bifunctional peptide-carbazole complexes with DNA and antimicrobial activity.

Two peptide-carbazole conjugates, CTAT and CNLS, were designed and synthesized using carbazole Schiff base to modify the cell membrane penetrating peptide TAT (47-57) and the nuclear localization peptide NLS at the N terminus. The interaction with ctDNA was investigated by multispectral and agarose gel electrophoresis. And the effects of CNLS and CTAT on the G-quadruplex structure were explored by circular dichroism titration experiments. The results show that both CTAT and CNLS interact with ctDNA in a minor groove binding manner. Both conjugates bind more tightly to DNA than the individual substances CIBA, TAT and NLS. In addition, CTAT and CNLS are capable of unfolding parallel G-quadruplex structures and are potential G-quadruplex unfolding agents. Finally, broth microdilution was performed to test the antimicrobial activity of the peptides. The results showed that CTAT and CNLS had a 4-fold increase in antimicrobial activity compared with the parent peptides TAT and NLS. They could exert antimicrobial activity by disrupting the integrity of cell membrane bilayer and binding to DNA, and could be used as novel antimicrobial peptides for the development of novel antimicrobial antibiotics.

Association between serum iron, blood lead, cadmium, mercury, selenium, manganese and low cognitive performance in old adults from National Health and Nutrition Examination Survey (NHANES): a cross-sectional study.

Cognitive decline is a public health problem for the world's ageing population. This study was to evaluate the relationships between serum Fe, blood Pb, Cd, Hg, Se and Mn and cognitive decline in elderly Americans. Data of this cross-sectional study were extracted from the National Health and Nutritional Examination Survey (NHANES 2011-2014). Cognitive performance was measured by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal Fluency and Digit Symbol Substitution Test (DSST) tests. Weighted univariable and multivariate logistic regression analyses were used to assess the associations between six trace elements and low cognitive performance. Subgroup analyses based on diabetes and hypertension history were further assessed the associations. A total of 2002 adults over 60 years old were included. After adjusting covariates, elevated serum Fe levels were associated with the decreased risk of low cognitive performance, especially in the elderly without diabetes history and with hypertension history. High blood Cd levels were associated with the high odds of low cognitive performance in old adults with diabetes and hypertension history. Elevated blood Mn levels were connected with low cognitive performance in old hypertensive people. High blood Pb levels were related to the high odds of low cognitive performance, especially in the elderly without diabetes and hypertension history. High blood Se levels were linked to the decreased risk of low cognitive performance in all the elderly. Appropriate Fe, Se supplementation and Fe-, Se-rich foods intake, while reducing exposure to Pb, Cd and Mn may be beneficial for cognitive function in the elderly.

Evaluation of the immunization effectiveness of bOPV booster immunization and IPV revaccination.

To provide a basis for further optimization of the polio sequential immunization schedule, this study evaluated the effectiveness of booster immunization with one dose of bivalent oral poliovirus vaccine (bOPV) at 48 months of age after different primary polio immunization schedules. At 48 months of age, one dose of bOPV was administered, and their poliovirus types 1-3 (PV1, PV2, and PV3, respectively)-specific neutralizing antibody levels were determined. Participants found to be negative for any type of PV-specific neutralizing antibody at 24, 36, or 48 months of age were re-vaccinated with inactivated polio vaccine (IPV). The 439 subjects who received a bOPV booster immunization at the age of 48 months had lower PV2-specific antibody levels compared with those who received IPV. One dose of IPV during basic polio immunization induced the lowest PV2-specific antibody levels. On the basis of our findings, to ensure that no less than 70% of the vaccinated have protection efficiency, we recommend the following: if basic immunization was conducted with 1IPV + 2bOPV (especially Sabin strain-based IPV), a booster immunization with IPV is recommended at 36 months of age, whereas if basic immunization was conducted with 2IPV + 1bOPV, a booster immunization with IPV is recommended at 48 months of age. A sequential immunization schedule of 2IPV + 1bOPV + 1IPV can not only maintain high levels of antibody against PV1 and PV3 but also increases immunity to PV2 and induces early intestinal mucosal immunity, with relatively good safety. Thus, this may be the best sequential immunization schedule for polio in countries or regions at high risk for polio.

Synthesis, molecular docking, and binding Gibbs free energy calculation of ß-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease.

The outbreak of novel coronavirus disease 2019 (COVID-19), caused by the novel coronavirus (SARS-CoV-2), has had a significant impact on human health and the economic development. SARS-CoV-2 3CL protease (3CLpro) is highly conserved and plays a key role in mediating the transcription of virus replication. It is an ideal target for the design and screening of anti-coronavirus drugs. In this work, seven ß-nitrostyrene derivatives were synthesized by Henry reaction and ß-dehydration reaction, and their inhibitory effects on SARS-CoV-2 3CL protease were identified by enzyme activity inhibition assay in vitro. Among them, 4-nitro-ß-nitrostyrene (compound a) showed the lowest IC50 values of 0.7297 µM. To investigate the key groups that determine the activity of ß-nitrostyrene derivatives and their interaction mode with the receptor, the molecular docking using the CDOCKER protocol in Discovery Studio 2016 was performed. The results showed that the hydrogen bonds between ß-NO2 and receptor GLY-143 and the π-π stacking between the aryl ring of the ligand and the imidazole ring of receptor HIS-41 significantly contributed to the ligand activity. Furthermore, the ligand-receptor absolute binding Gibbs free energies were calculated using the Binding Affinity Tool (BAT.py) to verify its correlation with the activity of ß-nitrostyrene 3CLpro inhibitors as a scoring function. The higher correlation(r2=0.6) indicates that the absolute binding Gibbs free energy based on molecular dynamics can be used to predict the activity of new ß-nitrostyrene 3CLpro inhibitors. These results provide valuable insights for the functional group-based design, structure optimization and the discovery of high accuracy activity prediction means of anti-COVID-19 lead compounds.

Comparison of the prognostic value of stromal tumor-infiltrating lymphocytes and CD3 + T cells between schistosomal and non-schistosomal colorectal cancer.

AIM: To compare the prognostic value of tumor-infiltrating lymphocytes (TILs) and CD3 + cells and CD20 + cells between schistosomal colorectal cancer (SCRC) and non-schistosomal CRC (NSCRC). BACKGROUND: Although schistosomiasis has been basically eliminated, it has not been completely extinction in China, and occasional outbreaks occur in Europe recently. The role of immune cells in the immune microenvironment of SCRC and NSCRC is remaining obscure, and the inflammation-based prognostic systems of SCRC has rarely been reported. METHODS: HE-stained sections of 349 colorectal cancer (CRC) tumors, which were completely resected, were evaluated for density of TILs. Meanwhile, we evaluated CD3 + T lymphocytes and CD20 + B lymphocytes by immunochemistry. The relationship of these infiltrating immune cells with clinicopathological features, including schistosomiasis, and clinical outcomes was evaluated, and the prognostic roles of TILs in SCRC and NSCRC were explored. RESULTS: Except for age (P < 0.0001), there were no significant differences between NSCRC and SCRC patients in clinicopathological features (P > 0.05). Beside, the positive expression pattern of sTILs, iTILs, CD3, and CD20 between NSCRC and SCRC patients was also similar (P > 0.05). In the whole cohort, sTILs and CD3 were defined as independent prognostic factors (P = 0.031 and P = 0.003, respectively). CD3 was an independent prognostic factor both in the NSCRC and SCRC set (P = 0.026 and P = 0.045, respectively). Higher sTILs, CD3, and CD20 were correlated with less aggressive tumor characteristics in the whole cohort and in subgroups. CONCLUSION: Although CD3 was an independent prognostic factor for both NSCRC and SCRC set, there were no significant differences between SCRC and NSCRC patients in sTILs, CD3, CD20, and in other clinicopathological features.

Spectroscopic studies on noncovalent binding of nicotinamide-modified BRCA1 (856-871) analogs to calf thymus DNA.

Various peptide drugs have entered the market with the development of molecular biology. Peptide drugs are used for treat diseases such as diabetes, breast cancer, and HIV infection. In this study, three nicotinamide-modified peptides were synthesized by modifying the N-terminus of BRCA1 (856-871, Y856R, K862Y, R866W) peptide with three nicotinic acid derivatives using solid-phase peptide synthesis. The results of calf thymus DNA (ctDNA) binding activity indicated that binding constants of BRCA1 (856-871, Y856R, K862Y, R866W) (P0) and three nicotinamide-modified peptides (P1, P2, and P3) to ctDNA were 1.89 × 103, 2.97 × 104, 7.61 × 104, and 8.09 × 104 L·mol-1, respectively. The binding affinity of the modified peptides was superior to that of BRCA1 (856-871, Y856R, K862Y, R866W). ΔHθ < 0 and ΔSθ < 0 indicated that van der Waals force and hydrogen bond contributed most to peptide-ctDNA binding. Results obtained by Circular dichroism (CD) indicated that peptide binding interaction led to conformational changes in ctDNA. Ultraviolet-visible (UV) spectroscopy, ethidium bromide (EB) competition experiments, DNA melting experiments, and viscosity measurements verified that peptides interacted with ctDNA via groove binding. Ionic strength experiments manifested that electrostatic binding was also involved in peptide-ctDNA binding.