TEAD Proteins Associate With DNA Repair Proteins to Facilitate Cellular Recovery From DNA Damage.

Transcriptional enhanced associate domain family members 1 to 4 (TEADs) are a family of four transcription factors and the major transcriptional effectors of the Hippo pathway. In order to activate transcription, TEADs rely on interactions with other proteins, such as the transcriptional effectors Yes-associated protein and transcriptional co-activator with PDZ-binding motif. Nuclear protein interactions involving TEADs influence the transcriptional regulation of genes involved in cell growth, tissue homeostasis, and tumorigenesis. Clearly, protein interactions for TEADs are functionally important, but the full repertoire of TEAD interaction partners remains unknown. Here, we employed an affinity purification mass spectrometry approach to identify nuclear interacting partners of TEADs. We performed affinity purification mass spectrometry experiment in parallel in two different cell types and compared a wildtype TEAD bait protein to a nuclear localization sequence mutant that does not localize to the nucleus. We quantified the results using SAINT analysis and found a significant enrichment of proteins linked to DNA damage including X-ray repair cross-complementing protein 5 (XRCC5), X-ray repair cross-complementing protein 6 (XRCC6), poly(ADP-ribose) polymerase 1 (PARP1), and Rap1-interacting factor 1 (RIF1). In cellular assays, we found that TEADs co-localize with DNA damage-induced nuclear foci marked by histone H2AX phosphorylated on S139 (γH2AX) and Rap1-interacting factor 1. We also found that depletion of TEAD proteins makes cells more susceptible to DNA damage by various agents and that depletion of TEADs promotes genomic instability. Additionally, depleting TEADs dampens the efficiency of DNA double-stranded break repair in reporter assays. Our results connect TEADs to DNA damage response processes, positioning DNA damage as an important avenue for further research of TEAD proteins.

A viral protein competitively bound to rice CIPK23 inhibits potassium absorption and facilitates virus systemic infection in rice.

Potassium (K+) plays a crucial role as a macronutrient in the growth and development of plants. Studies have definitely determined the vital roles of K+ in response to pathogen invasion. Our previous investigations revealed that rice plants infected with rice grassy stunt virus (RGSV) displayed a reduction in K+ content, but the mechanism by which RGSV infection subverts K+ uptake remains unknown. In this study, we found that overexpression of RGSV P1, a specific viral protein encoded by viral RNA1, results in enhanced sensitivity to low K+ stress and exhibits a significantly lower rate of K+ influx compared to wild-type rice plants. Further investigation revealed that RGSV P1 interacts with OsCIPK23, an upstream regulator of Shaker K+ channel OsAKT1. Moreover, we found that the P1 protein recruits the OsCIPK23 to the Cajal bodies (CBs). In vivo assays demonstrated that the P1 protein competitively binds to OsCIPK23 with both OsCBL1 and OsAKT1. In the nucleus, the P1 protein enhances the binding of OsCIPK23 to OsCoilin, a homologue of the signature protein of CBs in Arabidopsis, and facilitates their trafficking through these CB structures. Genetic analysis indicates that mutant in oscipk23 suppresses RGSV systemic infection. Conversely, osakt1 mutants exhibited increased sensitivity to RGSV infection. These findings suggest that RGSV P1 hinders the absorption of K+ in rice plants by recruiting the OsCIPK23 to the CB structures. This process potentially promotes virus systemic infection but comes at the expense of inhibiting OsAKT1 activity.

Identification of vancomycin exposure target in neonates: how much is enough?

OBJECTIVES: Vancomycin is commonly used in neonates with the same pharmacokinetics/pharmacodynamics (PK/PD) target as adults. However, no evidence supports this practice, and the association between trough concentrations and treatment outcomes has been widely questioned. This study aimed to identify the optimal PK/PD predictor and assess the correlation between AUC/MIC, trough concentration and the vancomycin efficacy in neonates. METHODS: This study retrospectively collected neonates who used vancomycin and constructed a population pharmacokinetic (PPK) model to estimate the AUC. Logistic analyses were used to identify the variables related to efficacy. Classification and regression tree analysis was used to explore thresholds. The correlation between trough concentration and AUC/MIC on the first day was analysed using a linear regression model. RESULTS: PPK modelling involved 131 neonates. Postmenstrual age and current weight were included in the covariate analysis. Forty-eight patients were included in the efficacy analysis, 13 of whom were infected with MRSA. The best-performance PK/PD target for efficacy was AUC0-24  h/MIC ≥ 331. The trough concentration was correlated with AUC0-24  h/MIC (r2 = 0.32), but individual differences existed. AUC0-24  h/MIC ranged up to 2.5-fold for a given trough concentration. CONCLUSIONS: AUC0-24  h/MIC ≥ 331 was the optimal target of vancomycin efficacy in neonates. The trough concentration was not a reliable predictor of efficacy and AUC0-24  h/MIC. AUC-guided dosage adjustments are more valuable in clinical applications.

Natural variation in CYCLIC NUCLEOTIDE-GATED ION CHANNEL 4 reveals a novel role of calcium signaling in vegetative phase change in Arabidopsis.

The timing of vegetative phase change (VPC) in plants is regulated by a temporal decline in the expression of miR156. Both exogenous cues and endogenous factors, such as temperature, light, sugar, nutrients, and epigenetic regulators, have been shown to affect VPC by altering miR156 expression. However, the genetic basis of natural variation in VPC remains largely unexplored. Here, we conducted a genome-wide association study on the variation of the timing of VPC in Arabidopsis. We identified CYCLIC NUCLEOTIDE-GATED ION CHANNEL 4 (CNGC4) as a significant locus associated with the diversity of VPC. Mutations in CNGC4 delayed VPC, accompanied by an increased expression level of miR156 and a corresponding decrease in SQUAMOSA PROMOTER BINDING-LIKE (SPL) gene expression. Furthermore, mutations in CNGC2 and CATION EXCHANGER 1/3 (CAX1/3) also led to a delay in VPC. Polymorphisms in the CNGC4 promoter contribute to the natural variation in CNGC4 expression and the diversity of VPC. Specifically, the early CNGC4 variant promotes VPC and enhances plant adaptation to local environments. In summary, our findings offer genetic insights into the natural variation in VPC in Arabidopsis, and reveal a previously unidentified role of calcium signaling in the regulation of VPC.

PEGylation of New Thrombin Inhibitor Peptide Ultravariegin for Prolonged In Vivo Circulation and Enhanced Antithrombotic Effects.

Anticoagulant therapy is commonly used to prevent and treat arterial and venous blood clots in patients with cardiovascular disease, cerebrovascular disease, and cancer. Venous blood clots are the third leading cause of cardiovascular death following acute coronary artery disease and stroke. There is a significant need for effective anticoagulant therapy with minimal risk of bleeding. Variegin and its variants are a new type of antithrombin peptide that has shown promising results in preclinical studies. Variegin and its best variant, ultravariegin (UV), can more effectively inhibit blood clot formation while causing less bleeding than traditional medications such as heparin and bivalirudin. However, the short lifespan of UV remains a limitation for its use in clinical settings. PEGylation, a method of conjugating poly(ethylene glycol) (PEG) chains to peptides or drugs, may help improve the effectiveness of UV by extending its circulation time in the body. In this study, UV was PEGylated using maleimide-PEG5k and 10k. The impact of PEGylation on the antithrombin activity of UV was assessed in vitro and ex vivo in rat and rabbit plasma, showing minimal effects on the efficacy. In vivo studies in rats and rabbits revealed that PEGylated UV had a longer half-life and greater anticoagulant effects than unmodified UV did, especially when it was administered subcutaneously. PEGylation significantly extended the half-life of UV in rabbits, resulting in sustained anticoagulant effects for up to 4 days. This demonstrated that increasing the size of UV and shielding it with PEG could reduce clearance by the kidneys and prolong its circulation time. The improved half-life and antithrombin activity of PEGylated UV make it a more favorable choice for anticoagulant therapy.

Codelivery of Doxorubicin and p53 Gene by ß-Cyclodextrin-Based Supramolecular Nanoparticles Formed via Host-Guest Complexation and Electrostatic Interaction.

We developed a supramolecular system for codelivery of doxorubicin (Dox) and p53 gene based on a ß-CD-containing star-shaped cationic polymer. First, a star-shaped cationic polymer consisting of a ß-CD core and 3 arms of oligoethylenimine (OEI), named CD-OEI, was used to form a supramolecular inclusion complex with hydrophobic Dox. The CD-OEI/Dox complex was subsequently used to condense plasmid DNA via electrostatic interactions to form CD-OEI/Dox/DNA polyplex nanoparticles with positive surface charges that enhanced the cellular uptake of both Dox and DNA. This supramolecular drug and gene codelivery system showed high gene transfection efficiency and effective protein expression in cancer cells. The codelivery of Dox and DNA encoding the p53 gene resulted in reduced cell viability and enhanced antitumor effects at low Dox concentrations. With its enhanced cellular uptake and anticancer efficacy, the system holds promise as a delivery carrier for potential combination cancer therapies.

[Dietary exposure assessment of aflatoxins of residents in Shanghai residents aged 15 years and above from 2018 to 2023].

OBJECTIVE: To understand the contents of aflatoxins(AFs) in foods sold in Shanghai, and to assess the exposure assessment of and its potential health risk among residents over 15 years old in Shanghai. METHODS: A total of 8114 samples from 8 categories of food were collected in Shanghai from 2018 to 2023. The samples were detected by GB 5009.24-2016 and GB 5009.22-2016. Combined with the food consumption data of "Shanghai Diet and Health Survey", the dietary exposure assessment of aflatoxin was conducted using the margin of exposure(MOE) and the risk of liver cancer. RESULTS: The detection rates of aflatoxin B_1(AFB_1), aflatoxin B_2(AFB_2), aflatoxin G_1(AFG_1), aflatoxin G_2(AFG_2), and aflatoxin M_(1 )(AFM_1) were 8.6%, 2.0%, 0.9%, 0.2% and 0.2%, respectively. The point assessment showed that the total exposure of AFB_1 in the diet of residents aged 15 and above in Shanghai was 0.783 ng/(kg·BW·d), with the contribution rates of dietary exposure to grains and their products, nuts and their products, and vegetable oils accounting for 60.6%, 25.0% and 8.5% of AFB_1's dietary exposure, respectively. The total exposure of total aflatoxins(the sum of AFB_1, AFB_2, AFG_1 and AFG_2)(AFT) was 7.363 ng/(kg·BW·d), and the dietary exposure of grains and their products, vegetable oils, nuts and their products contribute 77.1%, 8.4% and 7.2% to the dietary exposure of AFT, respectively. The probability assessment result indicated that the average dietary exposure of residents to AFB_1 and AFT were 0.734 and 7.220 ng/(kg·BW·d), respectively, and the P95 exposure of residents were 1.170 and 11.500 ng/(kg·BW·d). The AFB_1 exposure level of residents in suburban areas was higher than that in central urban areas and exurban areas(χ~2= 16.357, P<0.001), the AFT exposure of residents in the central urban area was lower than that in the exurban areas and suburban areas(χ~2= 40.996, P<0.001). According to the MOE method, the MOE values of AFB_1 and AFT average dietary exposure for residents aged 15 and above in Shanghai were 511 and 54. The risk of liver cancer caused by dietary exposure of AFB_1 and AFT among residents aged 15 and above in Shanghai were 0.024 cases/10~5 people and 0.227 cases/10~5 people. CONCLUSION: There is AFs contamination in food sold in Shanghai, and grains and their products, nuts and their products, and vegetable oils are the main sources of AFs exposure in the diet of residents aged 15 and above in Shanghai.

Clinical efficacy of Apatinib combined with Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in nonsmall cell lung cancer after EGFR-TKI resistance.

Objective: To evaluate the efficacy and safety of Apatinib combined with epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in the treatment of patients with non-small cell lung cancer (NSCLC) and acquired EGFR-TKI resistance. Methods: Clinical records of 106 patients with NSCLC at Shanxi Tumor Hospital of the Chinese Academy of Medical Sciences Cancer Hospital from January 2017 to October 2020, with acquired drug resistance after EGFR-TKI treatment were retrospectively analyzed. Among them, 52 patients received Apatinib combined with EGFR-TKI (Apatinib group), and 54 patients received a standard chemotherapy (pemetrexed combined with platinum) (chemotherapy group). Clinical efficacy indicators, follow-up results, and adverse reactions in both groups were compared. Results: There was no significant difference in the objective response rate and disease control rate between the two groups (P>0.05). The progression free survival (PFS) of the Apatinib group was significantly longer than that of the chemotherapy group (10.5 months vs. 5.7 months; P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Conclusions: Compared with standard chemotherapy, Apatinib combined with EGFR-TKI has the same efficacy in treating NSCLC patients with EGFR-TKI resistance, and was associated with longer PFS with no significant increase in adverse reactions.

The Associations of Maternal Blood Hemoglobin and Serum Triglyceride Levels and the Risk of Preterm Delivery.

The abnormal hemoglobin (HGB) and serum lipid concentrations during pregnancy will increase the risk of preterm delivery. Our study aimed to explore the correlation between prenatal HGB and serum lipid levels and preterm delivery. We enrolled 215 mother-infant pairs in a pilot cohort study. The logistic regression model and Restricted Cubic Spline model (RCS) were used to investigate the levels of prenatal blood HGB and serum lipid such as triglyceride (TG), total cholesterol, high-density lipoprotein, low density lipoprotein and preterm delivery. The results showed that moderate levels of prenatal blood HGB (OR=0.28; 95%CI: 0.10, 0.75, p-trend=0.018) and high level of serum TG (OR=0.29; 95%CI: 0.10, 0.84, p-trend=0.022) level were negatively associated with the risk of preterm delivery. The joint effect results showed that compared with lower level of prenatal blood HGB (≤123.13 g/l) and TG (≤3.7 mmol/l), we found that high levels prenatal blood HGB and serum TG (OR=0.32, 95%CI: 0.12, 0.89) had a negative association with the risk of preterm delivery. Moreover, prenatal blood HGB and serum TG levels had negative linear dose-effect relationships with the risk of preterm delivery in overall and girl group (p<0.05). Moderate levels of prenatal blood HGB and high level of serum TG were negatively associated with the risk of preterm delivery. The joint effect of high levels prenatal HGB and prenatal serum TG in the normal range were negatively correlated with preterm delivery. Moreover, the underlying mechanisms should be clarified in future studies.

Synthesis of O-Heterocycle Spiro-Fused Cyclopentaquinolinones and Cyclopentaindenes through Visible Light-Induced Radical Cyclization Reactions.

Presented herein is an effective and sustainable synthesis of O-heterocycle spiro-fused cyclopentaquinolinone and cyclopentaindene derivatives through light-driven cascade reactions of N-(o-ethynylaryl)acrylamides or 2-(2-(phenylethynyl)benzyl)acrylate with various O-heterocycles. Experimental mechanistic studies revealed that these reactions are initiated by visible light-induced radical formation from O-heterocycle and its regioselective addition onto the acrylamide or acrylate moiety followed by 6-exo-dig and 5-endo-trig cascade radical annulation, which is terminated by single electron oxidation and proton elimination. Compared with previously reported synthetic methods for similar purposes, this newly developed protocol has advantages such as a broad substrate scope, extremely mild reaction conditions, excellent atom-economy, high efficiency, and good compatibility with diverse functional groups. With all of these merits, this method is expected to find wide applications in the related research arena.

Effects of Weight Gain During Pregnancy in Normal-Weight Women on Changes in the Gut Microbiota of Pregnant Women in the Third Trimester.

With the improvement of living standards and the lack of nutrition awareness during pregnancy, the phenomenon of excessive weight gain (EWG) of pregnancy is increasing. EWG during pregnancy has profound effects on the health of mother and offspring. The role of intestinal flora in regulating metabolic diseases has gradually attracted attention in recent years. The study explored the effect of EWG during pregnancy on gut microbiota, and analyzed the diversity and composition of gut microbiota in pregnant women in third trimester. Fecal samples were collected and divided into: insufficient weight gain (IWG) during pregnancy (group A1, N = 4), and appropriate weight gain (AWG) during pregnancy (group A2, N = 9), and EWG during pregnancy (N = 9 in A3 group). MiSeq high-throughput sequencing technology and bioinformatics analysis were introduced to investigate relationship of gestational weight gain and maternal gut microbiota. General data analysis showed that gestational weight gain and delivery mode have significant differences among the three groups. The overall level and diversity of intestinal microbiota in A1 and A3 group were increased. Composition of gut microbiota has no difference among three groups at the phylum level, but species of gut microbiota were different. Alpha diversity index analysis showed that the richness of A3 group was increased versus A2 group. EWG during pregnancy affects the abundance and proportion of gut microbiota in the third trimester. Therefore, maintaining moderate weight gain during pregnancy helps to maintain intestinal homeostasis.

A Multidisciplinary Team Approach for Diabetic Foot Ulcer: A Case Study.

ABSTRACT: A multidisciplinary team (MDT) approach is the most efficient way to treat many chronic and serious diseases. In this case report, providers sought to implement an MDT approach to treat a patient with diabetes and foot ulcers, actively involving the patient's caregiving family members. Comprehensive evaluation, blood sugar control, and timely referral were established as the primary treatment course. Negative-pressure wound therapy was applied to completely remove necrotic tissue debris and seropurulent discharge from the foot ulcers under the consultation of the MDT team. Local wound management, protection of the periwound skin, and health education for the patient's wound care nurse specialists were integral to the treatment outcome. After 3 months of treatment, the patient's right foot wound bed was improved, and further skin-grafting surgery was performed to accelerate the healing process during follow-up treatments.

Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study.

BACKGROUND: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings. METHODS: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone. CONCLUSIONS: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Synthesis and Characterization of Palmitoyl-block-poly(methacryloyloxyethyl phosphorylcholine) Polymer Micelles for Anticancer Drug Delivery.

We report the synthesis and characterization of an amphiphilic polymer comprising a hydrophobic palmitoyl (Pal) group and a zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) block, which is capable of forming micelles as a drug carrier system for delivering hydrophobic anticancer drugs such as doxorubicin (DOX). We hypothesize that the sharp polarity contrast between the Pal domain and the pMPC block would strengthen the micelles and improve the drug loading capacity, while the pMPC shells improve the micelle stability and cellular uptake efficiency. In this study, the Pal-pMPC polymer was characterized and compared with a Pal-poly(ethylene glycol) (Pal-PEG) polymer in terms of their micelle formation, cytotoxicity, and drug loading of DOX. The DOX-loaded Pal-pMPC micelles were further evaluated for the cellular uptake and anticancer activities in cell culture systems including the non-multidrug-resistance HeLa cell line and the multidrug-resistance AT3B-1 cell line. The results showed that the Pal-pMPC polymer had a minimal toxicity. The Pal-pMPC micelles exhibited higher drug loading capacity and enhanced cellular internalization efficiency compared to micelles formed by the Pal-PEG polymer. It was also found that DOX-loaded Pal-pMPC micelles exhibited a more efficient anticancer effect than Pal-PEG micelles in multidrug-resistance cancer cells in an environment with fetal bovine serum.

Concise Synthesis of Spirocyclic Dihydrophthalazines through Spiroannulation Reactions of Aryl Azomethine Imines with Cyclic Diazo Compounds.

Spiroannulation reactions are fundamental and invaluable for the synthesis of spirocyclic compounds. Presented herein are novel cascade reactions of aryl azomethine imines with cyclic diazo compounds leading to the formation of spirocyclic dihydrophthalazine derivatives. Based on experimental mechanistic studies, the formation of the title products is believed to go through azomethine imine-assisted cylcometalation, Rh-carbene formation through dediazonization, and migratory insertion followed by reductive elimination and azomethine imine ring opening. Control experiments revealed that air acts as an effective and sustainable co-oxidant to facilitate the cascade reaction. In general, this concise synthesis of the unprecedented spirocyclic dihydrophthalazine derivatives has advantages such as easily accessible substrates, good functional group compatibility, mild reaction conditions, high efficiency and selectivity, and excellent atom-economy. In addition, the value of this protocol is underlined by its ready scalability and divergent derivation of products.

Sirtuin3 rs28365927 functional variant confers to the high risk of non-alcoholic fatty liver disease in Chinese Han population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition associated with aging, insulin resistance, metabolic syndrome, genetic factors and more. Although genetic traits are among the most important risks factors for NAFLD, the understanding of their influence is still quite limited. The present study aimed at identifying novel single nucleotide polymorphisms (SNPs) that may confer a risk for NAFLD in the Han Chinese population. METHODS: Based on the "two-hit hypothesis", candidate SNPs, including Sirtuin3 rs28365927, were genotyped by MassARRAY in B-type ultrasonography-proven NAFLD patients (n = 292) and healthy controls (n = 387). RESULTS: In a model analysis of individuals matched based on gender and age that compared 223 NAFLD and 223 non-NAFLD patients, the rs28365927 GA + AA genotype was a significant risk factor for the development of NAFLD in a dominant model. Rs28365927 was significantly associated with a higher NAFLD risk in both an additive model (A vs G) and genotypic model (GA vs GG). Among the NAFLD patients, serum levels of total bilirubin (TBIL), DBIL direct bilirubin (DBIL) and glutamic-pyruvic transaminase (ALT) in rs28365927 A allele carriers (GA + AA) were 11.1, 14.7 and 41.5% higher, respectively, than in non-carriers (GG). Furthermore, among the NAFLD patients, the carriers of Rs28365927 allele A were positively correlated with higher ALT levels. CONCLUSION: Sirtuin3 rs28365927 functional variant confers to the high risk of non-alcoholic fatty liver disease in Chinese Han population. The rs28365927 A allele significantly increased the ALT levels of NAFLD patients.

ß-Cyclodextrin-Polyacrylamide Hydrogel for Removal of Organic Micropollutants from Water.

Water pollution by various toxic substances remains a serious environmental problem, especially the occurrence of organic micropollutants including endocrine disruptors, pharmaceutical pollutants and naphthol pollutants. Adsorption process has been an effective method for pollutant removal in wastewater treatment. However, the thermal regeneration process for the most widely used activated carbon is costly and energy-consuming. Therefore, there has been an increasing need to develop alternative low-cost and effective adsorption materials for pollutant removal. Herein, ß-cyclodextrin (ß-CD), a cheap and versatile material, was modified with methacrylate groups by reacting with methacryloyl chloride, giving an average degree of substitution of 3 per ß-CD molecule. ß-CD-methacrylate, which could function as a crosslinker, was then copolymerized with acrylamide monomer via free-radical copolymerization to form ß-CD-polyacrylamide (ß-CD-PAAm) hydrogel. Interestingly, in the structure of the ß-CD-PAAm hydrogel, ß-CD is not only a functional unit binding pollutant molecules through inclusion complexation, but also a structural unit crosslinking PAAm leading to the formation of the hydrogel 3D networks. Morphological studies showed that ß-CD-PAAm gel had larger pore size than the control PAAm gel, which was synthesized using conventional crosslinker instead of ß-CD-methacrylate. This was consistent with the higher swelling ratio of ß-CD-PAAm gel than that of PAAm gel (29.4 vs. 12.7). In the kinetic adsorption studies, phenolphthalein, a model dye, and bisphenol A, propranolol hydrochloride, and 2-naphthol were used as model pollutants from different classes. The adsorption data for ß-CD-PAAm gel fitted well into the pseudo-second-order model. In addition, the thermodynamic studies revealed that ß-CD-PAAm gel was able to effectively adsorb the different dye and pollutants at various concentrations, while the control PAAm gel had very low adsorption, confirming that the pollutant removal was due to the inclusion complexation between ß-CD units and pollutant molecules. The adsorption isotherms of the different dye and pollutants by the ß-CD-PAAm gel fitted well into the Langmuir model. Furthermore, the ß-CD-PAAm gel could be easily recycled by soaking in methanol and reused without compromising its performance for five consecutive adsorption/desorption cycles. Therefore, the ß-CD-PAAm gel, which combines the advantage of an easy-to-handle hydrogel platform and the effectiveness of adsorption by ß-CD units, could be a promising pollutant removal system for wastewater treatment applications.

Surface Charge Switchable Polymer/DNA Nanoparticles Responsive to Tumor Extracellular pH for Tumor-Triggered Enhanced Gene Delivery.

A tumor-targeted surface charge switchable polymeric gene delivery system with the function of switching surface charge upon reaching the tumor site owing to the tumor extracellular pH (pHe) was developed. The delivery system was fabricated by two steps. First, the positively charged polyplexe nanoparticles were formed between ß-cyclodextrin-oligoethylenimine star polymer (CD-OEI) and plasmid DNA (pDNA). Next, the CD-OEI/pDNA polyplex nanoparticles were coated with a pHe-responsive anionic polymer via an electrostatic interaction to form ternary complexes. The pHe-responsive anionic polymer was block copolymers of poly(ethylene glycol) (PEG) and poly(2-aminoethyl methacrylate) (pAEMA) modified with 2,3-dimethylmaleic anhydride (denoted as PPD). The coating polymer was mixed with a small amount of pHe-insensitive PEG-pAEMA modified with succinic anhydride (denoted as PPS), giving a balanced negatively charged and PEG-shielded surface with a pHe-responsive property for achieving the expected tumor-triggered enhanced gene delivery. At physiological pH 7.4, owing to the charge shielding of anionic surface coating and the PEGylation, the negatively charged CD-OEI/pDNA/PPD+PPS polyplex complexes could avoid the undesirable interaction with serum proteins and nontargeted components. However, the amide bond of PPD was sensitive to pH changes and could be easily hydrolyzed under acidic pHe (<6.8) to expose the primary amine group due to nucleophile catalysis by the carboxylic acid. The PEG block in the copolymers was used to further enhance the surface-shielding effect. Our data showed that excellent particle salt stability and serum tolerance were achieved through the PPD+PPS surface coating. The CD-OEI/pDNA/PPD+PPS complexes achieved lower cellular uptake and transfection efficiency at neutral pH 7.4 while exhibiting comparable cellular uptake and transfection efficiency at acidic pH 6.5 as compared to the uncoated polyplexes, indicating that the surface charge switching worked well.

Thermoresponsive Hydrogel Induced by Dual Supramolecular Assemblies and Its Controlled Release Property for Enhanced Anticancer Drug Delivery.

Supramolecular hydrogels based on inclusion complexation between cyclodextrins (CDs) and polymers have attracted much interest because of their potential for biomedical applications. It is also attractive to incorporate stimuli-responsive properties into the system to create "smart" hydrogels. Herein, a poly(N-isopropylacrylamide) (PNIPAAm) star polymer with a ß-CD core and an adamantyl-terminated poly(ethylene glycol) (Ad-PEG) polymer were synthesized. They self-assembled into a thermoresponsive pseudo-block copolymer through host-guest complexation and formed supramolecular micelles with the change in environment temperature. Subsequently, an injectable polypseudorotaxane-based supramolecular hydrogel was formed between α-CD and the PEG chains of the pseudo-block copolymer. The hydrogel had a unique network structure involving two types of supramolecular self-assemblies between cyclodextrins and polymers, that is, the host-guest complexation between ß-CD units and adamantyl groups and the polypseudorotaxane formation between α-CD and PEG chains. We hypothesize that the dual supramolecular hydrogel formed at room temperature may be enhanced by increasing the temperature over the lower critical solution temperature of PNIPAAm because of the hydrophobic interactions of PNIPAAm segments. Furthermore, if the hydrogel is applied for sustained delivery of hydrophobic drugs, the copolymer dissolved from the hydrogel could micellize and continue to serve as micellar drug carriers with the drug encapsulated in the hydrophobic core. Rheological tests revealed that the hydrophobic interactions of the PNIPAAm segments could significantly enhance the strength of the hydrogel when the temperature increased from 25 to 37 °C. As compared to hydrogels formed by α-CD and PEG alone, the sustained release property of this thermoresponsive hydrogel for an anticancer drug, doxorubicin (DOX), improved at 37 °C. The hydrogel dissolved slowly and released the pseudo-block copolymer in the form of micelles that continued to serve as drug carriers with DOX encapsulated in the hydrophobic core, achieving a better cellular uptake and anticancer effect than free DOX controls, even in multidrug-resistant cancer cells. According to these findings, the dual supramolecular hydrogel developed in this work with remarkable thermoresponsive properties might have potential for sustained anticancer drug delivery with enhanced therapeutic effect in multidrug-resistant cancer cells.

Effect of purple grape juice on the pharmacokinetics of digoxin: Results of a food-drug interaction study
.

OBJECTIVE: Digoxin is a glycosidic, cardiotonic plant extract with a narrow therapeutic window. The purpose of the study was to investigate the effects of purple grape juice on the pharmacokinetics of digoxin in rats. MATERIALS AND METHODS: A randomized, controlled, single- and multiple-dose study was conducted to evaluate the pharmacokinetic profiles of orally and intravenously administered digoxin. The plasma concentration of digoxin was determined by radioimmunoassay using a gamma counter, and a Caco-2 cell transport model was used to investigate the potential mechanism by which purple grape juice affects the pharmacokinetics of digoxin. RESULTS: The results show that multiple-dose purple grape juice caused a remarkable increase in the AUC, Cmax, and Ka of orally administered digoxin (p < 0.05); only a single dose increased the digoxin AUC0-∞ by 72.80% (p < 0.05). Other parameters were not significantly affected. The study of intravenously administered digoxin found no significant difference in the pharmacokinetic characteristics of the two dosing groups (p > 0.05). The Caco-2 transwell experiments indicated that both the pure purple grape juice and its ethyl acetate extract significantly inhibited digoxin basolateral-to-apical (B→A) transport at concentrations of 10%, 30%, and 50% with dose dependency. These results confirmed that the improvement in bioavailability of digoxin resulted from the inhibition of P-gp by purple grape juice at the level of the gastrointestinal wall. CONCLUSION: Purple grape juice can increase the bioavailability of orally administered digoxin, especially with multiple doses. This information suggests that co-administration of oral digoxin and purple grape juice may require a dose adjustment.
.