Internet addiction and health-related quality of life in adolescents: The mediating role of sleep disturbance.

BACKGROUND: Internet addiction (IA) has emerged as a recognized risk factor associated with impaired health-related quality of life (HRQOL) in adolescents. However, the role of sleep disturbance in this association remains unclear. This study aimed to investigate the association of IA with HRQOL in Chinese adolescents and to evaluate the potential mediating role of sleep disturbance. METHODS: A cross-sectional study was conducted among adolescents attending six randomly selected middle schools in Guangzhou, China. Adolescents self-reported their internet use using the Young Diagnostic Questionnaire. HRQOL and sleep disturbance were assessed by the Pediatric Quality of Life Inventory version 4.0 and the Pittsburgh Sleep Quality Index, respectively. Multivariate linear regression analysis was employed to assess the association between IA and HRQOL. Baron and Kenny's causal steps method was used to examine the possible mediating role of sleep disturbance. RESULTS: Of the 6473 adolescents included, 23.5% had maladaptive internet use (MIU) and 16.6% had pathological internet use (PIU). Compared to adolescents with adaptive internet use (AIU), those with IA had significantly lower scores across all HRQOL dimensions and summary scales. Mediation analysis revealed that sleep disturbance was a significant mediator. Specifically, sleep disturbance mediated 34.55% of the effects of MIU and 34.06% of the effects of PIU on the HRQOL total scale score , respectively. CONCLUSIONS: IA was associated with poorer HRQOL, indicating the needs of preventing IA in Chinese adolescents. Additionally, our findings underscored the importance of enhancing sleep quality to mitigate the adverse impact of IA on adolescents' well-being.

The impacts of dietary sphingomyelin supplementation on metabolic parameters of healthy adults: a systematic review and meta-analysis of randomized controlled trials.

Background: Studies have shown that sphingomyelin (SM) and its metabolites play signaling roles in the regulation of human health. Endogenous SM is involved in metabolic syndrome (MetS), while dietary SM supplementation may maintain lipid metabolism and prevent or alleviate MetS. Therefore, we hypothesized that dietary SM supplementation is beneficial for human health. Aims: In order to examine the impacts of dietary SM on metabolic indexes in adults without MetS, we performed a meta-analysis to test our hypothesis. Methods: A comprehensive search was performed to retrieve randomized controlled trials that were conducted between 2003 and 2023 to examine the effects of dietary SM supplementation on metabolic parameters in the Cochrane Library, PubMed, Web of Science, Embase, and ClinicalTrials.gov databases. RevMan 5.4 and Stata 14.0 software were used for meta-analysis, a sensitivity analysis, the risk of bias, and the overall quality of the resulted evidence. Results: Eventually, 10 articles were included in this meta-analysis. Dietary SM supplementation did not affect the endline blood SM level. When compared to the control, SM supplementation reduced the blood total cholesterol level [MD: -12.97, 95% CI: (-14.57, -11.38), p < 0.00001], low-density lipoprotein cholesterol level [MD: -6.62, 95% CI: (-10.74, -2.49), p = 0.002], and diastolic blood pressure [MD: -3.31; 95% CI (-4.03, -2.58), p < 0.00001] in adults without MetS. The supplementation also increased high-density lipoprotein level [MD:1.41, 95% CI: (0.94, 1.88), p < 0.00001] and muscle fiber conduction velocity [MD: 95% 1.21 CI (0.53, 1.88), p = 0.0005]. The intake of SM had no effect on the blood phospholipids and lyso-phosphatidylcholine, but slightly decreased phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol concentrations. Dietary SM supplementation reduced insulin level [MD: -0.63; 95% CI (-0.96, -0.31), p = 0.0001] and HOMA-IR [MD: -0.23; 95% CI (-0.31, -0.16), p < 0.00001] without affecting blood levels of glucose and inflammatory cytokines. Conclusion: Overall, dietary SM supplementation had a protective effect on blood lipid profiles and insulin level, but had limited impacts on other metabolic parameters in adults without MetS. More clinical trials and basic research are required. Systematic review registration: PROSPERO, identifier CRD42023438460.

Self-Reinforced Bimetallic Mito-Jammer for Ca2+ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Decomposable Nanoagonists Enable NIR-Elicited cGAS-STING Activation for Tandem-Amplified Photodynamic-Metalloimmunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve the therapeutic outcomes of immunotherapy. However, the "constantly active" mode of current STING agonist delivery strategies typically leads to off-target toxicity and hyperimmunity. To address this critical issue, herein a metal-organic frameworks-based nanoagonist (DZ@A7) featuring tumor-specific and near-infrared (NIR) light-enhanced decomposition is constructed for precisely localized STING activation and photodynamic-metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria-targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia-responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger-associated molecular pattern that activates the cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS-STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitated the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes for primary tumor eradication, which also established a long-term anti-tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR-triggered, agonist-free, and tandem-amplified activation of the cGAS-STING pathway, thereby offering a distinct paradigm for photodynamic-metalloimmunotherapy.

Carbopol 940-based hydrogels loading synergistic combination of quercetin and luteolin from the herb Euphorbia humifusa to promote Staphylococcus aureus infected wound healing.

With the increasing prevalence of Staphylococcus aureus infections, rapid emergence of drug resistance and the slow healing of infected wounds, developing an efficient antibiotic-free multifunctional wound dressing for inhibiting S. aureus and simultaneously facilitating wound healing have become a huge challenge. Due to their excellent biocompatibility and biodegradability, some carbopol hydrogels based on plant extracts or purified compounds have already been applied in wound healing treatment. In China, Euphorbia humifusa Willd. (EuH) has been traditionally used as a medicine and food homologous medicine for the treatment of furuncles and carbuncles mainly caused by S. aureus infection. In an earlier study, EuH-originated flavonoids quercetin (QU) and luteolin (LU) could serve as a potential source for anti-S. aureus drug discovery when used in synergy. However, the in vivo effects of QU and LU on S. aureus-infected wound healing are still unknown. In this study, we found a series of Carbopol 940-based hydrogels loading QU and LU in combination could disinfect S. aureus and also could promote wound healing. In the full-thickness skin defect mouse model infected with S. aureus, the wound contraction ratio, bacterial burden, skin hyperplasia and inflammation score, as well as collagen deposition and blood vessels were then investigated. The results indicate that the optimized QL2 [QU (32 µg mL-1)-LU (8 µg mL-1)] hydrogel with biocompatibility significantly promoted S. aureus-infected wound healing through anti-infection, anti-inflammation, collagen deposition, and angiogenesis, revealing it as a promising alternative for infected wound repair.

Staphylococcus aureus biofilm: Formulation, regulatory, and emerging natural products-derived therapeutics.

Staphylococcus aureus can readily form biofilm which enhances the drug-resistance, resulting in life-threatening infections involving different organs. Biofilm formation occurs due to a series of developmental events including bacterial adhesion, aggregation, biofilm maturation, and dispersion, which are controlled by multiple regulatory systems. Rapidly increasing research and development outcomes on natural products targeting S. aureus biofilm formation and/or regulation led to an emergent application of active phytochemicals and combinations. This review aimed at providing an in-depth understanding of biofilm formation and regulation mechanisms for S. aureus, outlining the most important antibiofilm strategies and potential targets of natural products, and summarizing the latest progress in combating S. aureus biofilm with plant-derived natural products. These findings provided further evidence for novel antibiofilm drugs research and clinical therapies.

Terricoxanthones A-E, unprecedented dihydropyran-containing dimeric xanthones from the endophytic fungus Neurospora terricola HDF-Br-2 associated with the vulnerable conifer Pseudotsuga gaussenii.

An investigation on the secondary metabolites from a rice culture broth of the endophytic fungus Neurospora terricola HDF-Br-2 derived from the vulnerable conifer Pseudotsuga gaussenii led to the isolation and characterization of 34 structurally diverse polyketides (1-34). Seven of them are previously undescribed, including five unprecedented dihydropyran-containing (terricoxanthones A-E, 1-5, resp.) and one rare tetrahydrofuran-containing (terricoxanthone F, 6) dimeric xanthones. The structures were elucidated by spectroscopic methods and single-crystal X-ray diffraction analyses. Terricoxanthones each were obtained as a racemic mixture. Their plausible biosynthetic relationships were briefly proposed. Compounds 6, aspergillusone A (8), and alatinone (27) displayed considerable inhibition against Candida albicans with MIC values of 8-16 µg/mL. 4-Hydroxyvertixanthone (12) and 27 exhibited significant inhibitory activities against Staphylococcus aureus, with MIC values of 4-8 µg/mL. Furthermore, compounds 8 and 27 could disrupt biofilm of S. aureus and C. albicans at 128 µg/mL. The findings not only extend the skeletons of xanthone dimers and contribute to the diversity of metabolites of endophytes associated with the endangered Chinese conifer P. gaussenii, but could further reveal the important role of protecting plant species diversity in support of chemical diversity and potential sources of new therapeutics.

Metal-Free Eutectic Electrolyte with Weak Hydrogen Bonds for High-Rate and Ultra-Stable Ammonium-Ion Batteries.

As the need for sustainable battery chemistry grows, non-metallic ammonium ion (NH4 + ) batteries are receiving considerable attention because of their unique properties, such as low cost, nontoxicity, and environmental sustainability. In this study, the solvation interactions between NH4 + and solvents are elucidated and design principles for NH4 + weakly solvated electrolytes are proposed. Given that hydrogen bond interactions dominate the solvation of NH4 + and solvents, the strength of the solvent's electrostatic potential directly determines the strength of its solvating power. As a proof of concept, succinonitrile with relatively weak electronegativity is selected to construct a metal-free eutectic electrolyte (MEE). As expected, this MEE is able to significantly broaden the electrochemical stability window and reduce the solvent binding energy in the solvation shell, which leads to a lower desolvation energy barrier and a fast charge transfer process. As a result, the as-constructed NH4 -ion batteries exhibit superior reversible rate capability (energy density of 65 Wh kg-1 total active mass at 600 W kg-1 ) and unprecedent long-term cycling performance (retention of 90.2% after 1000 cycles at 1.0 A g-1 ). The proposed methodology for constructing weakly hydrogen bonded electrolytes will provide guidelines for implementing high-rate and ultra-stable NH4 + -based energy storage systems.

Association between healthy lifestyle factors and health-related quality of life among Chinese adolescents: the moderating role of gender.

BACKGROUND: To examine the associations of the independent and combined healthy lifestyle factors with health-related quality of life (HRQOL) in adolescents, and to test the moderating role of gender. METHODS: This cross-sectional study included 5125 adolescents aged between 11 and 20 years. They provided self-reported data on six healthy lifestyle factors, including never smoking, never drinking, good sleep quality, sufficient sleep duration, appropriate Internet use, and adequate physical activity. Adolescents' HRQOL was evaluated using the Pediatric Quality of Life Inventory version 4.0. Linear regression models were conducted to explore the association of individual and combined healthy lifestyle factors with adolescents' HRQOL. We further performed stratified analyses and likelihood ratio test to explore the moderating role of gender in these associations. RESULTS: Of the included adolescents, the proportions with 0-2, 3, 4, and 5-6 healthy lifestyle factors were 13.6%, 26.4%, 44.3%, and 15.7%, respectively. Compared to adolescents with composite healthy lifestyle scores of 0-2, those with scores of 3, 4, or 5-6 had significantly higher HRQOL scores across all dimensions, summary scales, and total scale in both unadjusted and adjusted models. Specifically, adolescents with 5-6 healthy lifestyle factors had a total scale score that was 19.03 (95%CI: 17.76 to 20.30) points higher than their counterparts who only had 0-2 healthy lifestyle factors. Significant dose-response patterns were also observed in aforementioned associations. Gender was a significant moderator in the associations between composite healthy lifestyle groups and HRQOL scores, except for the social functioning dimension. CONCLUSIONS: Our results confirmed that combined healthy lifestyle factors were associated with improved HRQOL among adolescents, with a stronger association observed in girls. These findings underscore the necessity for education and healthcare authorities to design health-promoting strategies that encourage multiple healthy lifestyle factors in adolescents, with the objective of enhancing their overall health outcomes.

Preparation and Characterization of a One-Step Electrospun Poly(Lactic Acid)/Wormwood Oil Antibacterial Nanofiber Membrane.

With the continuous improvement of the standard of living, people are increasingly inclined towards natural, green, and environmentally friendly products. Plant-based products that are safe, natural, non-toxic, and beneficial to human health are often more favored. Poly(lactic acid) (PLA) is a polymer obtained through lactate polymerization using renewable plant resources such as corn and has excellent biocompatibility and biodegradability. It is widely used in the field of food packaging. Wormwood oil (WO) is an oil extracted from the stems and leaves of Artemisia plants, and it has broad-spectrum antibacterial properties. In this article, through electrospinning technology, wormwood oil was directly incorporated into PLA, giving the PLA nanofiber membrane antioxidant and antibacterial functions. Various parameters such as voltage (11 KV, 13 KV, 15 KV), spinning solution concentration (8%, 10%, 12%), distance (15 cm, 17 cm, 19 cm), and feeding rate (0.4 mL/h, 0.5 mL/h, 0.6 mL/h) were explored, and the resulting spun fibers were characterized. Through SEM characterization, it was found that when the spinning voltage was 13 KV, the spinning solution concentration was 10%, the distance was 17 cm, and the feeding rate was 0.5 mL/h, the nanofiber membrane had a smooth morphology without bead formation, with an average diameter of 260 nm. The nanofiber membrane was characterized using FTIR, TG, and SEM, confirming the successful incorporation of artemisia essential oil into PLA. The prepared antimicrobial nanofilm was subjected to antimicrobial testing, and the results showed that as the concentration of the essential oil increased, the inhibition zones also increased. When wormwood oil concentration was 4%, the diameter of the inhibition zone for Staphylococcus aureus increased from 1.0 mm to 3.5 mm, while the diameter of the inhibition zone for Escherichia coli increased from 2.0 mm to 4.5 mm.

Diagnostic value of circulating microRNAs for esophageal cancer: a meta-analysis based on Asian data

Background and objective: esophageal cancer (EC) is one of the most common gastrointestinal malignant diseases. We conducted a comprehensive meta-analysis to explore the clinical applicability of circulating microRNA for the diagnosis of EC. Methods: as of September 10, 2021, a comprehensive literature search was conducted on PubMed, Embase, Web of Science, Cochrane Library, Wanfang Database, and China National Knowledge Infrastructure (CNKI) to identify eligible studies. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were pooled to evaluate the test performance. The potential sources of heterogeneity were analyzed by subgroup analysis. Deeks' funnel plot was used to assess publication bias. Results: 85 studies from 50 articles were included in the current meta-analysis. The overall pooled sensitivity was 0.82 (95 % CI, 0.79-0.84), specificity was 0.84 (95 % CI, 0.81-0.86), PLR was 4.9 (95 % CI, 4.2-5.9), NLR was 0.22 (95 % CI, 0.19-0.25), DOR was 22 (95 % CI, 17-29) and AUC was 0.89 (95 % CI, 0.86-0.92), respectively. Subgroup analysis suggested that miRNA clusters with a large sample size showed better diagnostic accuracy. Publication bias was not found. Conclusions: circulating miRNAs can be used as a potential non-invasive biomarker for the diagnosis of EC in Asian populations. (AU)

Adverse childhood experiences and depressive symptoms among middle-aged or older adults in China and the mediating role of short sleep duration.

BACKGROUND: Limited research has simultaneously examined the link between adverse childhood experiences (ACEs), short sleep duration, and depressive symptoms among middle-aged or older Chinese adults. This study aims to investigate the association between ACEs and later-life depressive symptoms, and to examine the mediating role of short sleep duration (<6 h/night) in this association. METHODS: Data of 11,452 participants aged ≥45 years were obtained from the China Health and Retirement Longitudinal Study. Information on ACEs, depressive symptoms, and sleep duration were reported via questionnaires. The mediating effect of short sleep duration in the association between ACEs and depressive symptoms was examined by Baron and Kenny's causal steps method and Karlson/Holm/Breen (KHB) method. RESULTS: Compared to non-exposed group, exposure to ACEs was significantly associated with increased odds of depressive symptoms in a dose-response pattern. The odds ratio of depressive symptoms increased from 1.27 (95 % CI: 1.11-1.46) for one ACE to 3.38 (95 % CI: 2.92-3.90) for ≥4 ACEs. The KHB method identified significant mediating role of short sleep duration in the association between experiencing three or more ACEs and depressive symptoms, with the proportional mediation estimated at 8.96 % and 8.85 % for the groups with 3 ACEs and ≥4 ACEs, respectively. The results were consistent across genders and gender did not moderate these associations. LIMITATIONS: The cross-sectional design limited the ability to make causal inference. CONCLUSIONS: ACEs were positively associated with depressive symptoms, and short sleep duration partially mediated this association. Promoting optimal sleep duration among ACE-exposed individuals might improve their mental health.

Spider Silk-Inspired Binder Design for Flexible Lithium-Ion Battery with High Durability.

The development of flexible lithium-ion batteries (LIBs) imposes demands on energy density and high mechanical durability simultaneously. Due to the limited deformability of electrodes, as well as the flat and smooth surface of the metal current collectors, stable/durable/reliable contact between electrode materials and the current collectors remains a challenge, in particular, for electrodes with high loading mass and heavily deformed batteries. Binders play an essential role in binding particles of electrode materials and adhering them to current collectors. Herein, inspired by spider silk, a binder for flexible LIBs is developed, which equips a cross-linked supramolecular poly(urethane-urea) to the polyacrylic acid. The binder imparts super high elastic restorability originating from the meticulously engineered hydrogen-bonding segments as well as extraordinary adhesion. The developed binder provides excellent flexibility and intact electrode morphologies without disintegration even when the electrode is largely deformed, enabling a stable cycling and voltage output even when the batteries are put under tough dynamic deformation tests. The flexible LIBs exhibit a high energy density of 420 Wh L-1 , which is remarkably higher than reported numbers. The unique binder design is greatly promising and offers a valuable material solution for LIBs with high-loading mass and flexible designs.

Application of quantitative NMR in pharmaceutical analysis: Method qualification and potency determination for two new chemical entities in early-stage clinical studies.

Quantitative NMR (qNMR), being a well-established analytical tool featuring efficiency, simplicity as well as versatility, has been extensively employed in pharmaceutical and medicinal testing. In this study, two 1H qNMR methods were developed to determine the %wt/wt potency of two new chemical entities (compound A and compound B) used in early clinical phase process chemistry and formulation development. The qNMR methods were demonstrated to be significantly more sustainable and efficient than the LC-based approach by substantially reducing the cost, hands-on-time, and materials consumed for testing. The qNMR methods were achieved on a 400 MHz NMR spectrometer equipped with 5 mm BBO S1 broad band room temperature probe. The methods with CDCl3 (for compound A) and DMSO-d6 (compound B) as solvent as well as commercially certified standards for quantitation were phase-appropriately qualified in terms of specificity, accuracy, repeatability/precision, linearity, and range. Both qNMR methods were demonstrated to be linear over the range of 0.8-1.2 mg/mL (80% to 120% of the nominal sample concentration of 1.0 mg/mL) with a correlation coefficient greater than 0.995. The methods were also demonstrated to be accurate with average recoveries ranging from 98.8% to 98.9% and 99.4-99.9% for compound A and compound B respectively as well as precise with %RSD of 0.46% and 0.33% for compound A and compound B respectively. The potency results of compound A and compound B determined by qNMR were compared with those determined by the conventional LC-based method and the qNMR results were demonstrated to be consistent with the LC-based method with absolute difference of 0.4% and 0.5% for compound A and B respectively.

Adverse childhood experiences, problematic internet use, and health-related quality of life in Chinese adolescents.

Background: The influence of adverse childhood experiences (ACEs) on an individual's health is substantial. However, the associations between ACEs, problematic internet use (PIU), and health-related quality of life (HRQOL) in adolescents remain underexplored.Objective: To assess the association between ACEs and HRQOL in Chinese adolescents and to evaluate the mediating role of PIU in this association.Method: A sample of 6,639 adolescents (3,457 boys and 3,182 girls) aged between 11-20 years (mean [SD] age: 14.5 [1.6] years) were recruited from 6 junior and senior middle schools using a proportional sampling approach in a cross-sectional study. Data on ACE exposure was collected through the short form of Childhood Trauma Questionnaire, the ACE-International Questionnaire, and two additional questions. HRQOL was assessed by the Pediatric Quality of Life Inventory version 4.0. The associations between ACEs and HRQOL were estimated using linear regression models. Mediation analysis was further conducted to explore the possible mediating role of PIU in the association between ACEs and HRQOL.Results: Our study collected 13 different ACEs. We found that adolescents exposed to any ACE had significantly lower scores in all HRQOL dimensions, psychosocial health summary scale, and total scale, than those without such exposure. Specifically, adolescents with ≥ 3 ACE exposure had a total scale score that was 14.70 (95%CI: 15.53 to 13.87) points lower than their non-exposed counterparts. Mediation analysis identified PIU as a significant mediator, with the proportion of the total effect attributable to PIU ranging from 14.38% for social functioning to 17.44% for physical functioning.Conclusions: Exposure to ACEs was associated with poorer HRQOL in Chinese adolescents, underscoring the importance to prevent ACEs and their negative impacts on adolescent well-being. These findings also highlighted the need of promoting appropriate internet use among adolescents exposed to ACEs, in order to avert potential impairment in their HRQOL.HIGHLIGHTSAdolescents with adverse childhood experiences have poorer health-related quality of life.The association between adverse childhood experiences and health-related quality of life shows a dose-response pattern.Problematic internet use partially mediates the associations between adverse childhood experiences and health-related quality of life in adolescents.

Distinct chemistry between Zn and Li at varied temperature.

The operating temperature of batteries is an essential consideration in actual applications. Understanding the temperature dependence is conducive to battery design. The experience in lithium-ion batteries (LIBs) indicates that the dendrite issue is exacerbated at lower temperatures and suppressed at higher temperatures. In this study, we revealed the dendrite evolution in aqueous rechargeable zinc-based batteries (RZBs), for which the opposite temperature dependence was observed. Detailed investigations elucidate that the degree of matching of the interface reaction rate and ion diffusivity, together with side reactions, are the key factors that determine the cycling performance. The different properties of organic and aqueous electrolytes result in a reversed temperature dependence. We further conducted a detailed investigation of hybrid electrolytes (organic and aqueous) for balancing the ion diffusivity and side reactions to broaden the working temperature window for RZBs. This work reveals a completely opposite temperature dependence for LIBs and RZBs and discloses the underlying mechanism, reminding one of the differences between LIBs and RZBs in many aspects.

Platform headspace gas chromatography method for high-throughput determination of residual solvents in pharmaceutical materials.

Static headspace capillary gas chromatography (HSGC) has been employed to monitor the level of residual solvents in the pharmaceutical materials. Most of the HSGC methods, however, consume significant amounts of diluents and require considerable amount of sample preparation time. Accordingly, a HSGC method featured with fast turnaround time, and minimal amount of solvent use has been developed for the quantitative analysis of 27 residual solvents frequently used in the development and manufacturing processes of pharmaceutical industry. This HSGC-FID method employs a commercially available fused silica capillary column, a split injection (40:1), and a programmed temperature ramp. It was qualified for specificity, accuracy, repeatability/precision, linearity, LOQ, solution stability, and robustness using two representative sample matrices. The standards, samples and spiked samples were demonstrated to be stable for at least 10 days at room temperature in sealed headspace vials with a recovery of ≥ 93%. The method was also shown to be robust, and its performance was not affected by small changes of carrier gas flow rate, initial oven temperature or the headspace oven temperature. In this new approach, the analytical sample was prepared by dissolving the sample into 1 mL of the diluent and the standard solution was prepared by diluting 1 mL of the custom-made stock into 9 mL of the diluent whereas the traditional approach requires liters of the diluent, making the new approach environmentally friendly, sustainable, economical, agile, error-proofing and thus appropriate for a variety of pharmaceutical applications.

Multiantigen epitope fusion recombinant proteins from capsids of serotype 4 fowl adenovirus induce chicken immunity against avian Angara disease.

Avian Angara disease caused by fowl adenovirus serotype 4 (FAdV-4) has spread widely and brought economic losses to the poultry industry in some countries. Effective vaccines for Angara disease control are currently lacking. In this study, four capsid proteins (hexon, penton, fiber1 and fiber2) from FAdV-4 were selected, and their optimal efficient antigenic epitopes predicted by bioinformatics software were tandemly linked with the flexible linker GGGGS. Based on their amino acid sequences, the DNA sequences for the genes encoding the multiantigen epitope tandem proteins (MAETPs) FAdV4:F1, FAdV4:P, FAdV4:F2 and FAdV4:H were chemosynthesized and then ligated by T4 ligases at the cleavage sites of restriction endonucleases to construct DNAs encoding the multilinked fusion recombinant proteins (MLFRPs) used as protective antigens from avian Angara disease. These genes ligated into the expression vector pET-28a were successfully expressed using the Escherichia coli prokaryotic expression system to prepare five kinds of MLFRPs (FAdV4:F1-P-F2-H, FAdV4:F1-F2-P-H, FAdV4:F1-F2-H-P, FAdV4:F1-P-H-F2 and FAdV4:F1-H-F2-P) for use to immunize chicks. FAdV-4 was injected into MLFRP-immunized chickens, and the challenge protection rate was evaluated. FAdV4:F1-P-F2-H produced the best protection against FAdV-4, with a single immunization resulting in a 100 % protection rate, followed by FAdV4:F1-F2-P-H (83.33 %) and FAdV4:F1-F2-H-P (66.67 %). FAdV4:F1-P-H-F2 and FAdV4:F1-H-F2-P were not able to induce a good immune protection effect after one immunization. However, all of the MLFRPs were capable of protecting the host from FAdV-4 infection after two immunizations. In conclusion, these MLFRPs generated based on capsid proteins of FAdV-4 are promising candidate subunit vaccines against Angara disease.

Novel combination strategy of high intensity focused ultrasound (HIFU) and checkpoint blockade boosted by bioinspired and oxygen-supplied nanoprobe for multimodal imaging-guided cancer therapy.

BACKGROUND: High-intensity focused ultrasound (HIFU) has shown considerable promise in treating solid tumors, but its ultrasonic energy is easily attenuated, resulting in insufficient energy accumulation in the target area. Moreover, HIFU ablation alone may inevitably lead to the presence of residual tumors, which may cause tumor recurrence and metastasis. Here, we describe a synergistic regimen combining HIFU facilitation with immunomodulation based on a novel oxygen-carrying biomimetic perfluorocarbon nanoparticle (M@P-SOP) to stimulate immunogenic cell death in tumor cells while alleviating immune suppression tumor microenvironment. METHODS: M@P-SOP was prepared by double emulsion and film extrusion method. The anticancer and antimetastatic effects of M@P-SOP were evaluated on a preclinical transplanted 4T1 tumor model by combining HIFU and immunotherapy. Flow cytometry and immunofluorescence were used to clarify the potential mechanism of HIFU+M@P-SOP and their role in anti-programmed death ligand-1 (PD-L1) therapy. RESULTS: Guided by photoacoustic/MR/ultrasound (US) multimodal imaging, M@P-SOP was abundantly enriched in tumor, which greatly enhanced HIFU's killing of tumor tissue in situ, induced stronger tumor immunogenic cell death, stimulated dendritic cell maturation and activated CD8+ T cells. At the same time, M@P-SOP released oxygen to alleviate the tumor hypoxic environment, repolarizing the protumor M2-type macrophages into antitumor M1-type. With concurrent anti-PD-L1 treatment, the antitumor immune response was further amplified to the whole body, and the growth of mimic distant tumor was effectively suppressed. CONCLUSIONS: Our findings offer a highly promising HIFU synergist for effectively ameliorating acoustic and hypoxia environment, eventually inhibiting tumor growth and metastasis by stimulating host's antitumor immunity under HIFU ablation, especially in synergizing with PD-L1 antibody immunotherapy.

Antibacterial and antibiofilm efficacy of the preferred fractions and compounds from Euphorbia humifusa (herba euphorbiae humifusae) against Staphylococcus aureus.

ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia humifusa Willd., known as Di-Jin-Cao in Chinese, has long been utilized as a traditional herb for the treatment of furuncles and carbuncles mainly caused by Staphylococcus aureus infection. Despite extensive chemical and pharmacological studies reported previously for E. humifusa, the antibacterial and antibiofilm activities against S. aureus as well as the related mechanism of action (MoA) remain largely obscure. AIM OF THE STUDY: To investigate the antibacterial and antibiofilm activities of the preferred fractions and compounds from E. humifusa against S. aureus and assess the associated MoA. MATERIALS AND METHODS: The bioactive fractions and compounds were obtained from the 75% ethanol extract of E. humifusa (75%-EEEH) with the assistance of the related antibacterial and antibiofilm screening. Their antibacterial activities were determined using the broth microdilution method, whilst the inhibition of biofilm formation and the disruption of preformed biofilm were assessed by crystal violet staining and confocal laser scanning microscopy (CLSM). To achieve more effective therapies, the combinatory effects of different components were also studied. The biofilm metabolic activities of isolated compounds were evaluated by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay. The scanning electron microscopy (SEM) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to explore the antibiofilm mechanism. RESULTS: Fractions DJC06 and DJC07 collected from the ethyl acetate extract of the 75%-EEEH exhibited antibacterial activity (MIC = 256 µg/mL) against S. aureus and further separation of these two fractions led to the isolation and characterization of 22 compounds. Among the isolates, luteolin (LU), quercetin (QU), and kaempferol (KA) are the verified components associated with the antibacterial and antibiofilm activities by displaying individual or combinational MIC values of 8-128 µg/mL and 70.9-99.7% inhibition for biofilm formation. Importantly, QU and KA can work in synergy with LU to significantly enhance the efficacy via destroying cell integrity, increasing membrane permeability, and down-regulating the biofilm-related gene expression. CONCLUSIONS: The preferred fractions and compounds from E. humifusa exerted desired antibacterial and antibiofilm efficacy against S. aureus via a MoA involving cell morphology disruption and altered genes expression. The findings herein not only support its traditional use in the treatment of furuncles and carbuncles, but reveal E. humifusa is a potential source for producing promising antibiofilm alternatives against S. aureus and highlight the isolated components (LU, QU, KA) that can potentiate the efficacy when used in synergy.