Swertiamarin relieves radiation-induced intestinal injury by limiting DNA damage.

Radiotherapy is the conventional treatment for pelvic abdominal tumors. However, it can cause some damage to the small intestine and colorectal, which are very sensitive to radiation. Radiation-induced intestinal injury (RIII) affects the prognosis of radiotherapy, causing sequelae of loss of function and long-term damage to patients' quality of life. Swertiamarin is a glycoside that has been reported to prevent a variety of diseases including but not limited to diabetes, hypertension, atherosclerosis, arthritis, malaria, and abdominal ulcers. However, its therapeutic effect and mechanism of action on RIII have not been established. We investigated whether swertiamarin has a protective effect against RIII. In this article, we use irradiator to create cellular and mouse models of radiation damage. Preventive administration of swertiamarin could reduce ROS and superoxide anion levels to mitigate the cellular damage caused by radiation. Swertiamarin also attenuated RIII in mice, as evidenced by longer survival, less weight loss and more complete intestinal barrier. We also found an increase in the relative abundance of primary bile acids in irradiated mice, which was reduced by both FXR agonists and swertiamarin, and a reduction in downstream interferon and inflammatory factors via the cGAS-STING pathway to reduce radiation-induced damage.

Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters.

The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of non-growing, dormant "persisters" subsets help bacteria evade antibiotic treatment and enhance bacterial resistance, which poses a serious threat to human life and health. It is urgent to discover novel antibacterial therapies effective against MRSA persisters. Thymol is a common nutraceutical with weak antibacterial and antitumor activities. A series of Thymol triphenylphosphine (TPP) conjugates (TPP-Thy3) was designed and synthesized. These compounds showed significantly improved inhibitory activity against Gram-positive bacteria compared with Thymol. Among them, Thy3d displayed a low probability of resistance selection and showed excellent biocompatibility. Interestingly, Thy3d elicited a rapid killing effect of MRSA persisters (99.999%) at high concentration. Fluorescence experiments, electron microscopy, molecular dynamics simulation and bilayer experiment confirmed that Thy3d conjugates exerted potent antimicrobial activity by disrupting the integrity of the membrane of bacterial even the persister. Furthermore, Thy3d exhibited considerable efficacy in a mouse model of subcutaneous murine MRSA infection. In summary, TPP-Thy3 conjugates are a series of novel antibacterial agents and could serve as a new therapeutic strategy for combating antibiotic resistance.

Uncovering the anti-biofilm activity of Ilicicolin B against Staphylococcus aureus.

The formation of bacterial biofilms reduces the entry of antibiotics into bacteria and helps bacteria tolerate otherwise lethal concentrations of antimicrobials, leading to antibiotic resistance. Therefore, clearing bacterial biofilm is an effective strategy to tackle drug resistance. Currently, there are no approved antibiotics for inhibiting bacterial biofilm formation. We found that Ilicicolin B had excellent antibacterial activity against MRSA without obvious hemolytic activity. More importantly, Ilicicolin B effectively inhibited the biofilm formation in a concentration-dependent manner by crystal violet colorimetric assay and fluorescence microscopy analysis. Exposure of Staphylococcus aureus to Ilicicolin B for 24 h reduced the protein and polysaccharide components in EPS, suggesting that Ilicicolin B disintegrated the biofilms by dissociating the EPS in a matrix. In addition, Ilicicolin B demonstrated strong antibacterial effects in a murine abscess model of S. aureus. Our findings suggest that Ilicicolin B has the potential to treat S. aureus infection by inhibiting biofilm formation.

Facile and stereospecific synthesis of diverse ß-N-glycosyl sulfonamide scaffolds via palladium catalysis.

Glycosylation is an important strategy to improve the druggability of lead compounds. Here, we present a palladium-catalysed stereospecific N-glycosylation of sulfonamides. This approach stands out with wide substrate scope, high functional group tolerance, and easy scalability, furnishing a broad spectrum of densely functionalized ß-N-glycosyl sulfonamides with good efficiency and exceptional regio-/stereoselectivity. Diverse drug-like glycosulfonamido scaffolds have been constructed via a late-stage diversification strategy and various facile synthetic transformations of the products. Collectively, the established protocol provides a valuable tool for efficiently preparing glycosyl sulfonamides to facilitate drug discovery.

Oropharyngeal administration of colostrum targeting gut microbiota and metabolites in very preterm infants: protocol for a multicenter randomized controlled trial.

BACKGROUND: Oropharyngeal administration of colostrum (OAC) has an immune-stimulating effect on oropharyngeal-associated lymphoid tissue, and can promote the maturation of the gastrointestinal tract. However, how OAC promotes intestinal maturation in preterm infants by altering gut microbiota remains unclear. We aim to assess changes in gut microbiota and metabolites after OAC in very preterm infants. METHODS: A multicenter, double-blind, randomized controlled trial will be conducted in three large neonatal intensive care units in Shenzhen, China, with preterm infants with gestational age less than 32 weeks at birth and birth weight less than 1500 g. It is estimated that 320 preterm infants will be enrolled in this study within one year. The intervention group will receive oropharyngeal administration of 0.2 ml colostrum every 3 h, starting between the first 48 to 72 h and continued for 5 consecutive days. Following a similar administration scheme, the control group will receive oropharyngeal administration of sterile water. Stool samples will be collected at the first defecation, as well as on the 7th, 14th, 21st and 28th days after birth for analysis of effect of OAC on gut microbiota and metabolites through 16sRNA gene sequencing and liquid chromatography-mass spectrometry. DISCUSSION: This proposal advocates for the promotion of OAC as a safe and relatively beneficial protocol in neonatal intensive care units, which may contribute to the establishment of a dominant intestinal flora. Findings of this study may help improve the health outcomes of preterm infants by establishment of targeted gut microbiota in future studies. TRIAL REGISTRATION: NCT05481866 (registered July 30, 2022 on ClinicalTrials.gov).

Short-term prognosis of very-preterm infants of ethnic minorities and Han nationality at high altitude: a single-center, retrospective study.

OBJECTIVE: We aimed to analyze the perinatal care of very-preterm infants (VPIs) in plateau areas of China and to explore any differences in short-term outcomes between ethnic minorities and Han nationality. METHODS: VPIs with gestational age (GA) <32 weeks admitted to Qinghai Red Cross Hospital from 1 January 2018 to 31 December 2020 were enrolled. Maternal information, neonatal information, perinatal care and discharge outcomes were retrospectively collected and analyzed. RESULTS: A total of 302 VPIs were examined, including 143 (47.4%) ethnic minority infants and 159 (52.6%) Han infants. Mothers of ethnic minority infants were significantly younger than those of Han infants (27 y vs. 30 y, p < .001). There were no differences in the incidence of assisted reproduction, multiple pregnancies, maternal hypertension, clinical chorioamnionitis or premature rupture of membranes >18 h between ethnic minority mothers and Han mothers. Lower proportions of cesarean section and incidence of maternal diabetes were observed in ethnic minority mothers than in Han mothers [(9.1 vs.17.6%, p < .05) and (42.7 vs. 57.9%, p < .05, respectively)]. Meanwhile, fewer antenatal steroids were used in minority group than Han group (65.7 vs. 81.1%, p < .05). No significant differences in rates of death, active treatment, necrotizing enterocolitis stage ≥2, moderate-to-severe BPD, and incidence of severe retinopathy of prematurity in VPIs were found between the two groups and in all GA subgroups. Severe neurological injury was significantly less common in the minority newborns than in the Han infants (1.2 vs. 6.1%, p < .05). Compared with Han group, no excess risk of death, death or major morbidity, death despite active treatment, death or major morbidity despite active treatment was observed in ethnic minorities, with or without adjusting for gestational age and prenatal steroids. CONCLUSIONS: Short-term prognosis of VPIs of ethnic minorities were similar to those of Han nationality.

Fan beam CT-guided online adaptive external radiotherapy of uterine cervical cancer: a dosimetric evaluation.

PURPOSE: To discuss the dosimetric advantages and reliability of the accurate delivery of online adaptive radiotherapy(online ART) for uterine cervical cancer(UCC). METHODS AND MATERIALS: Six UCC patients were enrolled in this study. 95% of the planning target volume (PTV) reached 100% of the prescription dose (50.4 Gy/28fractions/6weeks) was required. The patients were scanned with uRT-Linac 506c KV-FBCT then the target volume (TV) and organs at risk (OARs) were delineated by doctors. The dosimeters designed and obtained a routine plan (Plan0). KV-FBCT was used for image guidance before subsequent fractional treatment. The online ART was processed after registration, which acquired a virtual nonadaptive radiotherapy plan (VPlan) and an adaptive plan (APlan). VPlan was the direct calculation of Plan0 on the fractional image, while APlan required adaptive optimization and calculation. In vivo dose monitoring and three-dimensional dose reconstruction were required during the implementation of APlan. RESULTS: The inter-fractional volumes of the bladder and rectum changed greatly among the treatments. These changes influenced the primary gross tumor volume (GTVp) and the position deviation of GTVp and PTV and positively affected the prescription dose coverage of TV. GTVp decreased gradually along with dose accumulation. The Dmax, D98, D95, D50, and D2 of APlan were superior to those of VPlan in target dose distribution. APlan had good conformal index, homogeneity index and target coverage. The rectum V40 and Dmax, bladder V40, the small bowel V40 and Dmax of APlan were better than that of VPlan. The APlan's fractional mean γ passing rate was significantly higher than the international standard and the mean γ passing rate of all cases after the three-dimensional reconstruction was higher than 97.0%. CONCLUSION: Online ART in external radiotherapy of UCC significantly improved the dose distribution and can become an ideal technology to achieve individualized precise radiotherapy.

Higher ETCOc predicts longer phototherapy treatment in neonatal hyperbilirubinemia.

Objective: This study aimed to evaluate the predictive performance of end-tidal carbon monoxide corrected to ambient carbon monoxide (ETCOc) values phototherapy in neonates with significant hyperbilirubinemia. Methods: A prospective study was conducted on neonates with significant hyperbilirubinemia who received phototherapy between 3 and 7 days of life. The breath ETCOc and serum total bilirubin of the recruited infants were measured on admission. Results: The mean ETCOc at admission in 103 neonates with significant hyperbilirubinemia was 1.70 ppm. The neonates were categorized into two groups: phototherapy duration ≤72 h (n = 87) and >72 h (n = 16) groups. Infants who received phototherapy for >72 h had significantly higher ETCOc (2.45 vs. 1.60, P = 0.001). The cutoff value of ETCOc on admission for predicting longer phototherapy duration was 2.4 ppm, with a sensitivity of 62.5% and specificity of 88.5%, yielding a 50% positive predictive value and a 92.7% negative predictive value. Conclusion: ETCOc on admission can help predict the duration of phototherapy in neonates with hyperbilirubinemia, facilitate clinicians to judge disease severity, and make clinical communication easier and more efficient.

Prevalence of High-Altitude Polycythemia and Hyperuricemia and Risk Factors for Hyperuricemia in High-Altitude Immigrants.

Song Zhen, Anxin Zhang, Jie Luo, Guanghai Xiong, Haibo Peng, Rang Zhou, Yuanfeng Li, Hongqiang Xu, Zhen Li, Wei Zhao, and Haoxiang Zhang. Prevalence of high-altitude polycythemia and hyperuricemia and risk factors for hyperuricemia in high-altitude immigrants. High Alt Med Biol. 24:132-138, 2023. Background: Few studies have investigated the epidemiology of chronic mountain sickness (CMS) in high-altitude immigrants. This study evaluated the prevalence of polycythemia and hyperuricemia (HUA) and risk factors for HUA in high-altitude immigrants. Methods: A cross-sectional study was conducted with 7,070 immigrants 15-45 years of age living on the Tibetan Plateau between January and December 2021. Information from routine physical examinations was obtained from each participant. Binary logistic regression analysis was performed to determine the correlation of several risk factors for HUA. Results: The prevalence of high-altitude polycythemia (HAPC) and HUA was 25.8% (28.7% in males and 9.4% in females) and 54.2% (59.9% in males and 22.5% in females), respectively. The highest prevalence of HAPC in males and females was observed in participants 26-30 and 21-25 years of age, respectively. The highest prevalence of HUA in both males and females was observed in participants 26-30 years of age. Binary logistic regression analysis showed that age, sex, and hemoglobin (Hb) concentration were risk factors for HUA, among which age was a negative factor and male sex and Hb concentration were positive factors. Conclusions: Immigrants are more susceptible to HAPC and HUA. The high prevalence of CMS of immigrants may be associated with Hb concentration, age, and sex.

Tiotropium in Patients with Bronchiectasis: A Prospective Cohort Study.

PURPOSE: There are limited studies on the use of bronchodilators for the treatment of bronchiectasis. This study investigated the efficacy of tiotropium in patients with bronchiectasis and airflow limitation. METHODS: This study was a prospective cohort study, including 169 patients with bronchiectasis and airflow limitation from 2015 to 2019. The clinical outcomes observed in our study were the effect of tiotropium on the frequency of moderate exacerbations, the time to the first severe exacerbation, and the annual decline in FEV1. RESULTS: After 12 months, the annual decline in the FEV1 after bronchodilator use was 27.08 ml or 42.9 ml per year in the group with or without tiotropium, respectively. Treatment with tiotropium was associated with a decreased risk of moderate exacerbation of bronchiectasis (Adjusted RR 0.618 95% CI 0.493-0.774; P < 0.005). The time to the first severe acute exacerbation of bronchiectasis in the tiotropium group was longer than the non-tiotropium group (Adjusted HR 0.333 95% CI 0.219-0.506; P < 0.001). CONCLUSION: In conclusion, prospective cohort study showed that tiotropium effectively ameliorated the annual decline in the FEV1, with a lower-risk rate of moderate exacerbations and prolonging the time to the first-time severe exacerbation in patients with bronchiectasis and airflow limitation.

Evaluation and countermeasures of contracted services of Chinese family doctors from demanders' point of view - a case study of a city.

BACKGROUND: The "gatekeepers" for residents' health are their family doctors. The implementation of contracted services provided by family doctors is conducive to promoting hierarchical diagnosis and treatment and achieving the objective of providing residents comprehensive and full-cycle health services. Since its implementation in 2016, the contract service system for Chinese family doctors has yielded a number of results while also highlighting a number of issues that require further investigation. Consequently, the purpose of this study is to assess the impact of family doctors' contracted services in a Chinese city from the perspective of demanders (i.e., contracted residents), identify the weak links, and then propose optimization strategies. METHODS: In this study, a city in Shandong Province, China was selected as the sample city. In January 2020, 1098 contracted residents (including 40.5% men and 59.5% women) from 18 primary medical institutions (including township health centers and community health centers) were selected for on-site investigation. Take the PCAT-AS(Adult Short) scale revised in Chinese as the research tool to understand the medical experience of contracted residents in primary medical institutions, and interview some family doctors and residents to obtain more in-depth information. RESULTS: Among the four core dimensions of PCAT-AS, the score of Continuous was the highest (3.44 ± 0.58); The score of Coordinated was the lowest (3.08 ± 0.66); Among the three derived dimensions, the score of Family-centeredness was the highest (3.33 ± 0.65); The score of Culturally-competent was the lowest (2.93 ± 0.77). The types of contracting institutions, residents' age, marital status, occupation, and whether chronic diseases are confirmed are the influencing factors of PCAT scores. CONCLUSION: The family doctors' contracted services in the city has achieved certain results. At the same time, there are still some problems, such as difficult access to outpatient services during non-working hours, incomplete service items, an imperfect referral system, and inadequate utilization of traditional Chinese medicine services, it is recommended that the government continue to enhance and increase its investment in relevant policies and funds. Primary medical institutions should improve the compensation mechanism for family doctors and increase their work enthusiasm, improve and effectively implement the two-way referral system, gradually form an orderly hierarchical pattern of medical treatment, provide diversified health services in accordance with their own service capacity and the actual needs of residents, and improve the utilization rate of traditional Chinese medicine services in primary medical institutions.

Comparisons of care practices for very preterm infants and their short-term outcomes in two tertiary centers in northwest and south China: A retrospective cohort study.

BACKGROUND: Care practices for very preterm infants and the mortality and morbidity of the infants vary widely among countries and regions with different levels of economic development, including the different areas in China. We aimed to compare the obstetric and delivery room practices of two representative tertiary newborn centers in the northwestern and southern regions of China and the mortality and morbidity of their very preterm infants. METHODS: A retrospective cohort study was conducted. Very preterm infants born between 220/7 and 316/7 weeks of gestation, and admitted to Qinghai Red Cross Hospital (QHH) and Shenzhen Baoan Women's and Children's Hospital (SZH) from January 1, 2018 to December 31, 2020, were included. The infants' characteristics and short-term outcomes, and the hospitals' care practices were compared between the two cohorts. RESULTS: Three hundred and two infants in QHH and 505 infants in SZH were enrolled, and the QHH cohort was more mature than the SZH cohort was (gestational age 30.14 (29.14-31.14) vs. 29.86 (27.86-31.00 weeks, respectively), p < 0.001). Fewer antenatal steroids and more tracheal intubations were used in QHH than in SZH [(73.8% vs. 90.9%, p < 0.001) and (68.2% vs. 35.0%, p < 0.001, respectively)]. The odds of mortality [aOR = 10.31, 95%CI: (6.04, 17.61)], mortality or major morbidity [aOR = 5.95, 95%CI: (4.05, 8.74)], mortality despite active treatment [aOR = 3.14, 95%CI: (1.31, 7.53)], mortality or major morbidity despite active treatment [aOR = 3.35, 95%CI: (2.17, 5.17)], moderate or severe bronchopulmonary dysplasia [aOR = 3.66, 95%CI: (2.20, 6.06)], and severe retinopathy of prematurity [aOR = 3.24, 95%CI: (1.19, 8.83)] were higher in the QHH cohort. No significant difference in the rate of severe neurological injury or necrotizing enterocolitis ≥ Stage 2 was found between the cohorts. CONCLUSION: Obstetric and delivery room care practices used in the management of very preterm infants differed considerably between the QHH and SZH cohorts. Very preterm infants born in QHH have higher odds of mortality or severe morbidity compared with those born in SZH.

Prediction Models for Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review.

Objective: To provide an overview and critical appraisal of prediction models for bronchopulmonary dysplasia (BPD) in preterm infants. Methods: We searched PubMed, Embase, and the Cochrane Library to identify relevant studies (up to November 2021). We included studies that reported prediction model development and/or validation of BPD in preterm infants born at ≤32 weeks and/or ≤1,500 g birth weight. We extracted the data independently based on the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS). We assessed risk of bias and applicability independently using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). Results: Twenty-one prediction models from 13 studies reporting on model development and 21 models from 10 studies reporting on external validation were included. Oxygen dependency at 36 weeks' postmenstrual age was the most frequently reported outcome in both development studies (71%) and validation studies (81%). The most frequently used predictors in the models were birth weight (67%), gestational age (62%), and sex (52%). Nearly all included studies had high risk of bias, most often due to inadequate analysis. Small sample sizes and insufficient event patients were common in both study types. Missing data were often not reported or were discarded. Most studies reported on the models' discrimination, while calibration was seldom assessed (development, 19%; validation, 10%). Internal validation was lacking in 69% of development studies. Conclusion: The included studies had many methodological shortcomings. Future work should focus on following the recommended approaches for developing and validating BPD prediction models.

The relationship between glycosylated hemoglobin level and red blood cell storage lesion in blood donors.

BACKGROUND: Glycosylated hemoglobin (HbA1c), not routinely screened in blood donors, is associated with morphological, biochemical, and functional abnormalities of red blood cells (RBCs) and with enhanced oxidative stress. We aimed to explore HbA1c levels in blood donors and their effect on RBC storage. STUDY DESIGN AND METHODS: An analytical cross-sectional study was conducted on 875 eligible blood donors aged 18-60 years from May 1, 2021, to August 30, 2021. Two selected groups of donors (HbA1c <6.5%, n = 10; HbA1c ≥ 6.5%, n = 10) exhibiting as similar as possible baseline values (such as age, sex, and living habits, etc.) were recruited for blood donation in leukoreduced CPDA-1 units. RBC morphological, biochemical, structural, and oxidative stress states were measured during 5-35 days of storage. RESULTS: Elevated HbA1c prevalence was 37%, including 31.7% (277/875) in the prediabetes range (HbA1c 5.7%-6.4%) and 5.4% (47/875) in the diabetes range (HbA1c ≥ 6.5%). Age, body mass index (BMI), smoking, and alcohol consumption were the main factors influencing the HbA1c levels. During storage, high-HbA1c group had abnormal RBC morphology, impaired membrane function, and ion imbalance (higher mean corpuscular volume, distribution width, hemolysis rate, potassium ion efflux, and phosphatidylserine exposure) as compared with low HbA1c group. Additionally, RBC oxidative stress was significantly increased in donors with high HbA1c levels during 21-35 days. DISCUSSION: Blood donors proportion with abnormal HbA1c levels was relatively high, and donor HbA1c levels may be associated with stored RBCs capacity. Our study provides new insights into the different effects of donor HbA1c levels on RBC storage lesions.

Oral ibuprofen promoted cholestatic liver disease in very low birth weight infants with patent ductus arteriosus.

OBJECTIVES: Hemodynamically significant patent ductus arteriosus (hsPDA) in very low birth weight (VLBW) infants is routinely treated in many countries with oral ibuprofen. This study retrospectively assessed whether the risk of cholestatic liver disease (CLD) increased due to oral ibuprofen administration in VLBW infants. METHODS: A total of 122 VLBW preterm infants (26∼32 weeks, birth weight<1500g) diagnosed with patent ductus arteriosus (PDA) admitted to our neonatal intensive care unit (NICU) between September 2016 to August 2018 were included. Sixty-four infants were diagnosed with hs-PDA and received ibuprofen treatment. VLBW infants with PDA untreated with ibuprofen served as controls. Soybean oil and fat emulsions were routinely added to parenteral nutrition (PN). Once CLD was diagnosed, the fat emulsions were immediately replaced with multi-oil fat emulsion injections. To assess the independent association of treatment and duration of ibuprofen with CLD and duration of fasting and PN, binary logistic regression or multivariate linear regression analyses were conducted, adjusting for major confounders (birth weight, gestational age, Clinical Risk Index for Babies, and cholestasis-associated risk factors). RESULTS: The duration of PN increased due to ibuprofen treatment for 6.559 days (95% CI: 1.769, 11.349; P=0.008), and the risk of prolonged fasting (cutoff>5 days) might have increased due to ibuprofen treatment (OR: 3.043, 95% CI: 0.965, 9.594; P=0.057). Furthermore, CLD was influenced by ibuprofen treatment (OR: 6.730; 95% CI: 1.279, 35.41; P=0.024), early thrombocytopenia 7 days postnatal (OR: 6.996; 95% CI: 1.769, 27.658; P=0.004), and late onset sepsis (OR: 6.976; 95% CI: 1.561, 31.169; P=0.011). Further analysis adjusting for cholestasis-associated risk factors revealed that CLD was influenced by the duration of ibuprofen treatment (OR: 2.864; 95% CI: 1.104, 7.422; P=0.030), Platlets counts 7 days postnatal (OR: 0.971; 95% CI: 0.950, 0.994; P=0.013), and duration of antibiotics (OR: 1.134; 95% CI: 1.002, 1.282; P=0.046). CONCLUSIONS: This retrospective study indicated oral ibuprofen duration-dependently increased the risk of CLD in VLBW infants with PDA, and early thrombocytopenia served as the critical risk factor.

Eradicating intracellular MRSA via targeted delivery of lysostaphin and vancomycin with mannose-modified exosomes.

Intracellular methicillin-resistant Staphylococcus aureus (MRSA) is extremely difficult to remove by common antibiotics, leading to infection recurrence and resistance. Herein we report a novel exosome-based antibiotic delivery platform for eradicating intracellular MRSA, where mannosylated exosome (MExos) is employed as the drug carrier and preferentially taken up by macrophages, delivering lysostaphin (MExoL) and vancomycin (MExoV) to intracellular pathogens. Combination of MExoL and MExoV eradicated intracellular quiescent MRSA. Moreover, MExos rapidly accumulated in mouse liver and spleen, the target organs of intracellular MRSA, after intravenous (IV) administration. Thus, the MExos antibiotic delivery platform is a promising strategy for combating intracellular infection.

Controlled coassembly of dumbbell-like Au nanoparticles with a porous nitrogen doped carbon aerogel for cancer cell H2O2 detection.

The homogeneous dumbbell-like Au nanoparticles (DL-AuNPs) with large exposed active surfaces were obtained with a porous N-doped carbon aerogel (NCA). Such coassembly of DL-AuNPs with NCA (NCA@DL-AuNPs) had a large specific surface area (788 m2/g), rich mesopores, and a high N content (4.93 at%). The unique structures of NCA@DL-AuNPs yielded better electrocatalytic activity for the detection of H2O2 both in PBS and released from Hale cells than that of previously reported Au catalysts loaded on carbon materials, which demonstrates that such novel NCA@DL-AuNPs nanocomposite is promising for design of efficient nonenzymatic H2O2 biosensors.

Pillar[5]arene-based, dual pH and enzyme responsive supramolecular vesicles for targeted antibiotic delivery against intracellular MRSA.

A rationally designed mannosylated amphiphilic pillar[5]arene (Man@AP5) self-assembles into supramolecular vesicles with encapsulated vancomycin (Man@AP5-Van), which target macrophages, respond to both acid and cathepsin B, and release vancomycin (Van) rapidly inside macrophages. Man@AP5-Van significantly increases the intracellular concentration of Van, enhancing its antibacterial efficacy against intracellular MRSA.

Near-Infrared Laser-Triggered, Self-Immolative Smart Polymersomes for in vivo Cancer Therapy.

PURPOSE: Traditional chemotherapy is accompanied by significant side effects, which, in many aspects, limits its treatment efficacy and clinical applications. Herein, we report an oxidative responsive polymersome nanosystem mediated by near infrared (NIR) light which exhibited the combination effect of photodynamic therapy (PDT) and chemotherapy. METHODS: In our study, poly (propylene sulfide)20-bl-poly (ethylene glycol)12 (PPS20-b-PEG12) block copolymer was synthesized and employed to prepare the polymersome. The hydrophobic photosensitizer zinc phthalocyanine (ZnPc) was loaded in the shell and the hydrophilic doxorubicin hydrochloride (DOX·HCl) in the inner aqueous space of the polymersome. RESULTS: Under the irradiation of 660 nm NIR light, singlet oxygen 1O2 molecules were generated from ZnPc to oxidize the neighbouring sulfur atoms on the PPS block which eventually ruptured the intact structure of polymersomes, leading to the release of encapsulated DOX·HCl. The released DOX and the 1O2 could achieve a combination effect for cancer therapy if the laser activation and drug release occur at the tumoral sites. In vitro studies confirmed the generation of singlet oxygen and DOX release by NIR irradiation. In vivo studies showed that such a combined PDT-chemotherapy nanosystem could accumulate in A375 tumors efficiently, thus leading to significant inhibition on tumor growth as compared to PDT (PZ group) or chemotherapy alone (DOX group). CONCLUSION: In summary, this oxidation-sensitive nanosystem showed excellent anti-tumor effects by synergistic chemophotodynamic therapy, indicating that this novel drug delivery strategy could potentially provide a new means for cancer treatments in clinic.

Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity.

Second messenger molecules play important roles in the responses to various stimuli that can determine a cell's fate under stress conditions. Here, we report that lethal concentrations of aminoglycoside antibiotics result in the production of a dinucleotide alarmone metabolite-diadenosine tetraphosphate (Ap4A), which promotes bacterial cell killing by this class of antibiotics. We show that the treatment of Escherichia coli with lethal concentrations of kanamycin (Kan) dramatically increases the production of Ap4A. This elevation of Ap4A is dependent on the production of a hydroxyl radical and involves the induction of the Ap4A synthetase lysyl-tRNA synthetase (LysU). Ectopic alteration of intracellular Ap4A concentration via the elimination of the Ap4A phosphatase diadenosine tetraphosphatase (ApaH) and the overexpression of LysU causes over a 5,000-fold increase in bacterial killing by aminoglycosides. This increased susceptibility to aminoglycosides correlates with bacterial membrane disruption. Our findings provide a role for the alarmone Ap4A and suggest that blocking Ap4A degradation or increasing its synthesis might constitute an approach to enhance aminoglycoside killing potency by broadening their therapeutic index and thereby allowing lower nontoxic dosages of these antibiotics to be used in the treatment of multidrug-resistant infections.