PIAS1 upregulation confers protection against Cerulein-induced acute pancreatitis via FTO downregulation by enhancing sumoylation of Foxa2.

OBJECTIVE: This research discussed the specific mechanism by which PIAS1 affects acute pancreatitis (AP). METHODS: PIAS1, Foxa2, and FTO expression was assessed in Cerulein-induced AR42J cells and mice. Loss- and gain-of-function assays and Cerulein induction were conducted in AR42J cells and mice for analysis. The relationship among PIAS1, Foxa2, and FTO was tested. Cell experiments run in triplicate, and eight mice for each animal group. RESULTS: Cerulein-induced AP cells and mice had low PIAS1 and Foxa2 and high FTO. Cerulein induced pancreatic injury in mice and inflammation and oxidative stress in pancreatic tissues, which could be reversed by PIAS1 or Foxa2 upregulation or FTO downregulation. PIAS1 elevated SUMO modification of Foxa2 to repress FTO transcription. FTO upregulation neutralized the ameliorative effects of PIAS1 or Foxa2 upregulation on Cerulein-induced AR42J cell injury, inflammation, and oxidative stress. CONCLUSION: PIAS1 upregulation diminished FTO transcription by increasing Foxa2 SUMO modification, thereby ameliorating Cerulein-induced AP.

A study of subtropical park thermal comfort and its influential factors during summer.

Outdoor thermal comfort is significantly relevant to human's quality of life. Thus, it has been frequently studied by investigators. This study explored people's thermal responses to environments and the subjective factors that might affect thermal comforts with respect to two urban parks in Xindu, a satellite city in the Chengdu Plain (CDP). CDP is located at the southwest of China, which has a subtropical climate. The environment from each of the two parks was studied using current micrometeorology and hoped-for landscape changes (tree canopies, artificial canopies, non-canopying plants, and water surfaces); subjective factors included gender, age, body mass index, clothing isolation, and physical activities. It was found that canopies were the most preferred objective cooling elements, while individual thermal perceptions varied subjectively by age. The highest proportion of volunteers voted for tree canopies as their favourite thermal adjusting element. It was observed that those aged above 55 showed low thermal sensitivity. The remaining group's neutral temperatures (indicated by physiologically equivalent temperature, PET) were close, at approximately 25 °C. This study provides significant direction for future urban planning and landscape design.

PLGA nanoparticle-reinforced supramolecular peptide hydrogels for local delivery of multiple drugs with enhanced synergism.

Localized drug delivery offers great therapeutic efficacy at local tissues while avoiding the systemic toxicity of drugs. Yet it demands the development of structurally-stable drug carrier systems with excellent injectability, as well as the capability to facilitate controlled release of multiple drugs. Herein, we describe the design and synthesis of a supramolecular hydrogel (Cis/Peptide@NP/Irino) for the combined delivery of cisplatin (Cis) and irinotecan (Irino). The self-assembled hydrogel consisted of an inner phase of irinotecan-loaded PLGA nanoparticles (NP/Irino) and an outer phase of cisplatin-loaded peptide nanofibers (Cis/Peptide). Through the structural reinforcement of PLGA nanoparticles, the Cis/Peptide@NP/Irino hydrogel exhibited better mechanical properties than Cis/Peptide or Peptide hydrogels. With excellent shear-thinning properties, it facilitated the development of a localized drug delivery system with an improved retention time in vivo. The hydrogel incorporated two anticancer drugs, Cis and Irino, at the Peptide and PLGA domains, respectively, and exhibited a faster release of Cis prior to the continuous release of Irino in vitro. Furthermore, the Cis/Peptide@NP/Irino formulation showed a better inhibition efficacy against the proliferation of cancerous A549 cells, with the synergism of Cis and Irino exceeding that of the simple solution mixtures, which was plausibly due to the enhanced cellular uptake of drugs through endocytosis. We believe that structurally-stable supramolecular hydrogels show great promise in the local delivery of various drug combinations for cancer therapy.

Mechanistic studies of HF/BF3-catalyzed anthracene polymerization to prepare mesophase pitch.

CONTEXT: The mesophase pitch prepared by acid catalytic method typically had the advantages of low softening point and high solubility. To fully understand the mechanism of acid-catalyzed reactions and gain a deeper understanding of the microstructure of mesophase pitch, this article studied the mechanism of hydrofluoride/boron trifluoride (HF/BF3)-catalyzed anthracene using molecular simulation methods. The results showed that there might be two types of carbocations present in the system: classical and non-classical carbocations, and five reactions might occur, protonation reaction, chain elongation reaction, intramolecular cyclization reaction, deprotonation reaction, and dehydrogenation reaction. Classical carbocations acted as reactive intermediates in the chain elongation reaction and intramolecular cyclization reaction. When anthracene occurred chain elongation reactions with carbocations to form polymers, the generation of the tetramer required lager energy barriers than that of the dimer and trimer. The stiffness and flatness of molecules could be increased via intramolecular cyclization reactions. The polymers of anthracene might also occurred dehydrogenation reactions when the non-classical carbocations played the role of reactive intermediates. The dehydrogenation reactions required large energy barriers, which might be the reason for the product having a high aliphatic hydrogen content. METHOD: The Materials Studio (MS) 2020 software was used to complete the simulation. The atomic charge distribution calculation and the structure optimization of molecules were carried out using the B3LYP functional and DNP basis. The DFT-D (TS) dispersion corrections were added to calculate the dispersion interaction between aromatic molecules. The complete LST/QST method was used to search the transition states and calculate the reaction energy barrier.

Nanofibrillar peptide hydrogels for self-delivery of lonidamine and synergistic photodynamic therapy.

The use of lonidamine (LND) in photodynamic therapy (PDT) provides a viable approach to develop low-dose PDT modules with high efficacy, for LND potentiates cytotoxicity of photosensitizers through dysregulation of mitochondrial function. Yet, the efficacy of LND is restricted by its low accumulation in cancer cells, especially in the mitochondrial compartments. To address the problem, we design an LND-derived self-assembling peptide molecule (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. The targeted cellular delivery of LND-K gives higher efficacy in ablation of mitochondrial function in melanoma cells A375, as compared to free LND or the control molecule that lacks mitochondria-targeting moieties. To integrate LND-K in a typical PDT module, we develop a nanofibrillar hydrogel system through co-assembly of LND-K and TPPS4, an anionic photosensitizer that forms tight electrostatic interactions with cationic residues of LND-K. Notably, hydrogel formulation of LND-K/TPPS4 facilitates slow release of TPPS4 over 14 days in vitro, and displays a longer retention time than aqueous solution of TPPS4in vivo. By integrating a mitochondria-targeted molecule (LND-K) in a typical PDT module, we achieve synergistic killing of A375 cells with dual drugs, where LND-K not only serves as a chemotherapeutic drug, but also potentiates the cytotoxicities of TPPS4 toward A375 cells in vitro and in vivo. The peptide-based drug self-delivery system promises the development of efficacious combination treatments against cancer, that integrate cell sensitization with existing anticancer modules (e.g., chemotherapy and PDT) for enhanced therapeutic efficacy. STATEMENT OF SIGNIFICANCE: This study reports the design and synthesis of a lonidamine (LND)-derived self-assembling peptide (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. Under the precision guidance of a mitochondria-targeting sequence, LND-K-containing nanofibers target mitochondria and ablate mitochondrial functions. On one hand, the targeted delivery of LND-K reduces cell viabilities through a chemotherapy route; on the other hand, LND-K sensitizes cancer cells for subsequent PDT treatment with enhanced efficacy, which is mediated by induction of ROS, loss of mitochondrial membrane potential, and decrease of cellular ATP level. We believe that the design of mitochondria-targeted drug delivery systems with a self-assembling molecule provides a new approach to potentiate cytotoxicity of photosensitizers in a low-dose PDT module.

Corrosion protection properties of tetraphenylethylene-based inhibitors toward carbon steel in acidic medium.

Four novel corrosion inhibitors (1, 2, 3 and 4) integrating different tetraphenylethylene (TPE) cations and thiocyanate (SCN-) anions were developed. Weight-loss and electrochemical measurements were employed to assess their protective properties toward carbon steel in 0.5 M H2SO4, revealing them as effective corrosion inhibitors in the order of 3 > 4 > 2 > 1, with the inhibition efficiencies of 2, 3 and 4 all exceeding 97%. The inhibitory effect could be attributed to hard and soft acids and bases theory and the synergistic effect of the charged ingredients. The efficiency trend of the corrosion inhibition, as well as inhibition mechanism, was verified by multi-scaled theoretical simulations combined with grand canonical Monte Carlo and molecular dynamic methods.

Enzymatic Synthesis of Peptide Nanofibers for Self-Delivery of Indomethacin and Tyroservatide in Cancer Therapy.

Non-steroidal anti-inflammatory drugs (NSAIDs) have drawn considerable attention in the field of cancer treatment, yet these drugs display limited potency and selectivity against cancer cells. To address these problems, we designed a peptide-based self-delivery system [Indomethacin-Phe-Phe-Tyr (H2PO3)-Ser-Val, IDM-FFpYSV] that combines an NSAID molecule (indomethacin, or IDM) and a segment of anticancer tripeptide (tyroservatide, or YSV). IDM-FFpYSV is capable of self-assembling in an aqueous solution to afford nanofibrillar hydrogels under the catalysis of alkaline phosphatases (ALPs), which are overexpressed on the plasma membrane of cancer cells. The IDM-FFpYSV + ALP hydrogel displays a continuous release profile of peptide drugs, whereas a solution mixture of pure drugs (IDM-OH + pYSV + ALP) shows burst release of drug moieties. The treatment of IDM-FFpYSV selectively inhibits the proliferation of HeLa cells in vitro, with precise regulations of intracellular targeting proteins (COX-2 and AC-H3). The enhanced potency and selectivity of IDM-FFpYSV are found to be attributed to enhanced cellular uptake of peptide drugs, which involves a caveolae-mediated endocytosis pathway. Furthermore, intravenous administration of the IDM-FFpYSV formulation significantly inhibits the tumor growth in a HeLa-xenografted mouse model, whereas treatment of solution mixtures of pure drugs (IDM-OH + pYSV) fails to do so. Taken together, the study provides a viable strategy to augment anticancer efficacies of self-delivery system through molecular integration of multiple anticancer elements with an enzyme-instructed self-assembly process.

Unmet needs as indicator of improving chronic care delivery system in China.

In 2009, China strengthened its public health service system. Since then, the country has made remarkable achievements in community-based chronic disease prevention and control; however, certain groups still have unmet needs. During 2019 to 2029, China will consolidate the top-level design of its medical health system. During this period, the coordination of department policies, improvement of service delivery mechanisms, building an integrated health service system, and other issues will be highlighted. This study will provide a basis for designing China's chronic disease prevention and control system during the next stage of development. We will consider the unmet needs of patients with chronic diseases as an indicator for remodeling the prediction system in combination with the elements and structural theories of complex health systems. In this article, we first introduce the definition and measurement methods of unmet needs. Second, we identify the existing unmet needs found among patients with chronic diseases with reference to the chronic disease prevention and control policies of China as well as current service items. Finally, we propose the design of community chronic disease service package for the next development stage based on unmet needs of patients with chronic diseases. We also provide suggestions for how to improve China's chronic care delivery system.

Effects of using different exposure data to estimate changes in premature mortality attributable to PM2.5 and O3 in China.

The assessment of premature mortality associated with the dramatic changes in fine particulate matter (PM2.5) and ozone (O3) has important scientific significance and provides valuable information for future emission control strategies. Exposure data are particularly vital but may cause great uncertainty in health burden assessments. This study, for the first time, used six methods to generate the concentration data of PM2.5 and O3 in China between 2014 and 2018, and then quantified the changes in premature mortality due to PM2.5 and O3 using the Environmental Benefits Mapping and Analysis Program-Community Edition (BenMAP-CE) model. The results show that PM2.5-related premature mortality in China decreases by 263 (95% confidence interval (CI95): 142-159) to 308 (CI95: 213-241) thousands from 2014 to 2018 by using different concentration data, while O3-related premature mortality increases by 67 (CI95: 26-104) to 103 (CI95: 40-163) thousands. The estimated mean changes are up to 40% different for the PM2.5-related mortality, and up to 30% for the O3-related mortality if different exposure data are chosen. The most significant difference due to the exposure data is found in the areas with a population density of around 103 people/km2, mostly located in Central China, for both PM2.5 and O3. Our results demonstrate that the exposure data source significantly affects mortality estimations and should thus be carefully considered in health burden assessments.

Impacts of model resolution on predictions of air quality and associated health exposure in Nanjing, China.

Air quality models have been used in health studies to provide spatial and temporal information of various air pollutants. Model resolution is an important factor affecting the accuracy of exposure assessment using model predictions. In this study, the WRF/CMAQ model system was applied to quantitatively estimate the impacts of the model resolution on the predictions of air quality and associated health exposure in Nanjing, China in 2016. Air quality was simulated with a grid resolution of 1, 4, 12, and 36 km respectively. Predictions with 1 or 4 km resolution are slightly better for particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) and its compositions and predictions with 12 km are slightly better for daily 8-h maximum ozone (O3-8 h). Model resolution does not significantly improve predictions for PM2.5 and O3-8 h in Nanjing, however, the spatial distributions of PM2.5 and O3-8 h are better captured with finer resolutions. Population weighted concentrations (PWCs) of PM2.5 with different model resolutions are similar to the average of observations, but PWCs of O3-8 h with all resolutions are obviously larger than the observations, indicating that the current sites may well represent the population exposure to PM2.5, but under-estimate the exposure to O3. Model resolution results in about 6% in the estimated premature mortality due to exposure to PM2.5 but more than 20% difference in premature mortality due to exposure to O3. Future studies are needed to evaluate the impacts of the resolution on the exposure of PM2.5 compositions in the city scale when PM2.5 composition measurements available at multiple sites.