Serum untargeted lipidomics by UHPLC-ESI-HRMS aids the biomarker discovery of colorectal adenoma.

BACKGROUND: Colorectal adenoma (CA) is an important precancerous lesion and early screening target of colorectal cancer (CRC). Lipids with numerous physiological functions are proved to be involved in the development of CRC. However, there is no lipidomic study with large-scale serum samples on diagnostic biomarkers for CA. METHODS: The serum lipidomics of CA patients (n = 50) and normal control (NR) (n = 50) was performed by ultra high performance liquid chromatography-high resolution mass spectrometry with electrospray ionization (UHPLC-ESI-HRMS). Univariate and multivariate statistical analyses were utilized to screen the differential lipids between groups, and combining the constituent ratio analysis and diagnostic efficiency evaluation by receiver operating characteristic (ROC) curve disclosed the potential mechanism and biomarkers for CA. RESULTS: There were obvious differences in serum lipid profiles between CA and NR groups. Totally, 79 differential lipids were selected by criterion of P < 0.05 and fold change > 1.5 or < 0.67. Triacylglycerols (TAGs) and phosphatidylcholines (PCs) were the major differential lipids with ratio > 60%, indicating these two lipid metabolic pathways showed evident disequilibrium, which could contribute to CA formation. Of them, 12 differential lipids had good diagnostic ability as candidate biomarkers for CA (AUC ≥ 0.900) by ROC analysis. CONCLUSIONS: To our knowledge, this is the first attempt to profile serum lipidomics and explore lipid biomarkers of CA to help early screening of CRC. 12 differential lipids are obtained to act as potential diagnostic markers of CA. PCs and fatty acids were the main dysregulated biomarkers for CA in serum.

Catalyst-free synthesis of novel dimeric ß-carboline derivatives via an unexpected [2 + 2 + 2] annulation.

We report here an unexpected catalyst-free [2 + 2 + 2] annulation reaction which allows access to novel complex dimeric ß-carboline derivatives in a single step. Various substituted ynones could react with dihydro-ß-carboline imines to deliver interesting [2 + 2 + 2] annulation products in moderate to good yields. Alkynoates can also be tolerated in this system.

Stereoselective synthesis of enamino ketones through an aza-Michael/hydrolysis cascade reaction.

We have developed a mild, convenient and efficient synthesis of highly functionalized (Z)-ß-enamino ketones from readily available 3,4-dihydroisoquinoline imines and ynones through an aza-Michael/hydrolysis cascade reaction. This method is also suitable for the preparation of (Z)-ß-enamino esters using alkynoates as starting materials. Complex fully substituted pyrroles can be constructed from the obtained (Z)-ß-enamino ketones. It is an attractive alternative approach for the preparation of highly functionalized enamino ketones, esters and pyrroles.

[An analysis of occupational hazard in manufacturing industry in Guangzhou, China, in 2013].

OBJECTIVE: To provide data for the occupational health supervision by analyzing the occupational health status in manufacturing industry in Guangzhou, China. METHODS: The occupational health investigation was performed in 280 enterprises randomly selected from 8 industries based on industry stratification. According to the occupational health standards, 198 out of the 280 enterprises were supervised and monitored. Sample testing was performed in 3~5 workplaces where workers were exposed to the highest concentration/intensity of occupational hazard for the longest time. Comparative analyses of the overproof rates of hazard were performed among enterprises, workplaces, and testing items from different industries. RESULTS: The concentrations of occupational hazard in 42.93% (85/198) of enterprises and 22.96% (200/871) of workplaces were above the limit concentration. The most severe hazards were the noises in shipbuilding and wooden furniture industries and the welding fumes in shipbuilding industry. Less than 30% of enterprises were able to provide occupational health examination and periodic test reports of occupational hazard in workplaces. The rate of the workers with abnormal occupational health examination results and the need for reexamination reached 6.63% (832/12 549), and they were mostly from shipbuilding, wooden furniture, and chemical industries. CONCLUSION: The occupational health supervision should be strengthened in enterprises, and hazard from noises and dusts should be selectively controlled or reduced. The publication of relevant data and information of occupational health in enterprises should be promoted to enhance social supervision.

Combining bioinformatics and multiomics strategies to investigate the key microbiota and active components of Liupao tea ameliorating hyperlipidemia.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperlipidemia as a major health issue has attracted much public attention. As a geographical indication product of China, Liupao tea (LPT) is a typical representative of traditional Chinese dark tea that has shown good potential in regulating glucose and lipid metabolism. LPT has important medicinal value in hyperlipidemia prevention. However, the active ingredients and metabolic mechanisms by which LPT alleviates hyperlipidemia remain unclear. AIM OF THE STUDY: This study aimed to systematically investigate the metabolic mechanisms and active ingredients of LPT extract in alleviating hyperlipidemia. MATERIALS AND METHODS: Firstly, we developed a mouse model of hyperlipidemia to study the pharmacodynamics of LPT. Subsequently, network pharmacology and molecular docking were performed to predict the potential key active ingredients and core targets of LPT against hyperlipidemia. LC-MS/MS was used to validate the identity of key active ingredients in LPT with chemical standards. Finally, the effect and metabolic mechanisms of LPT extract in alleviating hyperlipidemia were investigated by integrating metabolomic, lipidomic, and gut microbiome analyses. RESULTS: Results showed that LPT extract effectively improved hyperlipidemia by suppressing weight gain, remedying dysregulation of glucose and lipid metabolism, and reducing hepatic damage. Network pharmacology analysis and molecular docking suggested that four potential active ingredients and seven potential core targets were closely associated with roles for hyperlipidemia treatment. Ellagic acid, catechin, and naringenin were considered to be the key active ingredients of LPT alleviating hyperlipidemia. Additionally, LPT extract modulated the mRNA expression levels of Fxr, Cyp7a1, Cyp8b1, and Cyp27a1 associated with bile acid (BA) metabolism, mitigated the disturbances of BA and glycerophospholipid (GP) metabolism in hyperlipidemia mice. Combining fecal microbiota transplantation and correlation analysis, LPT extract effectively improved species diversity and abundance of gut microbiota, particularly the BA and GP metabolism-related gut microbiota, in the hyperlipidemia mice. CONCLUSIONS: LPT extract ameliorated hyperlipidemia by modulating GP and BA metabolism by regulating Lactobacillus and Dubosiella, thereby alleviating hyperlipidemia. Three active ingredients of LPT served as the key factors in exerting an improvement on hyperlipidemia. These findings provide new insights into the active ingredients and metabolic mechanisms of LPT in improving hyperlipidemia, suggesting that LPT can be used to prevent and therapeutic hyperlipidemia.

Liposome-anchored mesenchymal stem cells for radiation pneumonia/fibrosis treatment.

The effectiveness of mesenchymal stem cells (MSCs) on inflammation-related disease is limited and the pharmaceutical preparation that was used to enhance the efficacy of MSCs cannot reach the diseased tissue in large quantities. Herein, antioxidant liposome (Lipo-OPC) is designed to anchor onto the surface of MSCs membrane via click chemical reaction (MSC-Lipo-OPC) without affecting the viability and physiological characteristics of MSCs, thus allowing efficient accumulation of MSC-Lipo-OPC in X-ray irradiated lung sites. More importantly, MSC-Lipo-OPC promotes the change of the quantity and polarity of innate immunocytes, mainly including neutrophils, macrophages and Tregs, in favor of anti-inflammatory, finally preventing the formation of radioactive pulmonary fibrosis. Therefore, it could enhance the treatment outcome of both of MSCs and drugs to radiation-induced lung injury via modifying the drug-loaded nanoparticle on the surface of MSCs membrane, further promoting the application of MSCs in radiation damage and protection.

UHPLC-HRMS-based serum untargeted lipidomics: Phosphatidylcholines and sphingomyelins are the main disturbed lipid markers to distinguish colorectal advanced adenoma from cancer.

Colorectal advanced adenoma (CAA) is a key precancerous lesion of colorectal cancer (CRC), and early diagnosis can lessen CRC morbidity and mortality. Although abnormal lipid metabolism is associated with the development of CRC, there are no studies on the biomarkers and mechanism of lipid metabolism linked to CAA carcinogenesis. Hence, we performed a lipidomics study of serum samples from 46 CAA, and 50 CRC patients by the ultra high-performance liquid chromatography tandem high resolution mass spectrometry (UHPLC-HRMS) in both electrospray ionization (ESI) modes. Differential lipids were selected by univariate and multivariate statistics analysis, and their diagnostic performance was evaluated using a receiver operating characteristic curve (ROC) analysis. Combining P < 0.05 and variable importance in projection (VIP) > 1, 59 differential lipids were obtained totally. Ten of them showed good discriminant ability for CAA and CRC (AUC > 0.900). Especially, the lipid panel consisting of PC 44:5, PC 35:6e, and SM d40:3 showed the highest selection frequency and outperformed (AUC = 0.952). Additionally, phosphatidylcholine (PC) and sphingomyelin (SM) were the main differential and high-performance lipids. In short, this is the first study to explore the biomarkers and mechanism for CAA-CRC sequence with large-scale serum lipidomics. The findings should provide valuable reference and new clues for the development of diagnostic and therapeutic strategies of CRC.

Nattokinase-Mediated Regulation of Tumor Physical Microenvironment to Enhance Chemotherapy, Radiotherapy, and CAR-T Therapy of Solid Tumor.

The therapy of solid tumors is always hampered by the intrinsic tumor physical microenvironment (TPME) featured with compact and rigid extracellular matrix (ECM) microstructures. Herein, we introduce nattokinase (NKase), a thrombolytic healthcare drug, to comprehensively regulate the TPME for versatile enhancement of various therapy modalities. Intratumoral injection of NKase not only degrades the major ECM component fibronectin but also inhibits cancer-associated fibroblasts (CAFs) in generating fibrosis, resulting in decreased tumor stiffness, enhanced perfusion, and hypoxia alleviation. The NKase-mediated regulation of the TPME significantly promotes the tumoral accumulation of therapeutic agents, leading to efficient chemotherapy without inducing side effects. Additionally, the enhancement of tumor radiotherapy based on radiosensitizers was also achieved by the pretreatment of intratumorally injected NKase, which could be ascribed to the elevated oxygen saturation level in NKase-treated tumors. Moreover, a xenografted human breast MDB-MA-231 tumor model is established to evaluate the influence of NKase on chimeric antigen receptor (CAR)-T cell therapy, illustrating that the pretreatment of NKase could boost the infiltration of CAR-T cells into tumors and thus be a benefit for tumor inhibition. These findings demonstrate the great promise of the NKase-regulated TPME as a translational strategy for universal enhancement of therapeutic efficacy in solid tumors by various treatments.

Toward high-performance refractive index sensor using single Au nanoplate-on-mirror nanocavity.

Refractive index sensors based on the localized surface plasmon resonance (LSPR) have emerged as powerful tools in various chemosensing and biosensing applications. However, owing to their limited decay length and strong radiation damping, LSPR sensors always suffer from low sensitivity and small figure of merit (FOM). Here, we fabricate a plasmonic nanocavity sensor consisting of a hexagonal Au nanoplate positioned over an ultrasmooth Au film. The strong coupling between the nanoplate and the lower metal film allows for the formation of a plasmonic gap mode that enhances the interaction of the local field with the ambient glycerol solution to increase the sensitivity. Meanwhile, the plasmonic gap mode has a trait of an antiphase charge oscillation in the gap region, imparting a strongly reduced radiative damping and a subsequently promoted FOM. The performance of our proposed refractive index sensor is further boosted by decreasing the gap size of the nanocavity, yielding an outstanding FOM of 11.2 RIU-1 that is the highest yet reported for LSPR sensing in a single nanostructure.

UHPLC-HRMS-based serum lipisdomics reveals novel biomarkers to assist in the discrimination between colorectal adenoma and cancer.

The development of a colorectal adenoma (CA) into carcinoma (CRC) is a long and stealthy process. There remains a lack of reliable biomarkers to distinguish CA from CRC. To effectively explore underlying molecular mechanisms and identify novel lipid biomarkers promising for early diagnosis of CRC, an ultrahigh-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS) method was employed to comprehensively measure lipid species in human serum samples of patients with CA and CRC. Results showed significant differences in serum lipid profiles between CA and CRC groups, and 85 differential lipid species (P < 0.05 and fold change > 1.50 or < 0.67) were discovered. These significantly altered lipid species were mainly involved in fatty acid (FA), phosphatidylcholine (PC), and triacylglycerol (TAG) metabolism with the constituent ratio > 63.50%. After performance evaluation by the receiver operating characteristic (ROC) curve analysis, seven lipid species were ultimately proposed as potential biomarkers with the area under the curve (AUC) > 0.800. Of particular value, a lipid panel containing docosanamide, SM d36:0, PC 36:1e, and triheptanoin was selected as a composite candidate biomarker with excellent performance (AUC = 0.971), and the highest selected frequency to distinguish patients with CA from patients with CRC based on the support vector machine (SVM) classification model. To our knowledge, this study was the first to undertake a lipidomics profile using serum intended to identify screening lipid biomarkers to discriminate between CA and CRC. The lipid panel could potentially serve as a composite biomarker aiding the early diagnosis of CRC. Metabolic dysregulation of FAs, PCs, and TAGs seems likely involved in malignant transformation of CA, which hopefully will provide new clues to understand its underlying mechanism.

Metabolic Homeostasis-Regulated Nanoparticles for Antibody-Independent Cancer Radio-Immunotherapy.

The special metabolic traits of cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are promising targets for developing novel cancer therapy strategies, especially the glycolysis and mitochondrial energy metabolism. However, therapies targeting a singular metabolic pathway are always counteracted by the metabolic reprogramming of cancer, resulting in unsatisfactory therapeutic effect. Herein, this work employs poly(ethylene glycol)-coated (PEGylated) liposomes as the drug delivery system for both mannose and levamisole hydrochloride to simultaneously inhibit glycolysis and restrain mitochondrial energy metabolism and thus inhibit tumor growth. In combination with radiotherapy, the liposomes can not only modulate the immunosuppressive TME by cellular metabolism regulation to achieve potent therapeutic effect for local tumors, but also suppress the M2 macrophage proliferation triggered by X-ray irradiation and thus enhance the immune response to inhibit metastatic lesions. In brief, this work provides a new therapeutic strategy targeting the special metabolic traits of cancer cells and immunosuppressive TAMs to enhance the abscopal effect of radiotherapy for cancer.

Radioactive nano-oxygen generator enhance anti-tumor radio-immunotherapy by regulating tumor microenvironment and reducing proliferation.

Oxygen (O2) is the substance irreplaceable of the body's metabolism, which is not only the primary consumable of life activities, but also provide the input energy for the whole body. Importantly, the O2 supply will act as an important role in the field of tumor theranostics. Herein, we successfully construct a radioactive nano-oxygen generator (177Lu-APPs-PEG) with superior properties, which can not only realize a high-performance radioisotope labelling, but also unfreeze the limitation of O2 dependence of internal radioisotope therapy (IRT). More importantly, such nano-oxygen generator also can effectively enhance the infiltration of cytotoxic T cells (CTLs) in distant tumors and reduce tumor metastasis. Meanwhile, the increase of O2 in tumor-site can affect the metabolism of tumor cells and regulatory T (Treg) cells to reduce cancer cells proliferation by down-regulating the expression of hypoxia-inducible factor-1α (HIF-1α) and c-Myc. In short, the strategies we designed provide a new idea for the influence of nano-enzymes on tumor metabolism and immunotherapy.

Biocompatible nanomicelles for sensitive detection and photodynamic therapy of early-stage cancer.

The lack of sensitive detection techniques and agents for early-stage tumors, which are characterized by small size, juvenile blood vessels and scarce secreted markers, has hampered timely cancer therapy and human well-being. Herein, the natural product pyropheophorbide-a (PPa) and FDA-approved Pluronic F127 are organized to develop F127-PPa nanomicelles with favorable size, red-shifted fluorescence and decent biocompatibility. After intravenous (i.v.) injection, the F127-PPa nanomicelles could not only accurately identify early-stage xenografted tumors, but also sensitively detect cancer metastasis in lungs through near-infrared (NIR) fluorescence imaging. The fluorescence signals are consistent with radionuclide imaging, photoacoustic (PA) imaging and bioluminescence imaging of tumors, consolidating the reliability of using F127-PPa nanomicelles for sensitive cancer diagnosis in a non-invasive and low-cost manner. Moreover, the fluorescence intensity of small tumors is linearly correlated with the tumoral mass ranging from 10 to 120 mg with a fluorescence coefficient of 4.5 × 107 mg-1. Under the guidance of multimodal imaging, the tumors could be thoroughly eradicated by F127-PPa under laser irradiation due to efficient reactive oxygen species (ROS) generation. These findings may provide clinically translatable agents and strategies for sensitive diagnosis of early-stage tumors and timely cancer therapy.

Thermal Stability Analysis of Lithium-Ion Battery Electrolytes Based on Lithium Bis(trifluoromethanesulfonyl)imide-Lithium Difluoro(oxalato)Borate Dual-Salt.

Lithium-ion batteries with conventional LiPF6 carbonate electrolytes are prone to failure at high temperature. In this work, the thermal stability of a dual-salt electrolyte of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and lithium difluoro(oxalato)borate (LiODFB) in carbonate solvents was analyzed by accelerated rate calorimetry (ARC) and differential scanning calorimetry (DSC). LiTFSI-LiODFB dual-salt carbonate electrolyte decomposed when the temperature exceeded 138.5 °C in the DSC test and decomposed at 271.0 °C in the ARC test. The former is the onset decomposition temperature of the solvents in the electrolyte, and the latter is the LiTFSI-LiODFB dual salts. Flynn-Wall-Ozawa, Starink, and autocatalytic models were applied to determine pyrolysis kinetic parameters. The average apparent activation energy of the dual-salt electrolyte was 53.25 kJ/mol. According to the various model fitting, the thermal decomposition process of the dual-salt electrolyte followed the autocatalytic model. The results showed that the LiTFSI-LiODFB dual-salt electrolyte is significantly better than the LiPF6 electrolyte in terms of thermal stability.

Thermal Effect and Mechanism Analysis of Flame-Retardant Modified Polymer Electrolyte for Lithium-Ion Battery.

In recent years, the prosperous electric vehicle industry has contributed to the rapid development of lithium-ion batteries. However, the increase in the energy density of lithium-ion batteries has also created more pressing safety concerns. The emergence of a new flame-retardant material with the additive ethoxy (pentafluoro) cyclotriphosphazene can ameliorate the performance of lithium-ion batteries while ensuring their safety. The present study proposes a new polymer composite flame-retardant electrolyte and adopts differential scanning calorimetry (DSC) and accelerating rate calorimetry to investigate its thermal effect. The study found that the heating rate is positively correlated with the onset temperature, peak temperature, and endset temperature of the endothermic peak. The flame-retardant modified polymer electrolyte for new lithium-ion batteries has better thermal stability than traditional lithium-ion battery electrolytes. Three non-isothermal methods (Kissinger; Kissinger-Akahira-Sunose; and Flynn-Wall-Ozawa) were also used to calculate the kinetic parameters based on the DSC experimental data. The apparent activation energy results of the three non-isothermal methods were averaged as 54.16 kJ/mol. The research results can provide valuable references for the selection and preparation of flame-retardant additives in lithium-ion batteries.

X-rays-optimized delivery of radiolabeled albumin for cancer theranostics.

Exploiting the specific biological behaviors of the metabolizable nano-drugs assisted by X-rays exposure will be benefit for the optimization of radiotherapy-based combination therapy. Herein, Human serum albumin (HSA) nanoparticle, a familiar and metabolizable nanomaterial, is selected to investigate the changes of tumor accumulation and retention under X-rays exposure. Caveolin-1, an important protein which has positive correlation with cell uptake of nanomaterials, is expressed increasingly under X-rays exposure, resulting the enhanced cell uptake and prolonged tumor retention of HSA nanoparticles. After being labeled by radioactive iodine-125, HSA could be used for SPECT/CT imaging of mice. Moreover, it discovered that 125I-HSA nanoparticles possess much longer-time retention time in pre-irradiated tumor than that of controlled tumor. Using this strategy, the therapeutic efficiency of 131I-HSA injected mice after irradiating their tumors by X-rays is better than that of opposite sequence treated mice. In order to further improve the targeting ability of HSA, GNQEQVSPLTLLKXC peptide (A15) is conjugated to HSA nanoparticles for targeting the thrombosis in the tumor tissue triggered by X-rays exposure, realizing the high tumor accumulation of 131I-HSA assisted by X-rays exposure. Therefore, taking advantage of the increased expression of Caveolin-1 and the induced thrombosis under X-rays exposure, we optimized the delivery of radiolabeled HSA via enhancing the cell uptake and prolonging tumor retention of HSA for cancer combination therapy. Our work make contribution to guide the clinical albumin based combination therapy.

Bacteria-triggered tumor-specific thrombosis to enable potent photothermal immunotherapy of cancer.

We discovered that attenuated Salmonella after intravenous injection would proliferate within various types of solid tumors but show rapid clearance in normal organs, without rendering notable toxicity. Bacteria-induced inflammation would trigger thrombosis in the infected tumors by destroying tumor blood vessels. Six types of tested tumors would all turn into darkened color with strong near-infrared absorbance, as observed by photoacoustic imaging. Under laser irradiation, those bacterial-infected tumors would be effectively ablated. Because of the immune-stimulation function, such bacteria-based photothermal therapy (PTT) would subsequently trigger antitumor immune responses, which could be further enhanced by immune checkpoint blockade to effectively suppress the growth of abscopal tumors. A robust immune memory effect to reject rechallenged tumors is also observed after bacteria-based PTT. Our work demonstrates that bacteria by themselves could act as a tumor-specific PTT agent to enable photoimmunotherapy cancer therapy to inhibit tumor metastasis and recurrence.

Prevalence and risk factors of mental distress in China during the outbreak of COVID-19: A national cross-sectional survey.

OBJECTIVE: As a result of the pandemic of COVID-19, the public have been experiencing psychological distress. However, the prevalence of psychological distress during the COVID-19 pandemic remains unknown. Our objective was to evaluate the prevalence of psychological distress during COVID-19 outbreak and their risk factors, especially their internal paths and causality. METHODS: A nationwide cross-sectional survey of the prevalence of mental disorders was conducted. We used Hospital Anxiety and Depression Scale (HADS) to estimate the prevalence of anxiety and depression. The internal paths and the causality of the psychological health were analyzed using a structural equation modeling (SEM) approach. RESULTS: A total of 24,789 respondents completed the survey. We found that the overall prevalence of anxiety, depression, combination of anxiety, and depression were 51.6% (95% CI: 51.0-52.2), 47.5% (95% CI: 46.9-48.1), and 24.5% (95% CI: 24.0-25.0), respectively. The risk of psychological disorders in men was higher than that in women. The status of psychological health was different across different age groups, education levels, occupations, and income levels. The SEM analysis revealed that inadequate material supplies, low income, low education, lack of knowledge or confidence of the epidemic, and lack of exercise are major risk factors for psychological distress. CONCLUSIONS: The evidence from this survey poses serious challenges related to the high prevalence of psychological distress, but also offers strategies to deal with the mental health problems caused by the COVID-19 pandemic.

Near-Infrared Light-Responsive Nitric Oxide Delivery Platform for Enhanced Radioimmunotherapy.

Radiotherapy (RT) is a widely used way for cancer treatment. However, the efficiency of RT may come with various challenges such as low specificity, limitation by resistance, high dose and so on. Nitric oxide (NO) is known a very effective radiosensitizer of hypoxic tumor. However, NO cannot circulate in body with high concentration. Herein, an NIR light-responsive NO delivery system is developed for controlled and precisely release of NO to hypoxic tumors during radiotherapy. Tert-Butyl nitrite, which is an efficient NO source, is coupled to Ag2S quantum dots (QDs). NO could be generated and released from the Ag2S QDs effectively under the NIR irradiation due to the thermal effect. In addition, Ag is also a type of heavy metal that can benefit the RT therapy. We demonstrate that Ag2S NO delivery platforms remarkably maximize radiotherapy effects to inhibit tumor growth in CT26 tumor model. Furthermore, immunosuppressive tumor microenvironment is improved by our NO delivery system, significantly enhancing the anti-PD-L1 immune checkpoint blockade therapy. 100% survival rate is achieved by the radio-immune combined therapy strategy based on the Ag2S NO delivery platforms. Our results suggest the promise of Ag2S NO delivery platforms for multifunctional cancer radioimmunotherapy.