DNA-functionalized metal or metal-containing nanoparticles for biological applications.

The conjugation of DNA molecules with metal or metal-containing nanoparticles (M/MC NPs) has resulted in a number of new hybrid materials, enabling a diverse range of novel biological applications in nanomaterial assembly, biosensor development, and drug/gene delivery. In such materials, the molecular recognition, gene therapeutic, and structure-directing functions of DNA molecules are coupled with M/MC NPs. In turn, the M/MC NPs have optical, catalytic, pore structure, or photodynamic/photothermal properties, which are beneficial for sensing, theranostic, and drug loading applications. This review focuses on the different DNA functionalization protocols available for M/MC NPs, including gold NPs, upconversion NPs, metal-organic frameworks, metal oxide NPs and quantum dots. The biological applications of DNA-functionalized M/MC NPs in the treatment or diagnosis of cancers are discussed in detail.

Pixelated Filter Array for On-Chip Polarized Spectral Detection.

On-chip multi-dimensional detection systems integrating pixelated polarization and spectral filter arrays are the latest trend in optical detection instruments, showing broad application potential for diagnostic medical imaging and remote sensing. However, thin-film or microstructure-based filter arrays typically have a trade-off between the detection dimension, optical efficiency, and spectral resolution. Here, we demonstrate novel on-chip integrated polarization spectral detection filter arrays consisting of metasurfaces and multilayer films. The metasurfaces with two nanopillars in one supercell are designed to modulate the Jones matrix for polarization selection. The angle of diffraction of the metasurfaces and the optical Fabry-Perot (FP) cavities determine the spectrum's center wavelength. The polarization spectral filter arrays are placed on top of the CMOS sensor; each array corresponds to one pixel, resulting in high spectral resolution and optical efficiency in the selected polarization state. To verify the methodology, we designed nine-channel polarized spectral filter arrays in a wavelength range of 1350 nm to 1550 nm for transverse electric (TE) linear polarization. The array has a 10 nm balanced spectral resolution and average peak transmission efficiency of over 75%, which is maintained by utilizing lossless dielectric material. The proposed array can be fabricated using overlay e-beam lithography, and the process is CMOS-compatible. The proposed array enables broader applications of in situ on-chip polarization spectral detection with high efficiency and spectral resolution, as well as in vivo imaging systems.

Predicting Atmospheric Particle Phase State Using an Explainable Machine Learning Approach Based on Particle Rebound Measurements.

The particle phase state plays a vital role in the gas-particle partitioning, multiphase reactions, ice nucleation activity, and particle growth in the atmosphere. However, the characterization of the atmospheric phase state remains challenging. Herein, based on measured aerosol chemical composition and ambient relative humidity (RH), a machine learning (ML) model with high accuracy (R2 = 0.952) and robustness (RMSE = 0.078) was developed to predict the particle rebound fraction, f, which is an indicator of the particle phase state. Using this ML model, the f of particles in the urban atmosphere was predicted based on seasonal average aerosol chemical composition and RH. Regardless of seasons, aerosols remain in the liquid state of mid-high latitude cities in the northern hemisphere and in the semisolid state over semiarid regions. In the East Asian megacities, the particles remain in the liquid state in spring and summer and in the semisolid state in other seasons. The effects of nitrate, which is becoming dominant in fine particles in several urban areas, on the particle phase state were evaluated. More nitrate led the particles to remain in the liquid state at an even lower RH. This study proposed a new approach to predict the particle phase state in the atmosphere based on RH and aerosol chemical composition.

Deep learning with explainability for characterizing age-related intrinsic differences in dynamic brain functional connectivity.

Although many deep learning models-based medical applications are performance-driven, i.e., accuracy-oriented, their explainability is more critical. This is especially the case with neuroimaging, where we are often interested in identifying biomarkers underlying brain development or disorders. Herein we propose an explainable deep learning approach by elucidating the information transmission mechanism between two layers of a deep network with a joint feature selection strategy that considers several shallow-layer explainable machine learning models and sparse learning of the deep network. At the end, we apply and validate the proposed approach to the analysis of dynamic brain functional connectivity (FC) from fMRI in a brain development study. Our approach can identify the differences within and between functional brain networks over age during development. The results indicate that the brain network transits from undifferentiated structures to more specialized and organized ones, and the information processing ability becomes more efficient as age increases. In addition, we detect two developmental patterns in the brain network: the FCs in regions related to visual and sound processing and mental regulation become weakened, while those between regions corresponding to emotional processing and cognitive activities are enhanced.

Ancient DNA reveals genetic admixture in China during tiger evolution.

The tiger (Panthera tigris) is a charismatic megafauna species that originated and diversified in Asia and probably experienced population contraction and expansion during the Pleistocene, resulting in low genetic diversity of modern tigers. However, little is known about patterns of genomic diversity in ancient populations. Here we generated whole-genome sequences from ancient or historical (100-10,000 yr old) specimens collected across mainland Asia, including a 10,600-yr-old Russian Far East specimen (RUSA21, 8× coverage) plus six ancient mitogenomes, 14 South China tigers (0.1-12×) and three Caspian tigers (4-8×). Admixture analysis showed that RUSA21 clustered within modern Northeast Asian phylogroups and partially derived from an extinct Late Pleistocene lineage. While some of the 8,000-10,000-yr-old Russian Far East mitogenomes are basal to all tigers, one 2,000-yr-old specimen resembles present Amur tigers. Phylogenomic analyses suggested that the Caspian tiger probably dispersed from an ancestral Northeast Asian population and experienced gene flow from southern Bengal tigers. Lastly, genome-wide monophyly supported the South China tiger as a distinct subspecies, albeit with mitochondrial paraphyly, hence resolving its longstanding taxonomic controversy. The distribution of mitochondrial haplogroups corroborated by biogeographical modelling suggested that Southwest China was a Late Pleistocene refugium for a relic basal lineage. As suitable habitat returned, admixture between divergent lineages of South China tigers took place in Eastern China, promoting the evolution of other northern subspecies. Altogether, our analysis of ancient genomes sheds light on the evolutionary history of tigers and supports the existence of nine modern subspecies.

Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.

OBJECTIVE: Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A+ TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. DESIGN: The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. RESULTS: MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. CONCLUSION: Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.

Relationship between heart rate variability and cognitive function in patients with enlarged perivascular space.

Objective: To explore the relationship between heart rate variability (HRV), the brain distribution of enlarged perivascular space (EPVS), and cognitive impairment in patients with EPVS. Materials and methods: The clinical and imaging data of 199 patients with EPVS were retrospectively analyzed. EPVS load in the basal ganglia (BG) and centrum semiovale (CS) regions were assessed using the Potter's method. Cognitive function was evaluated using the Montreal Cognitive Assessment Scale. A logistic regression model was used to analyze the relationship between HRV, the brain distribution of EPVS and cognitive function in patients with EPVS. A receiver operating characteristic curve was used to assess the predictive value of HRV for cognitive function in patients with EPVS. Results: Of the 199 patients, 27 and 42 presented with severe BG-EPVS and cognitive impairment, respectively. Significant differences were observed in the root mean square of successive differences of normal-normal (NN) intervals for period of interest (rMSSD), the percentage of adjacent NN intervals greater than 50 ms (PNN50), and the ratio of low-frequency power (LF) to high-frequency power (HF) between the mild and severe BG-EPVS groups (P < 0.05). Patients who presented with and without cognitive impairment differed significantly in the standard deviation of NN intervals (SDNN), rMSSD, PNN50, total power, LF, and LF/HF (P < 0.05). rMSSD (odds ratio [OR] 0.871, 95% confidence interval [CI] 0.768-0.988) and LF/HF (OR 3.854, 95% CI 1.196-12.419) were independent influencing factors of BG-EPVS, and rMSSD (OR 0.936, 95% CI 0.898-0.976) was an independent influencing factor of cognitive impairment in patients with EPVS. The optimal cut-off point was 0.312, with an area under the curve of 0.795 (95% CI 0.719-0.872) for predicting cognitive impairment in patients with EPVS by rMSSD. Conclusion: Reduced HRV is involved in the pathophysiological mechanisms of the formation and development of BG-EPVS and is associated with cognitive impairment in patients with EPVS, independent of CS-EPVS. For patients with HRV changes but without autonomic nervous system symptoms, positive intervention may slow the occurrence or progression of EPVS and cognitive impairment in patients with EPVS.

NUPR1 contributes to radiation resistance by maintaining ROS homeostasis via AhR/CYP signal axis in hepatocellular carcinoma.

BACKGROUND: Radiotherapy (RT) is one of the major therapeutic approaches to hepatocellular carcinoma (HCC). Ionizing radiation (IR) inducing the generation of reactive oxygen species (ROS) leads to a promising antitumor effect. However, the dysregulation of the redox system often causes radioresistance and impairs the efficacy of RT. Increasing evidence indicates that nuclear protein 1 (NUPR1) plays a critical role in redox reactions. In this study, we aim to explore the role of NUPR1 in maintaining ROS homeostasis and radioresistance in HCC. METHODS: The radioresistant role of NUPR1 was determined by colony formation assay, comet assay in vitro, and xenograft tumor models in vivo. Probes for ROS, apoptosis assay, and lipid peroxidation assay were used to investigate the functional effect of NUPR1 on ROS homeostasis and oxidative stress. RNA sequencing and co-immunoprecipitation assay were performed to clarify the mechanism of NUPR1 inhibiting the AhR/CYP signal axis. Finally, we analyzed clinical specimens to assess the predictive value of NUPR1 and AhR in the radiotherapeutic efficacy of HCC. RESULTS: We demonstrated that NUPR1 was upregulated in HCC tissues and verified that NUPR1 increased the radioresistance of HCC in vitro and in vivo. NUPR1 alleviated the generation of ROS and suppressed oxidative stress, including apoptosis and lipid peroxidation by downregulating cytochrome P450 (CYP) upon IR. ROS scavenger N-acetyl-L-cysteine (NAC) and CYP inhibitor alizarin restored the viability of NUPR1-knockdown cells during IR. Mechanistically, the interaction between NUPR1 and aryl hydrocarbon receptor (AhR) promoted the degradation and decreased nuclear translation of AhR via the autophagy-lysosome pathway, followed by being incapable of CYP's transcription. Furthermore, genetically and pharmacologically activating AhR abrogated the radioresistant role of NUPR1. Clinical data suggested that NUPR1 and AhR could serve as novel biomarkers for predicting the radiation response of HCC. CONCLUSIONS: Our findings revealed the role of NUPR1 in regulating ROS homeostasis and oxidative stress via the AhR/CYP signal axis upon IR. Strategies targeting the NUPR1/AhR/CYP pathway may have important clinical applications for improving the radiotherapeutic efficacy of HCC.

[Characteristics of PM2.5 Pollution in Beijing During the Historical Period of the 2022 Olympic Winter Games].

Based on the dataset derived from January to March between 2015 and 2021 in Beijing, the PM2.5 pollution characteristics and its potential source regions during the historical period of the Beijing 2022 Olympic Winter Games and Paralympic Winter Games were investigated. From 2015 to 2018, both the number of severely polluted days (daily average ρ(PM2.5)>75 µg·m-3) and the average PM2.5 concentrations during severe pollution episodes decreased significantly in the period of January to March. While, neither variable has changed obviously since 2018. On average, severely polluted days occurred 23 times in each year between 2018 and 2021 during the period of January to March, and the average of ρ(PM2.5) was approximately 120.0 µg·m-3 during such polluted days. From January to March in 2015-2021, the severely polluted event with more than 5 consecutive polluted days occurred 2-3 times in each year, and the severest one lasted 8 d. During the historical period of the Beijing 2022 Olympic Winter Games, severely polluted days took place 2-9 d every year. The large quantities of fireworks during the Spring Festival maybe one of important primary sources of the PM2.5. The number of severely polluted days during the historical period of the Paralympic Winter Games ranged from 1 to 5 d, except for 2021 with 9 d owing to the frequent stagnant weather condition. The PM2.5 chemical composition was dominated by secondary species on severely polluted days during the historical period of the Beijing 2022 Olympic Winter Games and Paralympic Winter Games. Nitrate accounted for 46% of the measurable chemical components of PM2.5 during severe pollution events in 2020, which was remarkably higher than that during clean days in the same year (11%). The mass fraction of SO42- ranged from 12% to 19% in 2018-2020, indicating that the contribution of sulfate was much less, but cannot be ignored. The main potential source regions of PM2.5 in Beijing during the period concerned in this study were central and western Inner Mongolia, Hebei Province, Tianjin City, Shanxi Province, Shaanxi Province, central and western Shandong Province, and northern Henan Province.

Identification of a Hydrogen-Sulfide-Releasing Isochroman-4-One Hybrid as a Cardioprotective Candidate for the Treatment of Cardiac Hypertrophy.

Cardiac pathological hypertrophy is associated with undesirable epigenetic changes and causes maladaptive cardiac remodeling and heart failure, leading to high mortality rates. Specific drugs for the treatment of cardiac hypertrophy are still in urgent need. In the present study, a hydrogen-sulfide-releasing hybrid 13-E was designed and synthesized by appending p-hydroxythiobenzamide (TBZ), an H2S-releasing donor, to an analog of our previously discovered cardioprotective natural product XJP, 7,8-dihydroxy-3-methyl-isochromanone-4. This hybrid 13-E exhibited excellent H2S-generating ability and low cellular toxicity. The 13-E protected against cardiomyocyte hypertrophy In Vitro and reduced the induction of Anp and Bnp. More importantly, 13-E could reduce TAC-induced cardiac hypertrophy In Vivo, alleviate cardiac interstitial fibrosis and restore cardiac function. Unbiased transcriptomic analysis showed that 13-E regulated the AMPK signaling pathway and influenced fatty acid metabolic processes, which may be attributed to its cardioprotective activities.

Ancient DNA reveals five streams of migration into Micronesia and matrilocality in early Pacific seafarers.

Micronesia began to be peopled earlier than other parts of Remote Oceania, but the origins of its inhabitants remain unclear. We generated genome-wide data from 164 ancient and 112 modern individuals. Analysis reveals five migratory streams into Micronesia. Three are East Asian related, one is Polynesian, and a fifth is a Papuan source related to mainland New Guineans that is different from the New Britain-related Papuan source for southwest Pacific populations but is similarly derived from male migrants ~2500 to 2000 years ago. People of the Mariana Archipelago may derive all of their precolonial ancestry from East Asian sources, making them the only Remote Oceanians without Papuan ancestry. Female-inherited mitochondrial DNA was highly differentiated across early Remote Oceanian communities but homogeneous within, implying matrilocal practices whereby women almost never raised their children in communities different from the ones in which they grew up.

GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Abundant metabolic fuels have been implicated as potential drivers of CRC. However, it remains unclear whether fructose, an ample sugar in daily diets, is essential for CRC growth. In the present study, we found that glucose levels were always insufficient in human CRC tissues. Compensating for this, fructose was flexibly utilized by tumor cells as an alternative energy source to maintain proliferation and exert chemotherapy resistance in vitro by upregulating GLUT5, a major fructose transporter encoded by SLC2A5. Mechanistically, in glucose-deprived but fructose-rich environments, GLUT5 could interact with ketohexokinase and inhibit its autophagy-dependent degradation, thus trapping fructose into glycolysis and tricarboxylic acid cycle for the malignant growth of CRC cells. In addition, reducing dietary fructose or pharmacological blockade of fructose utilization significantly reduced CRC growth and sensitized CRC cells to chemotherapy in vivo. Taken together, our findings highlight the role of elevated fructose utilization mediated by the GLUT5-KHK axis in governing CRC growth and imply that efforts to refine fructose intake or inhibit fructose-mediated actions may serve as potential therapeutic strategies.

Historically understanding the spatial distributions of particle surface area concentrations over China estimated using a non-parametric machine learning method.

A non-parametric ensemble model was proposed to estimate the long-term (2015-2019) particle surface area concentrations (SA) over China for the first time on basis of a vilification dataset of measured particle number size distribution. This ensemble model showed excellent cross-validation R2 value (CV R2 = 0.83) as well as a relatively low root-mean-square error (RMSE = 195.0 µm2/cm3). No matter in which year, considerable spatial heterogeneity of SA was found over China with higher SA in Beijing-Tianjin-Hebei (BTH), Yangtze River Delta (YRD), and Middle Lower Reaches of Yangtze River (MLYR). From 2015 to 2019, SA significantly decreased in representative city clusters. The reduction rates were 140.1 µm2·cm-3·a-1 in BTH, 110.7 µm2·cm-3·a-1 in Pearl River Delta (PRD), 105.2 µm2·cm-3·a-1 in YRD, and 92.4 µm2·cm-3·a-1 in Sichuan Basin (SCB), respectively. Even though such quick reduction, high SA (ranged from ~800 µm2/cm3 to ~1750 µm2/cm3) during the heavy pollution period (PM2.5 > 75 µg/m3) still existed in the above-mentioned city clusters and may provide rich reaction vessels for multiphase chemistry. A dichotomy of enhanced annual 4th maximum daily 8-h average O3 concentrations (4MDA8 O3) and decreased SA during summertime was found in Shanghai, a representative city of YRD. In Chengdu (SCB), increased 4MDA8 O3 concentration was associated with a synchronous increase of SA from 2017 to 2019. Differently, 4MDA8 O3 concentrations enhanced in Beijing (BTH) and Guangzhou (PRD), while not significant for SA before 2018. This work will greatly deepen our understanding of the historical variation and spatial distributions of SA over China.

Application of lipidomics strategy to explore aging-related biomarkers and potential anti-aging mechanisms of ginseng.

Aging often leads to an increase risk of age-related diseases, and the development of anti-aging drugs have become the trend and focus of the current scientific research. In this experiment, serum samples from healthy people of different ages were analyzed based on clinical lipidomics, and a total of 10 potential biomarkers in middle-aged and youth group, 20 biomarkers in the youth and the elderly group were obtained. Furthermore, dhSph and dhCer involved above may affect the aging process through sphingolipid metabolic pathway. As the first and rate-limiting step of catalyzing de novo sphingolipid pathway, SPT may play a key role in human anti-aging, which is revealed by lipidomics liposome tracer analysis. The potential active components in ginseng on SPT was further verified by molecular docking virtual screening and atomic force microscope. Four ingredients of ginseng may reduce the levels of metabolites dhSph and dhCer by inhibiting the activity of SPT, and play an anti-aging effect by affecting the sphingolipid metabolism pathway.A clinical trials registration number: ChiCTR1900026836.

S100P contributes to promoter demethylation and transcriptional activation of SLC2A5 to promote metastasis in colorectal cancer.

BACKGROUND: SLC2A5 is a high-affinity fructose transporter, which is frequently upregulated in multiple human malignant tumours. However, the function and molecular mechanism of SLC2A5 in colorectal cancer (CRC) remain unknown. METHODS: We detected the expression levels of SLC2A5 in CRC tissues and CRC cell lines by western blotting, qRT-PCR and immunohistochemistry. CRC cell lines with stable overexpression or knockdown of SLC2A5 were constructed to evaluate the functional roles of SLC2A5 in vitro through conventional assays. An intrasplenic inoculation model was established in mice to investigate the effect of SLC2A5 in promoting metastasis in vivo. Methylation mass spectrometry sequencing, methylation specific PCR, bisulphite sequencing PCR, ChIP-qPCR and luciferase reporter assay were performed to investigate the molecular mechanism underlying transcriptional activation of SLC2A5. RESULTS: We found that SLC2A5 was upregulated in colorectal tumour tissues. Functionally, a high level of SLC2A5 expression was associated with increased invasion and metastasis capacities of CRC cells both in vitro and in vivo. Mechanistically, we unveiled that S100P could integrate to a specific region of SLC2A5 promoter, thereby reducing its methylation levels and activating SLC2A5 transcription. CONCLUSIONS: Our results reveal a novel mechanism that S100P mediates the promoter demethylation and transcription activation of SLC2A5, thereby promoting the metastasis of CRC.

The particle phase state during the biomass burning events.

The phase state of biomass burning aerosols (BBA) remains largely unclear, impeding our understanding of their effects on air quality, climate and human health, due to its profound roles in mass transfer between gaseous and particulate phase. In this study, the phase state of BBA was investigated by measuring the particle rebound fraction ƒ combining field observations and laboratory experiments. We found that both ambient and laboratory-generated BBA had unexpectedly lower rebound fraction ƒ (<0.6) under the dry conditions (RH = 20-50%), indicating that BBA were in non-solid state at such low RH. This was obviously different from the secondary organic aerosols (SOA) derived from the oxidation of both anthropogenic and biogenic volatile organic compounds, typically with a rebound fraction ƒ larger than 0.8 at RH below 50%. Therefore, we proposed that the diffusion coefficient of gaseous molecular in the bulk of BBA might be much higher than SOA under the dry conditions.

Humidity-Dependent Phase State of Gasoline Vehicle Emission-Related Aerosols.

The phase states of primarily emitted and secondarily formed aerosols from gasoline vehicle exhausts were investigated by quantifying the particle rebound fraction (f). The rebound behaviors of gasoline vehicle emission-related aerosols varied with engines, fuel types, and photochemical aging time, showing distinguished differences from biogenic secondary organic aerosols. The nonliquid-to-liquid phase transition of primary aerosols emitted from port fuel injection (PFI) and gasoline direct injection (GDI) vehicles started at a relative humidity (RH) = 50 and 60%, and liquefaction was accomplished at 60 and 70%, respectively. The RH at which f declined to 0.5 decreased from 70 to 65% for the PFI case with 92# fuel, corresponding to the photochemical aging time from 0.37 to 4.62 days. For the GDI case, such RH enhanced from 60 to 65%. Our results can be used to imply the phase state of traffic-related aerosols and further understand their roles in urban atmospheric chemistry. Taking Beijing, China, as an example, traffic-related aerosols were mainly nonliquid during winter with the majority ambient RH below 50%, whereas they were mostly liquid during the morning rush hour of summer, and traffic-related secondary aerosols fluctuated between nonliquid and liquid during the daytime and tended to be liquid at night with increased ambient RH.

A Proteomics- and Metabolomics-Based Study Revealed That Disorder of Palmitic Acid Metabolism by Aconitine Induces Cardiac Injury.

Currently, research on cardiac injury by aconitine focuses on its effect to directly interfere with the function of cardiac ion channels. Further, abnormal lipid metabolism could cause cardiac injury via inflammatory signaling pathway. In our preliminary study, we discovered that aconitine could alter the metabolism processes of various substances, including palmitic acid. Inspired by these studies, we investigated how elevation of palmitic acid by aconitine causes cardiac injury. Aconitine induced cardiac injury in rats (0.32 mg/kg, d = 7), and the cardiac injury was confirmed by electrocardiogram and serum biochemical study. The proteomic and metabolomic results showed that the palmitic acid level increases in heart tissue, and the NOD-like receptor (NLR) signaling pathway showed a strong effect of cardiac injury. The palmitic acid results in cell viability decline and activates NLR signaling in vitro. The shRNA-mediated knockdown of NLRP3 and NOD1/2 attenuates palmitic acid-induced inhibitory effect on cells and inhibited activation of the NLR signaling pathway. Collectively, this study reveals that aconitine provoked palmitic acid elevation could aggravate cardiac injury via the NLR signaling pathway. This study suggests that drug triggered disorder of the metabolism process could evoke cardiac injury and could propose a new strategy to study drug cardiac injury.

Isoproterenol Triggers ROS/P53/S100-A9 Positive Feedback to Aggravate Myocardial Damage Associated with Complement Activation.

Negative feelings caused by external stress can continually agonize adrenergic receptors via promoting catecholamine secretion, causing cardiovascular disease. This study examines the mechanism by which persistent ß-adrenergic receptor agonism induces myocardial injury. A rat model of cardiac injury was herein established using isoproterenol (5 mg/kg, continuous intraperitoneal injection for 3 days), and multiomics technology combined with metabolomics and proteomics was used to explore the mechanism by which persistent ß-adrenergic receptor agonism induces myocardial injury. The mechanism underlying this phenomenon was further verified at the cellular level. Isoproterenol-induced persistent ß-adrenergic receptor agonism promoted the release of reactive oxygen species, and P53, S100-A9, and complement 3 were shown to be involved in complement system activation pathways. Our data have demonstrated that isoproterenol could trigger ROS/P53/S100-A9 positive feedback to aggravate myocardial damage associated with complement activation.

Analysis of biomarkers and metabolic pathways in patients with unstable angina based on ultra­high­performance liquid chromatography­quadrupole time­of­flight mass spectrometry.

Unstable angina (UA) is a coronary disease with a high mortality and morbidity worldwide. The present study aimed to use non­invasive techniques to identify urine biomarkers in patients with UA, so as to provide more information for the early diagnosis and treatment of the disease. Based on metabolomics, urine samples from 28 patients with UA and 28 healthy controls (HCs) were analyzed using ultra­high­performance liquid chromatography­quadrupole time­of­flight mass spectrometry (UPLC­Q­TOF/MS). A total of 16 significant biomarkers that could distinguish between patients with UA and HCs, including D­glucuronic acid, creatinine, succinic acid and N­acetylneuraminic acid, were identified. The major metabolic pathways associated with UA were subsequently analyzed by non­targeted metabolomics. The results demonstrated that amino acid and energy metabolism, fatty acid metabolism, purine metabolism and steroid hormone biosynthetic metabolism may serve important roles in UA. The results of the current study may provide a theoretical basis for the early diagnosis of UA and novel treatment strategies for clinicians. The trial was registered with the Chinese Clinical Trial Registration Center (registration no. ChiCTR­ROC­17013957) at Tianjin University of Traditional Chinese Medicine.