Therapeutic effect of Ginkgetin on smoke-induced airway inflammation by down-regulating the c/EBPß signaling pathway and CCL2 expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba leaf and seed have been traditionally used in ancient China for the treatment of cough and asthma. However, there is limited literature available on the anti-COPD effects and mechanisms of Ginkgo biloba. AIMS OF THE STUDY: The aim of this study was to comprehensively investigate the therapeutic potential of ginkgo extracts in COPD through a combination of in vivo and in vitro functional experiments. Transcriptomic analyses were also employed to uncover novel molecular mechanisms underlying the therapeutic effects of ginkgetin in COPD. MATERIALS AND METHODS: The therapeutic efficacy of ginkgo extracts was assessed in a COPD model. The anti-inflammatory effects of ginkgetin and its underlying molecular mechanisms were examined in A549 cells treated with cigarette smoke extract (CSE). Additionally, transcriptomic analyses were conducted to identify novel molecular pathways influenced by ginkgetin. These findings were further validated using quantitative real-time polymerase chain reaction (qPCR) and Western blot techniques. RESULTS: The ethyl acetate extract of Ginkgo biloba L. seeds and ginkgetin treatment significantly reduced cytokine production in COPD mice. Following drug administration, lung function improved in different groups. The transcriptome data strongly supports the inhibitory effect of ginkgetin on CSE-induced inflammation through the downregulation of the c/EBPß signaling pathway and subsequent inhibition of CCL2 expression. CONCLUSION: Our results demonstrate that ginkgetin, one of the biflavones found in Ginkgo biloba, exhibits inhibitory effects on smoke-induced airway inflammation. This effect is achieved through the downregulation of the c/EBPß signaling pathway and the reduction of CCL2 expression.

A physical fitness-evaluation system for outstanding Chinese male boxers.

Background: We sought to create a system to evaluate the physical fitness of outstanding Chinese male boxers that included an evaluation index, fitness level criteria, and modeling. This system was then used to assess athletes' physical fitness and development. Methods: Documentation, expert interviews, questionnaires, measurements, and statistical analyses were used in this study. Results: The physical fitness evaluation system included the following three components: (1) body shape indexes (n = 4) including the backhand upper arm circumference differential, finger span height, Cottrell index, and pelvic width/shoulder width × 100; (2) body function indexes (n = 4) including relative maximum anaerobic power, relative maximal oxygen uptake, and creatine kinase and testosterone concentrations; and (3) athletic quality indexes (n = 9) including the speed strength index, the backhand straight punch strength, 3-min cumulative punching force, backhand straight punch reaction time, backhand straight punch speed, 30-m sprint, 9-min double shake jump rope, 1-min double shake jump rope, and sitting forward bend tests. A five-point grading system to evaluate physical fitness was established and an evaluation model was proposed. Conclusions: The reference values were determined to be objective and effective using a back substitution process. Individual and differential assessments reflected the athletes' level of physical fitness. The critical values were established under the best and worst conditions and the optimal values were found to be valid and effective.

Arterial Adventitial Vasa Vasorum Density Reflects The Progression Of Unstable Plaques: A Retrospective Clinical Study.

OBJECTIVE: Arterial adventitial vasa vasorum (AVV) plays an important role in the occurrence and development of atherosclerotic (AS) disease. AS is a systemic disease, and plaque is not only a local vascular event, but also occurs at multiple sites throughout the vascular bed. Currently, effective anti-AVV therapies are lacking. Therefore, we posed the following scientific questions: "does human carotid adventitial vasa vasorum density reflect plaque neovascularization and intimal-media hyperplasia in carotid?"; and "is it possible to reduce human AVV density by sonodynamic therapy (SDT)?" METHODS: A retrospective study was conducted on 160 patients with carotid atherosclerosis. Duplex ultrasound scanning (DUS), contrast-enhanced ultrasound (CEUS), coronary angiography, and coronary CT angiography (CTA) were used for diagnosis and screening. Pearson correlation tests and Receiver operating characteristic (ROC) curve were used to analyze the relationships between AVV hyperplasia, vasa vasorum (VV) hyperplasia and the intima-media thickness (IMT). SDT was developed for the treatment of arterial AVV hyperplasia and AS plaques. RESULTS: The presence of local AVV in carotid unstable plaques correlated with the echogenic properties of the carotid plaque and the extent of plaque progression; Furthermore local AVV hyperplasia in patients with carotid atherosclerotic plaques was associated with acute coronary syndrome (ACS) events; Local AVV hyperplasia in patients with carotid atherosclerotic plaques was associated with coronary artery stenosis. Notably, SDT reduced local AVV hyperplasia and shrank the plaques in human femoral and carotid atherosclerotic lesions. CONCLUSIONS: The presence of AVV in human carotid arteries reflects the severity of carotid and coronary artery AS. Further, SDT can reduce the hyperplasia of local AVV in human femoral and carotid plaques.

Relationship between isokinetic strength of the knee joint and countermovement jump performance in elite boxers.

Background: The lower limbs play a key role to develop the linear momentum for hitting power in effective boxing. The knee extensor and flexor strength guarantees the dynamic stability of boxers. The insufficient extensor strength of the lower extremities causes compensation during flexion resulting in movement errors or damage to knee joint muscles. This study was conducted to explore the isokinetic concentric strength of the knee flexor and extensor and the relationship between isokinetic knee extensors strength and countermovement jump (CMJ) performance in elite boxers. Methods: Thirteen elite male boxers (Age: 25.15 ± 3.98 years, height 1.72 ± 0.04 m, weight 61.82 ± 10.46 kg, training years = 11.56 ± 2.67 years) performed the CMJ, and the isokinetic knee test was performed using the Biodex dynamometer. Results: The maximal isokinetic peak torque of the knee extensor and flexor muscles was recorded at three angular velocities (60°/s, 180°/s, and 240°/s) on both sides of the legs. The relative peak value of torque in the knee extensors decreased significantly with increasing angular velocity. A difference in relative peak torque (RPT) was only seen at 60°/s in knee flexors. However, the H/Q ratio increased as the velocity increased from 60°/s to 240°/s (P < 0.05). The highest peak torque was found in the knee extensors at a velocity of 240°/s (r = 0.73, P < 0.001). The correlation between RPT and vertical jump height was the strongest at 240°/s. The strongest relationship was found between the height of the CMJ and the RPT of the deficit of knee extensors. Conclusions: We suggest that explosive force training of the isokinetic muscles should be optimally carried out at a speed of 240°/s. The results of this study provide a reference for boxers to improve their jump height and lower-limb explosive strength through isokinetic strength training of the knee flexor and extensor.

Research on the Recognition and Tracking of Group-Housed Pigs' Posture Based on Edge Computing.

The existing algorithms for identifying and tracking pigs in barns generally have a large number of parameters, relatively complex networks and a high demand for computational resources, which are not suitable for deployment in embedded-edge nodes on farms. A lightweight multi-objective identification and tracking algorithm based on improved YOLOv5s and DeepSort was developed for group-housed pigs in this study. The identification algorithm was optimized by: (i) using a dilated convolution in the YOLOv5s backbone network to reduce the number of model parameters and computational power requirements; (ii) adding a coordinate attention mechanism to improve the model precision; and (iii) pruning the BN layers to reduce the computational requirements. The optimized identification model was combined with DeepSort to form the final Tracking by Detecting algorithm and ported to a Jetson AGX Xavier edge computing node. The algorithm reduced the model size by 65.3% compared to the original YOLOv5s. The algorithm achieved a recognition precision of 96.6%; a tracking time of 46 ms; and a tracking frame rate of 21.7 FPS, and the precision of the tracking statistics was greater than 90%. The model size and performance met the requirements for stable real-time operation in embedded-edge computing nodes for monitoring group-housed pigs.

Antioxidative 2D Bismuth Selenide via Halide Passivation for Enhanced Device Stability.

The topological insulator 2D Bi2Se3 is promising for electronic devices due to its unique electronic properties; however, it is challenging to prepare antioxidative nanosheets since Bi2Se3 is prone to oxidation. Surface passivation using ligand agents after Bi2Se3 exfoliation works well to protect the surface, but the process is time-consuming and technically challenging; a passivation agent that is stable under a highly biased potential is significant for in situ passivation of the Bi2Se3 surface. In this work, the roles of halide anions (Cl-, Br-, and I-) in respect of the chemical properties of synthetic Bi2Se3 nanosheets during electrochemical intercalated exfoliation were investigated to determine the antioxidation capacity. It was found that Bi2Se3 nanosheets prepared in a solution of tetrabutylammonium chloride (TBA+ and Cl-) have the best oxidation resistance via the surface bonding of Bi with Cl, which promotes obtaining better device stability. This work paves an avenue for adjusting the components of the electrolyte to further promote the stability of 2D Bi2Se3-nanosheet-based electronic devices.

Preclinical safety and biodistribution assessment of Ad-KCNH2-G628S administered via atrial painting in New Zealand white rabbits.

Post-operative atrial fibrillation (POAF) is the most common complication after cardiac surgery. Despite implementation of several pharmacological strategies, incidence of POAF remains at approximately 30%. An adenovirus vector encoding KCNH2-G628S has proven efficacious in a porcine model of AF. In this preclinical study, 1.5 × 1010 or 1.5 × 1012 Ad-KCNH2-G628S vector particles (vp) were applied to the atrial epicardium or 1.5 × 1012 vp were applied to the whole epicardial surface of New Zealand White rabbits. Saline and vector vehicle served as procedure controls. Animals were followed for up to 42 days. Vector genomes persisted in the atria up to 42 days, with no distribution to extra-thoracic organs. There were no adverse effects attributable to test article on standard toxicological endpoints or on blood pressure, left atrial or ventricular ejection fractions, electrocardiographic parameters, or serum IL-6 or troponin concentrations. Mononuclear infiltration of the myocardium of the atrial free walls of low-dose, but not high-dose animals was observed at 7 and 21 days, but these changes did not persist or affect cardiac function. After scaling for heart size, results indicate the test article is safe at doses up to 25 times the maximum proposed for the human clinical trial.

Molecularly Imprinted Chemiresistive Sensor for Specific Recognition of Furaneol as a Biomarker of Strawberry Flavor Conditions.

This work introduces the concept of a molecularly imprinted gas sensor to monitor the condition of naturally ripened strawberries. Furaneol, 2,5-dimethyl-4-hydroxy-3(2H)-furanone, is considered as an important biomarker related to the strawberry flavor. Identification of furaneol concentration is still a challenge because of its weak adsorption, nonpolar, and unreactive properties. Therefore, no study has been reported yet to measure furaneol gases via a simple chemiresistive mechanism. Herein, we demonstrate the sensor based on molecularly imprinted polymer (MIP)-based polyaniline (PANI). The sensitive and selective detection of furaneol gas with a MIP-PANI gas sensor was observed at room temperature and under different humidity conditions. The comparison between MIP and the nonimprinted (NIP)-based PANI shows a strong interaction between furaneol and the molecularly imprinted polymer. The furaneol gas sensing mechanism is explained based on the interaction between the gas molecules and the charge carriers of MIP-PANI, which results in the functional group change in the carboxylic group. Furthermore, the developed MIP-chemiresistive sensor for real strawberries was compared with a commercial e-nose system. The results show the potential to offer a rapid and cost-effective platform for specific recognition of furaneol.

Flavored E-cigarette product aerosols induce transformation of human bronchial epithelial cells.

OBJECTIVES: E-cigarettes are the most commonly used nicotine containing products among youth. In vitro studies support the potential for e-cigarettes to cause cellular stress in vivo; however, there have been no studies to address whether exposure to e-liquid aerosols can induce cell transformation, a process strongly associated with pre-malignancy. We examined whether weekly exposure of human bronchial epithelial cell (HBEC) lines to e-cigarette aerosols would induce transformation and concomitant changes in gene expression and promoter hypermethylation. MATERIALS AND METHODS: An aerosol delivery system exposed three HBEC lines to unflavored e-liquid with 1.2% nicotine, 3 flavored products with nicotine, or the Kentucky reference cigarette once a week for 12 weeks. Colony formation in soft agar, RNA-sequencing, and the EPIC Beadchip were used to evaluate transformation, genome-wide expression and methylation changes. RESULTS: Jamestown e-liquid aerosol induced transformation of HBEC2 and HBEC26, while unflavored and Blue Pucker transformed HBEC26. Cigarette smoke aerosol transformed HBEC4 and HBEC26 at efficiencies up to 3-fold greater than e-liquids. Transformed clones exhibited extensive reprogramming of the transcriptome with common and distinct gene expression changes observed between the cigarette and e-liquids. Transformation by e-liquids induced alterations in canonical pathways implicated in lung cancer that included axonal guidance and NRF2. Gene methylation, while prominent in cigarette-induced transformed clones, also affected hundreds of genes in HBEC2 transformed by Jamestown. Many genes with altered expression or epigenetic-mediated silencing were also affected in lung tumors from smokers. CONCLUSIONS: These studies show that exposure to e-liquid aerosols can induce a pre-malignant phenotype in lung epithelial cells. While the Food and Drug Administration banned the sale of flavored cartridge-based electric cigarettes, consumers switched to using flavored products through other devices. Our findings clearly support expanding studies to evaluate transformation potency for the major categories of e-liquid flavors to better inform risk from these complex mixtures.

Long-term efficacy of no-touch radiofrequency ablation in the treatment of single small hepatocellular carcinoma: A single center long-term follow-up study.

OBJECTIVE: To evaluate the long-term efficacy of no-touch radiofrequency ablation (NT-RFA) for treating single hepatocellular carcinoma (HCC) less than 3 cm. METHODS: A total of 331 patients with HCC less than 3 cm undergoing RFA in Southwest Hospital from 2015 to 2020 were analyzed retrospectively. All patients were divided into NT-RFA group (n = 113) and conventional RFA (C-RFA) group (n = 218). The survival rate, local tumor progression (LTP) and intrahepatic distant recurrence (IDR) of the two groups were calculated and compared. RESULTS: A significant difference was observed in ablation range (p = 0.000) and safety margin (p = 0.000) between the two groups. The 1-, 2-, 3-, 4-and 5-year overall survival (OS) rates in NT-RFA and C-RFA group were 99.12%, 93.73%, 76.18%, 57.00%, 45.17% and 99.08%, 89.91%, 71.26%, 54.28%, 41.77%, respectively. There was no significant difference between the two groups (p = 0.281). The 1-, 2-, 3-, 4-and 5-year recurrence-free survival (RFS) rates in NT-RFA and C-RFA group were 78.51%, 52.59%, 41.02%, 34.36%, 30.92% and 68.81%, 44.95%, 30.88%, 23.73%, 22.88%, respectively. The two groups differed significantly (p = 0.044). The 1-, 3-and 5-year LTP-free survival rates in NT-RFA and C-RFA group were 87.12%, 74.99%, 72.32% and 75.75%, 65.52%, 65.52%, respectively. The two groups also differed significantly (p = 0.024). Furthermore, the RFS rates of D ≤ 2 cm subgroups in NT-RFA and C-RFA groups differed significantly (p = 0.037), while the RFS rates of 2 cm < D ≤ 3 cm subgroups in two groups showed no significant difference (p = 0.578). CONCLUSIONS: The RFS rates of single HCC less than 3 cm treated by NT-RFA was significantly higher than that of C-RFA. Due to a larger ablation range and safety margin, NT-RFA could significantly reduce LTP and improve RFS. Dual-electrode NT-RFA can significantly improve the RFS rate of patients with HCC less than 2 cm, but there is no obvious advantage compared with C-RFA in the treatment of HCC over 2 cm.

Exploring the mechanism of MP gel against skin photoaging based on network pharmacology, molecular docking, and experimental validation.

OBJECTIVE: Long-term and high exposure to UV radiation can lead to the development of skin photoaging diseases. Therefore, there is an ongoing need for more natural and safe drugs to prevent or treat skin photoaging diseases. METHODS: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database were used to collect the active compounds and corresponding targets of Cnidii Fructus, Arnebiae Radix, Angelicae Sinensis Radix, Poria, and Borneolum. The GeneCards database and the NCBI Gene database were used to collect the targets of skin photoaging diseases. The STRING database was used to construct a protein-protein interaction network formed by the intersecting targets of drugs and diseases. The Metascape database was applied for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the targets. Molecular docking between active compounds and targets was verified by Autodock. After that, the skin photoaging model of mice was established and treated with MP gel. The skin characterization on the back of mice was observed, and the ameliorative effect of MP gel on skin photoaging was evaluated by histological and epidermal thickness assays. The MDA content and SOD activity were measured. Caspase-3 expression in mouse skin tissues was detected by immunohistochemistry, quantitative real-time polymerase chain reaction assay, and Western blot. RESULTS: The results of network pharmacology experiments showed that the natural drugs have multi-component, multi-target therapeutic disease characteristics. The results of animal studies showed that MP gel improved the health of photoaged skin, promoted skin structural integrity, had antioxidant properties and significantly inhibited caspase-3 expression. CONCLUSION: The experimental validation of the results of the preliminary network pharmacology analysis was carried out in animal experiments, which confirmed part of the mechanism of action of MP gel in the prevention and treatment of skin photoaging.

Establishment of lung adenocarcinoma classification and risk model based on necroptosis-related genes.

Lung adenocarcinoma (LUAD) is the most widely known histological subtype of lung cancer. Its classification is significant for the characteristic evaluation of patients. The aim of this research is to assess the categorization of LUAD and its risk model based on necroptosis and to investigate its potential regulatory mechanisms for diagnosing and treating LUAD. According to the expression profile data along with the clinical information related to LUAD from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we constructed a consistency matrix through consistency clustering, and used the ConsensusClusterPlus as the measurement distance to cluster and subtype the samples, and performed gene set enrichment analysis and immune infiltration analysis. Least absolute shrinkage and selection operator (Lasso) regression was utilized for obtaining prognostic significant necroptosis phenotype-related genes. Finally, we measured each patient's riskscore (RS) and build a risk model, and predicted the effect of immunotherapy for different groups of risk factors in the model. Three molecular subtypes of LUAD were obtained by cluster analysis of necroptosis-related genes in LUAD samples. Compared with C1, C3 had a better prognosis and higher immune cell infiltration. The prognosis of the C1 subtype was poor and had a high clinical grade. The proportion of Stage II, Stage III, and Stage IV was much more in comparison with that of the other two subtypes. TP53 gene had a high mutation frequency in the C1 subtype. Gene Set Enrichment Analysis (GSEA) indicated that the aberrant pathways in the C1 and C3 subtypes mainly included some cell cycle-related pathways. In addition, seven genes were identified as related genes of necroptosis phenotype affecting prognosis. High RS had a poor prognosis, while low RS had a good prognosis. The RS was verified to have a strong ability to predict survival. LUAD can be classified by the genes linked with cell necrosis and apoptosis. The difference among various types is helpful to deepen the understanding of LUAD. In addition, a risk model was constructed based. In conclusion, this study provides potential detection targets and treatment methods for LUAD from a new perspective.

Polyaniline/Graphene-Functionalized Flexible Waste Mask Sensors for Ammonia and Volatile Sulfur Compound Monitoring.

A flexible resistive-type polyaniline-based gas sensor was fabricated by simple dip-coating of graphene combined with in situ polymerization of aniline on a flexible waste mask substrate. The prepared polypropylene/graphene/polyaniline (PP/G/PANI) hybrid sensor demonstrated a fast response (114 s) and recovery time (23 s), ppb-level detection limit (100 ppb), high response value (250% toward 50 ppm NH3, which is over four times greater than that of the pristine PANI sensor), acceptable flexibility, excellent selectivity, and long-term stability at room temperature. The morphological and structural properties of the composite sensor materials were characterized by scanning electron microscopy and energy-dispersive spectroscopy characterization, and the surface chemistry of the hybrid sensors was analyzed by Fourier transform infrared spectroscopy. The excellent sensing performance was mainly ascribed to the larger specific surface area and efficient conducting paths of the porous PP/G/PANI network. Moreover, the PP/G/PANI hybrid gas sensor exhibited excellent sensing capability on volatile sulfur compounds contained in human breath, indicating that the hybrid sensor can be applied to breath analysis and kidney disease diagnosis.

Prognostic value of Beclin 1, EGFR and ALK in non-squamous non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most malignant tumors. The study was carried out to investigate the prognostic value of Beclin 1, EGFR and ALK for this cancer. Patients diagnosed with non-squamous NSCLC and admitted to our hospital from January 2011 to September 2016 were analyzed. Expression of Beclin 1 and mutation of EGFR and ALK were assessed using polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) and analyzed for their relationship with demographic and clinical characteristics of the patients. Multivariate Cox regression models were applied to analyze the risk factors associated with survival and receiver response curves (ROC) were plotted to determine the prognostic value of Beclin 1, EGFR and ALK for patients with non-squamous NSCLC. Compared with adjacent normal tissue, Beclin 1 expression was elevated in the cancer tissue significantly; assessments of EGFR and ALK mutations showed that out of the 480 patients, 233 (48.5%) and 75 (12.6%) patients had EGFR and ALK mutations. Univariate analysis revealed that Beclin 1 level, EGFR and ALK mutations were associated with lymph node metastasis, TNM stage, tumor differentiation and prognosis, but not with gender, age and smoking status. The Kaplan-Meier survival analysis indicated that low Beclin 1 expression and positive EGFR and ALK rearrangements were associated with higher survival rate and longer progress-free survival (PFS). Multivariate Cox regression analysis showed that Beclin 1, EGFR, ALK mutations, tumor differentiation grade, TNM stage and lymph node metastasis were independently associated with PFS. ROC analysis showed that Beclin 1, EGFR and ALK were significant predictors for PFS; the areas under curve (AUC) for Beclin 1, EGFR and ALK were 0.812 (P = 0.018, cut-off value: 1.2), 0.781 (P = 0.011, cut-off value: 15%) and 0.722 (P = 0.010, cut-off value: 11%), respectively, suggesting that they have significant prognostic value for lung cancer patients. Our data indicate that Beclin 1, EGFR and ALK genes are associated with the prognosis of patients with non-squamous NSCLC. High Beclin 1 expression and negative EGFR and ALK mutations predict a poor prognosis with PFS.

Small ubiquitin-related modifier (SUMO)ylation of SIRT1 mediates (-)-epicatechin inhibited- differentiation of cardiac fibroblasts into myofibroblasts.

CONTEXT: (-)-Epicatechin (EPI) is a crucial substance involved in the protective effects of flavanol-rich foods. Previous studies have indicated EPI has a cardioprotective effect, but the molecular mechanisms in inhibition of cardiac fibrosis are unclear. OBJECTIVE: We evaluated the effect of EPI in preventing cardiac fibrosis and the underlying molecular mechanism related to the SIRT1-SUMO1/AKT/GSK3ß pathway. MATERIALS AND METHODS: Cardiac fibrosis mice model was established with transaortic constriction (TAC). Male C57BL/6 mice were randomly separated into 4 groups. Mice received 1 mg/kg/day of EPI or vehicle orally for 4 weeks. The acutely isolated cardiac fibroblasts were induced to myofibroblasts with 1 µM angiotensin II (Ang II). The cardiac function was measured with the ultrasonic instrument. Histological analysis of mice's hearts was determined with H&E or Masson method. The protein level of fibrosis markers, SUMOylation of SIRT1, and AKT/GSK3ß pathway were quantified by immunofluorescence and western blot. RESULTS: EPI treatment (1 mg/kg/day) could reverse the TAC-induced decline in LVEF (TAC, 61.28% ± 1.33% vs. TAC + EPI, 74.00% ± 1.64%), LVFS (TAC, 28.16% ± 0.89% vs. TAC + EPI, 37.18% ± 1.29%). Meantime, we found that 10 µM EPI blocks Ang II-induced transformation of cardiac fibroblasts into myofibroblasts. The underlying mechanism of EPI-inhibited myofibroblasts transformation involves activation of SUMOylation of SIRT1 through SP1. Furthermore, SUMOylation of SIRT1 inhibited Ang II-induced fibrogenic effect via the AKT/GSK3ß pathway. CONCLUSION: EPI plays a protective effect on cardiac fibrosis by regulating the SUMO1-dependent modulation of SIRT1, which provides a theoretical basis for use in clinical therapies.

Tandem mass tag-based proteomics analysis reveals the effects of Guri Gumu-13 pill on drug-induced liver injury.

The incidence of drug-induced liver injury (DILI) is second only to viral hepatitis and steatohepatitis in China, and DILI has become a serious public health problem that cannot be ignored. Guri Gumu-13 pill (GRGM) is a traditional Chinese medicine (TCM), which has a protective effect on liver diseases. However, the underlying therapeutic mechanisms of GRGM for DILI are still vague. In this study, the protective effect of GRGM on acetaminophen (APAP)-induced DILI was investigated based on the proteomics clues. The effects of GRGM on APAP-induced DILI in rats were studied using tandem mass tag (TMT)-based quantitative proteomics technology. Besides, western blotting was exerted to verify related proteins. Using the TMT-based quantitative proteomics approach, 237 proteins were identified as regulated in APAP-induced DILI and 58 proteins were regulated by GRGM. The 17 overlapping differentially expressed proteins (DEPs) were identified, and 7 proteins were inversely regulated. Enrichment analysis of KEGG indicated that metabolic pathways, linoleic acid metabolism, and retinol metabolism might be affected in DILI. Next, Cyp2c11, Aldh1a1, and Fads2 were verified with molecular biotechnology. GRGM exerts therapeutic effects through multi-pathways regulation in the treatment of DILI. This work may provide proteomics clues for the continuation of research on DILI treatment with GRGM.

SUMOylation of SIRT1 activating PGC-1α/PPARα pathway mediates the protective effect of LncRNA-MHRT in cardiac hypertrophy.

Long noncoding RNA-Myosin heavy chain associated RNA transcript (LncRNA-MHRT) has been reported to prevent pathological cardiac hypertrophy. However, the underlying inhibition mechanism has not been fully elucidated. Further, whether MHRT inhibits hypertrophy by regulating post-translational modification of certain proteins remains unclear. Therefore, this study aims to find potential role of MHRT in inhibiting cardiac hypertrophy via regulating modification of certain proteins. Here, Angiotensin II (Ang II) -treated neonatal rat cardiomyocytes and transverse aortic constriction (TAC) mice were used to investigate the effect and mechanism of MHRT in cardiac hypertrophy in vitro and in vivo. Moreover, the regulatory effects of MHRT on SUMOylation of NAD-dependent protein deacetylase sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α)/peroxisome proliferator-activated receptor-α (PPARα), specificity protein 1 (SP1)/histone deacetylase 4 (HDAC4) pathway were investigated. Here, we found that MHRT improved heart function by attenuating pathological cardiac hypertrophy in vivo and in vitro. MHRT also promoted the SUMOylation of SIRT1 protein that activated PGC1-α/PPAR-α pathway. Furthermore, MHRT enhanced SUMOylation of SIRT1 by upregulating SP1/HDAC4. Our findings suggested that SUMOylation of SIRT1 could mediate the protective effect of MHRT in cardiac hypertrophy. The new regulatory pathway provides a potential new therapeutic target for pathological cardiac hypertrophy.

Mechanisms exploration of terrestrosin D on pulmonary fibrosis based on plasma metabolomics and network pharmacology.

Terrestrosin D (TED) is the active ingredient of Tribulus terrestris L., which is used in traditional Chinese medicine (TCM) formulations and has a wide range of pharmacological activities. A previous study showed that TED alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) in mice. However, the mechanisms underlying the therapeutic effect of TED are still unclear and need further investigation. In this study, we evaluated the effect of TED in a mice of BLM-induced PF in terms of histopathological and biochemical indices. UHPLC-MS-based plasma metabolomics combined with network pharmacology was used to explore the pathological basis of PF and the mechanism of action of TED. Histological and biochemical analyses showed that TED mitigated inflammatory injury in the lungs, especially at the dosage of 20 mg/kg. Furthermore, BLM changed the plasma metabolite profile in the mice, which was reversed by TED via regulation of amino acid and lipid metabolism. Subsequently, a biomarkers-targets-disease network was constructed, and tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß1 were identified as the putative therapeutic targets of TED. Both factors were quantitatively analyzed using enzyme-linked immunosorbent assay (ELISA). Taken together, the combination of UHPLC-MS-based metabolomics and network pharmacology can unveil the mechanisms of diseases and drug action.

Quantitative Determination of Four Potential Genotoxic Impurities in the Active Pharmaceutical Ingredients in TSD-1 Using UPLC-MS/MS.

A novel method of ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed for the identification and quantification of four potential genotoxic impurities (PGIs) in the active pharmaceutical ingredients of TSD-1, a novel P2Y12 receptor antagonist. Four PGIs were named, 4-nitrobenzenesulfonic acid, methyl 4-nitrobenzenesulfonate, ethyl 4-nitrobenzenesulfonate, and isopropyl 4-nitrobenzenesulfonate. Following the International Conference of Harmonization (ICH) guidelines, this methodology is capable of quantifying four PGIs at 15.0 ppm in samples of 0.5 mg/mL concentration. This validated approach presented very low limits (0.1512−0.3897 ng/mL), excellent linearity (coefficients > 0.9900), and a satisfactory recovery range (94.9−115.5%). The method was sufficient in terms of sensitivity, linearity, precision, accuracy, selectivity, and robustness and, thus, has high practicality in the pharmaceutical quality control of TSD-1.

Establishing an 8-gene immune prognostic model based on TP53 status for lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) results in a majority of cancer burden worldwide. TP53 is the most commonly mutated in LUAD. This study aimed to reveal the relation between TP53 and tumor microenvironment (TME) for improving LUAD treatment. METHODS: Differentially expressed genes (DEGs) related to immunity were analyzed between TP53-WT and TP53-MUT groups. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to screen prognostic DEGs. Two independent datasets were included to evaluate the robustness of the prognostic model. RESULTS: An 8-gene prognostic model containing ANLN, CCNB1, DLGAP5, FAM83A, GJB2, NAPSA, SFTPB, and SLC2A1 was established based on DEGs. LUAD samples were classified into high- and low-risk groups with differential overall survival in the two datasets. M0 macrophages, M1 macrophages, and activated memory CD4 T cells were more enriched in high-risk group. Immune checkpoints of PDCD1, LAG3, and CD274 were also high-expressed in high-risk group. CONCLUSION: The study improved the understanding of the role of TP53 in the TME modulation. The 8-gene model had robust performance to predict LUAD prognosis in clinical practice. In addition, the eight prognostic genes may also serve as potential targets for designing therapeutic drugs for LUAD patients.