Capecitabine plus bevacizumab versus capecitabine in maintenance treatment for untreated characterised KRAS exon 2 wild-type metastatic colorectal cancer: a retrospective analysis in Chinese postmenopausal women.

BACKGROUND: Capecitabine plus bevacizumab (CAP-B) maintenance treatment after 6 cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOXB) has demonstrated clinical activity and failure to compromise quality of life in patients with metastatic colorectal cancer (MCC) in a previous phase 3 CAIRO3 study. The objective of this study is to evaluate the efficacy and safety of CAP-B versus CAP in maintenance treatment after 6-cycle CAPOXB induction therapy in Chinese postmenopausal women with untreated characterised KRAS exon 2 wild-type MCC. METHODS: During 2012-2016, prospectively maintained databases were reviewed to evaluate cohorts with untreated characterised KRAS exon 2 wild-type MCC and stable disease or better after 6-cycle CAPOXB induction treatment. After induction treatment, all patients received either CAP-B or capecitabine (CAP) as maintenance treatment. Median progression-free survival (mPFS) and median overall survival (mOS) were the primary endpoints. Safety was the secondary endpoint. RESULTS: A total of 263 women with untreated characterised KRAS exon 2 wild-type MCC and stable disease or better after 6-cycle CAPOXB induction treatment were included for the evaluation of efficacy and safety (CAP-B-treated cohort, n = 130 and CAP-treated cohort, n = 133). The mPFS was 11.5 months (95% confidence interval [CI], 5.6-17.4) and 9.2 months (95% CI, 3.6-14.8) for the CAP-B-treated and CAP-treated cohorts, respectively (HR 0.54, 95% CI 0.32~0.85; P = 0.013). The mOS was 16.2 months (95% CI, 11.4-18.7) and 12.4 months (95% CI, 10.6-15.5) for the CAP-B- and CAP-treated cohorts, respectively (HR 0.72, 95% CI 0.51~0.94; P = 0.022). The CAP-B-treated cohort experienced significantly more grade 3 or 4 diarrhoea (P < 0.001) than the CAP-treated cohort. CONCLUSIONS: CAP-B maintenance treatment after 6-cycle CAPOX-B in Chinese postmenopausal women with untreated KRAS exon 2 wild-type MCC is poorer tolerated but has a more modest, if any, benefit compared with that of CAP maintenance treatment.

Metabolic Discrimination of Different Rhodiola Species Using 1H-NMR and GEP Combinational Chemometrics.

Rhodiola is widely consumed in traditional folk medicine and nutraceuticals. To establish a procedure for the hydrogen (1H)-NMR spectroscopic fingerprinting of secondary metabolites from three different Rhodiola species, the variation among three Rhodiola species were studied using 1H-NMR metabolomics combined with multivariate data analysis. Gene expression programming (GEP) was used to generate a formula to distinguish Rhodiola crenulata from two other Rhodiola species. Finally, HPLC was used to demonstrate the results. Same metabolites were compared by quantitative 1H-NMR (qNMR). Three Rhodiola species were clearly discriminated by 1H-NMR fingerprinting involved 22 nuclear magnetic signals of chemical constituents. y = d166 × 2 + C1 + d56 + d236 - d128 × C2 can be used to distinguish R. crenulata from two other Rhodiola species by GEP. The gallic acid concentration in R. crenulata was significantly higher than in the other. Rhodiola species as was the level of salidroside. R. crenulata also exhibited substantially higher levels of α-glucose. The fatty acid level in Rhodiola kirilowii was lower than the other species. These findings demonstrated that 1H-NMR fingerprinting combined with principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), hierarchical cluster analysis (HCA) and GEP can be used to distinguish different Rhodiola species and these methods were applicable and effective approaches for metabolic analysis, species differentiation, and quality assessment. In addition, gallic acid, salidroside, α-D-glucose, glycine, alanine, caffeic acid and tyrosol and are the discriminators.

[Correlation study on Tibetan medicine Pterocephalus hookeri of bitter taste receptors based on molecular docking technology].

In order to study the interaction between Pterocephalus hookeri and bitter taste receptors,three-dimensional structural models of bitter taste receptors TAS2 R16,TAS2 R14 and TAS2 R13 were established by homology modeling in this paper. Maestro software was used for docking the chemical constituents of P. hookeri with bitter taste receptors. The results showed that 25 chemical components of P. hookeri can regulate three bitter taste receptors. And these components were mainly iridoid glycosides and phenolic acids.This research focused on the comprehensive application of homology modeling and molecular docking technology to explore the interaction between bitter chemical constituents of P. hookeri and bitter taste receptors. This study provided assistance in revealing pharmacodynamic basis of bitter Tibetan medicine at molecular level. It also provided new ideas and methods for the study of Tibetan medicine.

[Investigation on intestinal absorption ingredients and their absorption characteristics in Pterocephali Herba by everted intestinal sac method].

The intestinal absorption characteristics of ten iridoid glycosides and phenolic acids in the Pterocephali Herba were evaluated via rat intestinal valgus model. The intestinal sac fluids at different time after administration of high,medium and low concentrations of Pterocephali Herba extract were collected and ten chemical components in fluid samples were detected by UPLC-PDA. Accumulative absorbed doses( Q) and absorption rate constants( Ka) of ten chemical constituents were calculated,while proportions between Pterocephali Herba extract and intestinal absorption liquid were compared. The results showed that the intestinal absorption of 10 chemical components was linear absorption( R2>0. 9) at different concentrations,which accorded with the zero-order absorption rate. The absorption rate constant was related to the concentration of the drug and the intestinal site,which indicated that intestinal adsorption mechanism of the components were passive diffusion and active transport. Proportions of chemical constituents in intestinal sac fluid were different from those in Pterocephali Herba extract. Therefore,those ten chemical components in Pterocephali Herba extract can be absorbed in whole intestine. Everted intestinal sac model can be used to evaluate intestinal absorption characteristics of ingredients in Pterocephali Herba extract effectively.

Fog-Based Two-Phase Event Monitoring and Data Gathering in Vehicular Sensor Networks.

Vehicular nodes are equipped with more and more sensing units, and a large amount of sensing data is generated. Recently, more and more research considers cooperative urban sensing as the heart of intelligent and green city traffic management. The key components of the platform will be a combination of a pervasive vehicular sensing system, as well as a central control and analysis system, where data-gathering is a fundamental component. However, the data-gathering and monitoring are also challenging issues in vehicular sensor networks because of the large amount of data and the dynamic nature of the network. In this paper, we propose an efficient continuous event-monitoring and data-gathering framework based on fog nodes in vehicular sensor networks. A fog-based two-level threshold strategy is adopted to suppress unnecessary data upload and transmissions. In the monitoring phase, nodes sense the environment in low cost sensing mode and generate sensed data. When the probability of the event is high and exceeds some threshold, nodes transfer to the event-checking phase, and some nodes would be selected to transfer to the deep sensing mode to generate more accurate data of the environment. Furthermore, it adaptively adjusts the threshold to upload a suitable amount of data for decision making, while at the same time suppressing unnecessary message transmissions. Simulation results showed that the proposed scheme could reduce more than 84 percent of the data transmissions compared with other existing algorithms, while it detects the events and gathers the event data.

[Potential distribution of the traditional Tibetan herb Pterocephalus hookeri by Maxent model].

In order to study the ecology suitability of Pterocephalus hookeri, and provide a reference for GAP planting location and regional development, the Maxent model and GIS technology were used to investigate ecology suitability regions for P. hookeri based on the distribution points collected from Chinese virtual herbarium, the references and field trips. The potential distribution areas mainly concentrated in the eastern Tibet, western Sichuan, southern Qinghai, northwest Yunnan, and southern Gansu. There were 7 major environmental factors to have obvious influence on ecology suitability distributions of P. hookeri, including altitude (contribution rate of 62%), precipitation of warmest quarter (contribution rate of 14.4%), coefficient of variation of precipitation seasonality (contribution rate of 7.2%), mean temperature of driest quarter (contribution rate of 3.5%), the electrical conductivity of top and sub-soil (contribution rate of 3%), the total exchangeable bases in the top- and subsoil (contribution rate of 2.4%) and SD of temperature seasonality (contribution rate of 2.2%). The study of the ecological suitability regionalization of P. hookeri based on Maxent model can provide scientific basis for the selection of artificial planting base and GAP planting location.

[Resource investigation about Tibetan medicine Rhodiola kirilowii].

The investigation aims to better understand the resource status of Rhodiola kirilowii, analysis the suitable habitat of wild Rh. kirilowii and protect the wild resources of Rh. Kirilowii, promoting the sustainable utilization of Rh. kirilowii resources. In this paper, we investigated the wild resources of Rh. kirilowii in 16 counties of Sichuan, Qinghai, Gansu and Yunnan by means of investigation and sampling investigation combined with interview. The results showed that the population densities of wild Rh. kirilowii in 4 provinces were very different and the reserve of wild resources decreased gradually in many areas. According to the survey results, the current total reserve of Rh. kirilowii in four provinces was about 1 100 t. The reserve of wild Rh. kirilowii in Sichuan province was the largest. Simultaneously, the Rh. kirilowii had a certain ecological value. We found that a sand control base with planting Rh. kirilowii was set up in Hongyuan County of Sichuan Aba Tibetan and Qiang Autonomous Prefecture. The investigation provides a scientific basis for the development and sustainable utilization of Rh. kirilowii resources.

[Correlation between flavonoids contents in Hippophae rhamnoides subsp. inensis leaf and ecological factors, and ecological suitability analysis of H. rhamnoides subsp. sinensis].

The study aims at providing a new suitable way to promote artificial cultivation, solving the problem of resources increasingly endangered wild medicine, and protecting the wild resources of Tibetan medicine. The content of quercetin,kaempferol and isorhamnetin was determined by HPLC. The correlation between flavonoids components and ecological factors was analyzed using partial least-squares regression (PLSR). Based on Maxent model combining using ArcGIS software, suitable regionalization for H.rhamnoides subsp. sinensis was studied.The results showed that the difference of quercetin,kaempferol and isorhamnetin content in samples from different regions were obvious. The main factors effecting quercetin content accumulation were the altitude andthe average monthly precipitation in January and August. The main factors effecting kaempferol accumulation were the altitude andthe average monthly precipitation in the coldest quarter and December. The main factors effecting isorhamnetin accumulation were the average monthly precipitation in August, January and the coldest quarter.The regional distribution suitability index for H.rhamnoides subsp. sinensis was 0-0.708. The suitable area 590 500 km², accounting for 6.13% of the total area. The preferably suitable area was 552 500 km², accounting for 5.73% of the total area.The methods used in the study is simple and feasible, the result is reliable which provide a new approach for Tibetan medicine resources sustainable exploitation and utilization.

[Endangered situation and conservation strategy of Tibetan medicine in Qinghai-Tibet Plateau].

With the rapid development of Tibetan medicine industry, the study on plateau medicinal plants' endangered status is not enough, measures to protect is weak and the plateau ecological environment' inherent vulnerability, resulted in the shortage of Tibetan medicinal resources and affect the sustainable development . According to the existing endangered information of Tibetan medicine resources, how to formulate feasible protection plan, is an urgent problem of the rational development and utilization of Tibetan medicine resources to be solved. To find out the endangered Tibetan medicines in Qinghai Tibet Plateau, the Grade division method of Chinese Rare and Endangered Plants was applied, the endangered species were sorted out, which divided into class one (threatened) eleven species, class two (rare) twenty-one species, and class three (fading) forty-two species,a total of seventy-four species.In addition to national protection list in "Chinese rare and endangered plants". It's proposed to increase the endangered Tibetan medicinal species. Finally, according to the endangered status of the resources,from the survey of endangered Tibetan medicinal species regularly, the germplasm repository establishment of endangered Tibetan medicine, in situ conservation, artificial cultivation research and renew the idea, reasonable development and utilization, a total of 5 aspects to discussed the protection strategy, to provide a scientific basis for the protection and sustainable utilization of Tibetan medicine resources in Qinghai-Tibet Plateau.

Exploration of the ubiquitination-related molecular classification and signature to predict the survival and immune microenvironment in colon cancer.

Background: Ubiquitination, a major post-translational modification, significantly impacts tumorigenesis, progression, and prognosis. This study aims to classify colon cancer at the molecular level and create a reliable signature using ubiquitination-related genes (URGs) to assess the immune microenvironment and prognosis. Methods: We employed non-negative matrix factorization to subtype colon cancer based on ubiquitination-related gene (URG) expression patterns. Quantitative scores for 28 immune cell infiltrates and the tumor microenvironment were computed using single-sample gene set enrichment analysis (ssGSEA) and the Estimate algorithm. Subtype feature genes were selected through Lasso logistic regression and SVM-RFE algorithm. The ubiquitination-related signature was constructed using univariate Cox, Lasso, and stepwise regression methods to categorize patients into high and low-risk groups. Validation included log-rank tests, receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and external dataset validation. Immune therapy response was compared using Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenoscore (IPS), and submap analyses. Clinical variables and risk scores were integrated into an enhanced nomogram. The early diagnostic value of four URGs was confirmed via quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. The cell proliferation was assessed through colony formation, EdU staining, and xenograft tumorigenesis assays. Results: Prognostic ubiquitination-related genes (URGs) stratified patients into subtypes, revealing differences in survival, immune cell infiltration, and pathological staging. A signature of 6 URGs (ARHGAP4, MID2, SIAH2, TRIM45, UBE2D2, WDR72) was identified from 57 subtype-related genes. The high-risk group exhibited characteristics indicative of enhanced epithelial-mesenchymal transition, immune escape, immunosuppressive myeloid-derived suppressor cells, regulatory T cell infiltration, and lower immunogenicity. In contrast, the low-risk group demonstrated the opposite trend but showed a better response to CTLA4 checkpoint inhibitors. The predictive performance of the nomogram significantly improved with the integration of risk score, stage, and age. ARHGAP4 and SIAH2 exhibit promising early diagnostic capabilities. Additionally, WDR72 knockdown significantly inhibited CRC cell proliferation both in vitro and in vivo. Conclusion: Our developed ubiquitination-related signature and genes serve as promising biomarkers for colon cancer prognosis, immune microenvironment, and diagnosis.

Abelmoschus manihot (L.) medik. seeds alleviate rheumatoid arthritis by modulating JAK2/STAT3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Abelmoschus manihot (L.) Medik. Seeds (AMS, སོ་མ་ར་ཛ།), a Tibetan classical herbal in China, are rich in flavonoids and phenolic glycosides compounds, such as quercetin and its derivatives. Moreover, it has been found to possess anti-rheumatoid arthritis (RA) effects. Nonetheless, its anti-RA mechanism is yet unknown. AIM OF THE STUDY: This research aimed to examine the active ingredients of AMS as well as potential pharmacological mechanisms in AMS on RA. MATERIALS AND METHODS: The ultra-performance liquid chromatography-electrospray ionization-tandem multistage mass spectrometry (UPLC-ESI-IT-MSn) technique was used to determine the primary chemical components of AMS that were responsible for the therapeutic effects on RA. In addition, 36 male Wistar rats weighing between 200 and 220 g were classified at random into six groups [normal control group, collagen-induced arthritis (CIA) group, methotrexate group (positive control, 1.05 mg/kg), AMS group (157.5 mg/kg, 315 mg/kg, 630 mg/kg)]. CIA rats were given AMS extract by intragastric administration for 28 days, and their ankles were photographed to observe the degree of swelling. Further, the arthritis score, paws swelling, and body weight changes of CIA rats were determined to observe whether AMS has any effect on RA, and synovial and cartilage tissue injuries were identified by histopathology. Besides, the levels of IL-10, TNF-α, IL-1ß, INF-γ, etc. in serum were estimated by ELISA. Western blot experiments were implemented to identify the expression levels of protein involved in the JAK2/STAT3 signaling pathway in the CIA rats' synovial tissues. Moreover, the mechanisms and targets of active ingredient therapy of AMS for RA were predicted using network pharmacology and then verified using molecular docking. RESULT: In the present study, 12 compounds were detected by UPLC-ESI-IT-MSn, such as quercetin and its derivative which could be potential active ingredients that contribute to the anti-RA properties of AMS. Our in vivo studies on CIA rats revealed that an AMS-H dose of 630 mg/kg significantly improved joint damage while decreasing the arthritic index and paw swelling. Furthermore, AMS inhibited the INF-γ, IL-6, IL-17, IL-1ß, and TNF-α, levels while upregulating the expression of anti-inflammatory cytokines IL-10 and IL-4 in serum. Besides, AMS inhibited the protein Bcl-2/Bax, STAT3, and JAK2 levels, and promoted the expression of Caspase3, SOCS1, and SOCS3 in the JAK2/STAT3 pathway. Additionally, the JAK/STAT signaling pathway was found to perform a remarkable function in the AMS therapy of RA as evidenced by enrichment in GO terms and KEGG pathways. Meanwhile, data from molecular docking experiments indicated that the core targets of PIK3CA, JAK2, and SRC bound stably to the active ingredients of mimuone, 4'-methoxy-bavachromanol, and quercetin. CONCLUSION: According to these findings, the AMS could improve joint inflammation in CIA rats, and its underlying mechanism could be linked to the regulation of the JAK2/STAT3 pathway. Therefore, AMS might become a promising agent for alleviating inflammation in RA patients.

Applications of single­cell omics and spatial transcriptomics technologies in gastric cancer (Review).

Gastric cancer (GC) is a prominent contributor to global cancer-related mortalities, and a deeper understanding of its molecular characteristics and tumor heterogeneity is required. Single-cell omics and spatial transcriptomics (ST) technologies have revolutionized cancer research by enabling the exploration of cellular heterogeneity and molecular landscapes at the single-cell level. In the present review, an overview of the advancements in single-cell omics and ST technologies and their applications in GC research is provided. Firstly, multiple single-cell omics and ST methods are discussed, highlighting their ability to offer unique insights into gene expression, genetic alterations, epigenomic modifications, protein expression patterns and cellular location in tissues. Furthermore, a summary is provided of key findings from previous research on single-cell omics and ST methods used in GC, which have provided valuable insights into genetic alterations, tumor diagnosis and prognosis, tumor microenvironment analysis, and treatment response. In summary, the application of single-cell omics and ST technologies has revealed the levels of cellular heterogeneity and the molecular characteristics of GC, and holds promise for improving diagnostics, personalized treatments and patient outcomes in GC.

Preoperative risk factors influencing the incidence of postoperative sepsis in human immunodeficiency virus-infected patients: a retrospective cohort study.

BACKGROUND: Compared to noninfected patients, human immunodeficiency virus (HIV)-infected patients undergoing surgery have an increased postoperative risk of developing sepsis. We aimed to investigate the preoperative risk factors that affect the incidence of sepsis after surgery in HIV-infected patients. METHODS: Clinical parameters of 215 patients with HIV/acquired immunodeficiency syndrome (AIDS) who had undergone surgery between January 2011 and February 2012 were examined retrospectively for the effect of HIV/AIDS on the incidence of postoperative sepsis. RESULTS: Logistic regression analysis identified four independent risk factors of postoperative sepsis in HIV-infected patients: CD4 counts [B = -0.007, odds ratio (OR) 0.993]; blood albumin levels (B = -0.077, OR 0.926); surgical infection (B = 1.887, OR 6.598); major surgery (B = 1.013, OR 2.754). The incidence of postoperative sepsis was high with CD4 counts ≤ 100 cells/µl, albumin levels <35 g/L, the presence of surgical infection, the patient had undergone major surgery--81.25%, 39/48; 76.47%, 26/34; 70.73%, 29/41; and 54.76%, 46/84, respectively, compared to that of the total cohort (40.93%, 88/215). When CD4 counts were >350 cells/µl, the incidence of postoperative sepsis was significantly lower (16.36%, 9/55). CONCLUSIONS: Low CD4 cell counts, hypoalbuminemia, surgical infection, and major surgery are independent risk factors for the development of postoperative sepsis among HIV-infected patients. CD4 cell numbers and albumin levels negatively correlated with the incidence of postoperative sepsis, whereas surgical infections and major surgical procedures positively correlated with the incidence of postoperative sepsis.

Field Collection and Laboratory Routine Identification of Rhodiola crenulata.

The identification of medicinal materials is the premise and guarantee of drug safety. The majority of scientific researchers are bound to favor the simple, fast, effective, and inexpensive identification process of herbals. Rhodiola crenulata is a traditional Tibetan medicine grown at high altitudes, mainly distributed in Tibet, Yunnan, and Sichuan regions of China. Rhodiola crenulate possesses multiple bioactivities, such as anti-inflammatory, anti-hypoxia, and antioxidant properties, and has great potential for development. With the increasing market demand and a rapid decrease in resource content, a large number of confused products of Rhodiola crenulata have been troubling people. Therefore, this protocol introduces a standard process for the identification of Rhodiola crenulata in the field combined with routine laboratory testing. The combination of habitat, microscopic features, and thin-layer chromatography will undoubtedly identify Rhodiola crenulata quickly, efficiently, and economically, contributing to the continuous development of Tibetan medicine and the quality control of medicinal materials.

Tibetan medicine Qi-Sai-Er-Sang-Dang-Song Decoction inhibits TNF-α-induced rheumatoid arthritis in human fibroblast-like synoviocytes via regulating NOTCH1/NF-κB/NLRP3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qi-Sai-Er-Sang-Dang-Song Decoction (QSD, ཆུ་སེར་སེང་ལྡེང་སུམ་ཐང་།), a Tibetan classical herbal formula, is commonly used in Tibetan hospital preparation for the treatment of rheumatoid arthritis (RA). Its efficacy is to relieve inflammation, dispel cold, remove dampness, and alleviate pain. However, its anti-RA mechanism is still unclear. AIM OF THE STUDY: This study aimed to investigate the effect of QSD on rheumatoid arthritis and explore its anti-inflammatory mechanism against human fibroblast-like synoviocytes (HFLSs) by regulating the notch family of receptors (NOTCH1)/Nuclear factor-κB (NF-κB)/nucleotide-binding (NLRP3) pathway. MATERIALS AND METHODS: We used ultra-performance liquid chromatography coupled with Q-TOF mass spectrometry (UPLC-Q-TOF-MS) to identify the chemical composition of QSD. Then, HFLSs were exposed to drug-containing serum. The effect of QSD drug-containing serum on HFLS viability was detected using the cell counting kit-8 (CCK-8) assay. Next, we explored the anti-inflammatory effect of QSD using enzyme-linked immunosorbent assay (ELISA) for inflammatory factors, such as interleukin-18 (IL-18), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). The expression of NOTCH-related proteins, a member of the NOTCH1, Cleaved NOTCH1, hairy and enhancer of split-1 (HES-1), NF-κB p65, NF-κB pp65, NLRP3, and delta-like 1 (DLL-1), was examined using western blotting. Furthermore, the relative mRNA expression levels of NOTCH1, NF-κB p65, NLRP3, DLL-1, and HES-1 were detected using real-time quantitative (RT-qPCR). To explore the mechanism underlying the anti-RA effect of QSD, we the used the NOTCH signaling pathway inhibitor LY411575 and transfection with a NOTCH1 siRNA. In addition, we employed immunofluorescence to determine the expression of HES-1 and NF-κB p65 in vitro. RESULT: Our results revealed that QSD ameliorated inflammation in HFLSs. Compared with the model group, the QSD drug-containing serum group had obviously down-regulated levels of IL-18, IL-1ß, and IL-6. Consistently, the CCK-8 results showed that the QSD drug-containing serum had no obvious toxicity towards HFLSs. Moreover, both LY411575 and siNOTCH1, QSD could reduce NOTCH1, NLRP3, and HES-1 protein expression levels, and LY411575 could significantly inhibit the expression levels of NF-κB p65, NF-κB pp65, and Cleaved NOTCH1 (p < 0.05). siNOTCH1 could also suppress the expression of DLL-1. The RT-qPCR results indicated that QSD could downregulate the relative mRNA expression levels of NOTCH1, NF-κB p65, NLRP3, DLL-1, and HES-1 in HFLSs (p < 0.05). In the immunofluorescence experiment, the fluorescence intensities of HES-1 and NF-κB p65 in HFLSs were found to decrease after exposure to QSD drug-containing serum (p < 0.05). Ultimately, 44 chemical components were detected in QSD using UPLC-Q-TOF-MS. CONCLUSION: This study reveals that the QSD can markedly ameliorate inflammation induced by TNF-α on HFLS. The effect of QSD on HFLS may be exerted by inhibition of the NOTCH1/NF-κB/NLRP3 signaling pathway.

Standardized Identification of Compound Structure in Tibetan Medicine Using Ion Trap Mass Spectrometry and Multiple-Stage Fragmentation Analysis.

Tibetan medicines are complex and contain numerous unknown compounds, making in-depth research on their molecular structures crucial. Liquid chromatography-electrospray ionization time-of-flight mass spectrometry (LC-ESI-TOF-MS) is commonly used to extract Tibetan medicine; however, many unpredictable unknown compounds remain after using the spectrum database. The present article developed a universal method for identifying components in Tibetan medicine using ion trap mass spectrometry (IT-MS). The method includes standardized and programmed protocols for sample preparation, MS setting, LC prerun, method establishment, MS acquisition, multiple-stage MS operation, and manual data analysis. Two representative compounds in the Tibetan medicine Abelmoschus manihot seeds were identified using multiple-stage fragmentation, with a detailed analysis of typical compound structures. In addition, the article discusses aspects such as ion mode selection, mobile phase adjustment, scanning range optimization, collision energy control, collision mode switchover, fragmentation factors, and limitations of the method. The developed standardized analysis method is universal and can be applied to unknown compounds in Tibetan medicine.

In vitro and in vivo exploration of the anti-atopic dermatitis mechanism of action of Tibetan medicine Qi-Sai-Er-Sang-Dang-Song decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Tibetan medicine Qi-Sai-Er-Sang-Dang-Song Decoction(QSD, ཆུ་སེར་སེང་ལྡེང་སུམ་ཐང་།)is a traditional Tibetan medical formulation with demonstrated clinical benefits in atopic dermatitis (AD). However, its potential mechanism and molecular targets remain to be elucidated. AIM OF THE STUDY: This study aims to explore the activity and mechanism of QSD on AD in multiple dimensions by combining in vitro and in vivo experiments with network pharmacology. MATERIALS AND METHODS: The AD effect of QSD was investigated by evaluating the levels of nitric oxide (NO) and interleukin-6 (IL-6) in the lipopolysaccharide (LPS) stimulated RAW264.7 cells. AD-like skin lesions in female BALB/c mice were induced by 2,4-dinitrochlorobenzene (DNCB). QSD or dexamethasone (positive control) were gavagely administered daily for 15 consecutive days. The body weight and skin lesion severity were recorded throughout the study. Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analysis were used to illuminate the molecular targets associated with the anti-AD effects of QSD. Meanwhile, the ingredients of QSD in the blood were revealed and analyzed by Ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method. Network pharmacology was used to predict the targets and mechanism of active ingredient therapy for AD. In addition, the network pharmacology outcomes were further verified by molecular docking. RESULT: After treatment with QSD, the levels of NO and IL-6 were decreased in the cell supernatant. Herein, QSD markedly decreased the eosinophil and mast cells infiltration in the dorsal skin of the 2,4-dinitrochlorobenzene. Moreover, QSD reconstructed the epidermal barrier by increasing the content of collagen fibers and changing the arrangement of DNCB-treated mice. QSD not only inhibited the levels of tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12) but also inhibited phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) proteins in the dorsal skin. Four active ingredients were identified through UPLC-Q-TOF/MS, including (-)-epicatechin, kaempferol-7-O-glucoside, cassiaside, and questin. After the network pharmacological analysis, six core targets of QSD closely related to AD were obtained, including TNF-α, IL-6, Caspase-3 (CASP3), Epidermal growth factor (EGFR), Peroxisome proliferator-activated receptor gamma (PPARG), and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1). Meanwhile, through Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, the Mitogen-activated protein kinase (MAPK) signaling pathway occupies an important position in the QSD treatment of AD. The molecular docking results showed that the six core targets are stable in binding to the four active ingredients as indicated by the molecular docking results. CONCLUSIONS: The anti-AD effect of QSD might be related to the reconstruction of the epidermal barrier and inhibition of inflammation, which regulated the MAPK pathway. Hence, it provided a promising idea for the study of Tibetan medicine prescriptions for the treatment of AD.

Blapsimidazolium A: A new imidazolium carboxylate derivative with anti-inflammatory activity from medicinal insect Blaps rynchopetera.

Blaps rynchopetera Fairmaire is a medicinal insect of Yi-nationality medicine used for a long time in Yunnan, China. In the present study, a new blapsimidazolium A (1), together with twelve known N-containing compounds (2-13), were isolated from this insect. The structures were elucidated by extensive spectroscopic analyses (1D and 2D NMR, HR-MS) and comparisons with the reported literature. Blapsimidazolium A was identified as racemic mixture by optical rotation and chiral analysis. Blapsimidazolium A (1) has a unique architecture containing an imidazolium carboxylate moiety. The results of molecular docking showed that blapsimidazolium A bound well to IL-1ß, IL-6 and iNOS. The racemates of (±)-blapsimidazolium A (1) exerted anti-inflammatory activity in LPS-stimulated THP-1 cells by significantly decreasing the production of the proinflammatory cytokines IL-1ß, IL-6 and iNOS. This is the first report describing the anti-inflammatory activity of this type imidazolium carboxylate derivative.

A Multi-Task Multi-Stage Transitional Training Framework for Neural Chat Translation.

Neural chat translation (NCT) aims to translate a cross-lingual chat between speakers of different languages. Existing context-aware NMT models cannot achieve satisfactory performances due to the following inherent problems: 1) limited resources of annotated bilingual dialogues; 2) the neglect of modelling conversational properties; 3) training discrepancy between different stages. To address these issues, in this paper, we propose a multi-task multi-stage transitional (MMT) training framework, where an NCT model is trained using the bilingual chat translation dataset and additional monolingual dialogues. We elaborately design two auxiliary tasks, namely utterance discrimination and speaker discrimination, to introduce the modelling of dialogue coherence and speaker characteristic into the NCT model. The training process consists of three stages: 1) sentence-level pre-training on large-scale parallel corpus; 2) intermediate training with auxiliary tasks using additional monolingual dialogues; 3) context-aware fine-tuning with gradual transition. Particularly, the second stage serves as an intermediate phase that alleviates the training discrepancy between the pre-training and fine-tuning stages. Moreover, to make the stage transition smoother, we train the NCT model using a gradual transition strategy, i.e., gradually transiting from using monolingual to bilingual dialogues. Extensive experiments on two language pairs demonstrate the effectiveness and superiority of our proposed training framework.

A Real-Time Global Inference Network for One-Stage Referring Expression Comprehension.

Referring expression comprehension (REC) is an emerging research topic in computer vision, which refers to the detection of a target region in an image given a test description. Most existing REC methods follow a multistage pipeline, which is computationally expensive and greatly limits the applications of REC. In this article, we propose a one-stage model toward real-time REC, termed real-time global inference network (RealGIN). RealGIN addresses the issues of expression diversity and complexity of REC with two innovative designs: adaptive feature selection (AFS) and Global Attentive ReAsoNing (GARAN). Expression diversity concerns varying expression content, which includes information such as colors, attributes, locations, and fine-grained categories. To address this issue, AFS adaptively fuses features of different semantic levels to tackle the changes in expression content. In contrast, expression complexity concerns the complex relational conditions in expressions that are used to identify the referent. To this end, GARAN uses the textual feature as a pivot to collect expression-aware visual information from all regions and then diffuses this information back to each region, which provides sufficient context for modeling the relational conditions in expressions. On five benchmark datasets, i.e., RefCOCO, RefCOCO+, RefCOCOg, ReferIT, and Flickr30k, the proposed RealGIN outperforms most existing methods and achieves very competitive performances against the most advanced one, i.e., MAttNet. More importantly, under the same hardware, RealGIN can boost the processing speed by 10-20 times over the existing methods.