Objective:To analyze the effect of panax notoginseng saponins(PNS)on mTORC1-HIF1α signaling pathway,and to explore its effect and mechanisms on the differentiation balance of Th17/Treg cells in CD4+T cells.Methods:Isolate the spleens of C57BL/6 mice,then select CD4+T cells by magnetic beads and cultured in vitro.The optimal concentration of PNS was screened by the CCK-8,and then these cells were divided into control group and PNS treatment group(5,10 and 20 μg/ml),each gives correspond-ing drug treatment after 48 h.Afterwards,flow cytometry was used to detect differentiation of Th17/Treg cells.Real-time quantitative fluorescent PCR was used to detect the expressions of RORγt,Foxp3,mTOR,Raptor,HIF1α mRNA.ELISA was used to detect the levels of IL-17A and IL-10 in the supernatant of cell culture.Western blot was used to detect the expressions and phosphorylation levels of 4EBP1,S6K and HIF1α proteins.Results:5,10,20 μg/ml PNS could significantly inhibit Th17 cells differentiation and promote Treg cells differentiation;5,10,20 μg/ml PNS could significantly reduce the expression of RORγt mRNA,and then reduce the level of IL-17A;20 μg/ml PNS could significantly promote the expression of Foxp3 mRNA and increase the level of IL-10;10,20 μg/ml PNS could significantly decrease the phosphorylation of 4EBP1 and S6K;5,10,20 μg/ml PNS could significantly reduce the expression of HIF1α mRNA and inhibit the expression of HIF1α protein.Conclusion:Certain concentrations of PNS can inhibit the differentiation of Th17 cells in CD4+T cells,and promote the differentiation of Treg cells,which is related with modulating mTORC1-HIF1α signaling pathway.

Objective To use metabolomics method to study the metabolic profiles of amino acids and lysophosphatidylcholine(LPC)in the serum of rats with nonalcoholic fatty liver disease(NAFLD),to identify biomarkers for NAFLD,and to speculate on the possible mechanism responsible for its occurrence.Methods NAFLD rats were prepared by feeding a high-fat diet and intraperitoneal injection of carbon tetrachloride.Levels of 15 LPCs and 18 amino acids in the serum were determined in control and NAFLD rats by liquid chromatography-mass spectrometry.Changes in serum LPC and amino acid metabolic profiles in NAFLD rats were analyzed by principal component analysis and orthogonal partial least squares discriminant analysis.Correlations between biomarkers and NAFLD were analyzed by Pearson's correlation analysis.Results The metabolic profiles of serum LPC and amino acids differed significantly between the NAFLD group and the control group and were completely distinct.LPC(20∶1),arginine,and glutamic acid had significant contributions to NAFLD and were identified as biomarkers.Furthermore,LPC(20∶1)and arginine were significantly correlated with serum biochemical indicators such as aspartate transaminase,alanine transaminase,low-density lipoprotein,and total bilirubin.Conclusions The metabolic profiles of serum LPC and amino acids may be closely related to NALFD.

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC₅₀: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC₅₀: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

According to understanding of the pathogenesis of acne, scholars have established animal models of acne inflammation, animal models of grafting human skin acne, and natural acne animal models. The acne inflammation model is mainly induced by bacterial infection, chemical drug application, and foreign matter injection. Natural acne animal models include animals that some are sensitivity to hormones and some have clinical symptoms of acne. It is necessary to select appropriate model animals and replicate model methods for the development of acne intervention products with different degrees and mechanisms. At present, there are only human evaluation standards of acne health functions in China, but no animal evaluation standards, which has affected the in-depth study of the pathogenesis of acne as well as the research and development progress of acne products. This article summarizes the conditions for the occurrence of acne, the characteristics of human skin, the bidirectional effect of Cutibacterium acnes on human skin, acne animal models, and commonly used observation and evaluation indicators, providing the reference for studying the pathogenesis of acne, promoting acne treatment and health care, and developing treatment products.

Objective:To explore the disturbance of metal element balance in mice after exposure to radon.Methods:Mice were randomly divided into control group, radon exposure of 30 WLM group, 60 WLM group and 120 WLM groups, with 10 mice in each group. After radon exposure with the cumulative dose, the lung function of mice was detected by a non-invasive pulmonary function testing instrument. Mice blood was taken from eyeballs. The lungs, heart, liver, kidney and spleen were also collected. HE staining was used to observe the pathological changes of lung tissue. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect the content of metal elements, including essential trace elements in the body: chromium (Cr), molybdenum (Mo), cobalt (Co), selenium (Se), copper (Cu), zinc (Zn), manganese (Mn), nickel (Ni), and potentially toxic elements: arsenic (As), tin (Sn), lead (Pb), aluminum (Al), mercury (Hg), cadmium (Cd), and silver (Ag).Results:Compared with the control group, lung ventilation function of the radon-exposed mice was decreased, alveolar structure was destroyed, and the contents of pulmonary metal elements Cr, Al, Pb, Sn( F=0.34, 0.66, 3.14, 1.16, P<0.05) and essential trace elements Mn, Cr, Zn, and Mo in the blood were decreased( F=0.65, 1.44, 0.97, 2.08, P<0.05), while the elements of Cu, Mo, Se and As in the lungs were increased( F=1.31, 1.26, 0.81, 2.04, P<0.05), and the element contents in other tissues also fluctuated. Conclusions:Inhalation of a certain cumulative dose of radon can reduce the lung ventilation function of mice and induce lung inflammation, as well reduce the content of essential trace elements in the lung and blood so that the content of metal elements in the body fluctuates.

The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer's disease.In this study,an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices.The plasma pharmacokinetics,tissue distri-bution,and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were system-atically investigated.Despite its complicated structural composition,the absorption,distribution,metabolism,and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate.Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration,with very low oral bioavail-ability in rats(0.6％-1.6％)and dogs(4.5％-9.3％).Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues.So-dium oligomannate could penetrate the blood-cerebrospinal fluid(CSF)barrier of rats,showing a con-stant area under the concentration-time curve ratio(CSF/plasma)of approximately 5％.The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability,supporting that excretion was predominantly renal,whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats.Moreover,only 33.7％(male)and 26.3％(female)of the oral dose were recovered in the rat excreta within 96 h following a single oral administration,suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.

Purpose: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, and Th17 cells are key factors in the pathogenesis of human inflammatory conditions, such as RA. Catalpol (CAT), a component in Rehmanniae Radix (RR), has been found to regulate human immunity. However, the effects of CAT on Th17 cell differentiation and improvement of RA are not clear. Materials and Methods: Collagen-induced arthritis (CIA) mice were constructed to detect the effects of CAT on arthritis and Th17 cells. The effect of CAT on Th17 differentiation was evaluated with let-7g-5p transfection experiments. Flow cytometry was used to detect the proportion of Th17 cells after CAT treatment. Levels of interleukin-17 and RORγt were assessed by qRT-PCR and enzyme-linked immunosorbent assay. The expression of signal transducer and activator of transcription 3 (STAT3) was determined by qRT-PCR and Western blot. Results: We found that the proportion of Th17 cells was negatively associated with let-7g-5p expression in CIA mice. In in vitro experiments, CAT suppressed traditional differentiation of Th17 cells. Simultaneously, CAT significantly decreased Tregs-to-Th17 cells transdifferentiation. Our results demonstrated that CAT inhibited Tregs-to-Th17 cells transdifferentiation by up-regulating let-7g-5p and that the suppressive effect of CAT on traditional differentiation of Th17 cells is not related with let-7-5p. Conclusion Our data indicate that CAT may be a potential modulator of Tregs-to-Th17 cells transdifferentiation by up-regulating let-7g-5p to reduce the expression of STAT3. These results provide new directions for research into RA treatment.

Objective:To investigate the efficacy and safety of bronchoscopic lavage in children with severe adenoviral pneumonia.Methods:Patients with severe adenovirus pneumonia who were admitted to ICU department of Hunan Children′s Hospital for bronchoscopy were collected from February to June 2019 and divided into lavage group( n=36) and non-lavage group( n=15) in line with whether lavage was performed.Their results, namely, bronchoscopic diagnosis, blood gas analysis before and 2 hours, 24 hours and 48 hours after bronchoscopy, improvement time of clinical symptoms(fever and pulmonary moist rales), the positive rate of pathogen detection and mortality rate, main vital signs such as heart rate, respiratory rate, mean arterial pressure and bronchoscopy-related complications were recorded before and 1 hour, 2 hours and 24 hours after bronchoscopy. Results:A total of 51 children were collected, all of whom suffered from endobronchitis.More secretions were observed in the airways of 36 patients in the lavage group, and only a little or no secretions were observed in 15 patients in the non-lavage group.P/F value and PCO 2 at 2 hours, 24 hours and 48 hours after treatment in the lavage group were improved comparing to those before treatment and were superior to those in the non-lavage group( P<0.05). P/F values at 24 hours and 48 hours after treatment in the non-lavage group increased and PCO 2 decreased at 48 hours after treatment( P<0.05). The thermal duration, time to resolution of moist rales in the lungs in the lavage group were shorter than those in the non-lavage group( P<0.05). The mortality rate in the lavage group was lower than that in the non-lavage group[2.8%(1/36) vs.26.7%(4/15), P<0.05]. The positive rate of pathogen detection in lavage group was higher than that in non-lavage group[55.6%(20/36) vs. 20.0%(3/15), P<0.05]. There was no significant difference in heart rate, respiratory rate, and mean arterial pressure at each time point before and after bronchoscopic treatment( P>0.05). Associated complications were 11 cases of intraoperative transient hypoxemia, four cases of bronchial mucosal bleeding, and one case each of postoperative hypoxemia, intraoperative hypertension and hypotension.There was no significant difference in the incidence of complications between the two groups( P>0.05). Conclusion:Bronchoscopic lavage, in treating children with severe adenovirus pneumonia, may improve clinical symptoms, respiratory function, and rate of pathogen detection, reduce mortality, and is effective and safe.

Objective To investigate the efficacy and application of bronchoalveolar lavage in chil-dren with severe pneumonia undergoing mechanical ventilation. Methods Using a prospective randomized controlled clinical study, 202 children with severe pneumonia received mechanical ventilation in Hunan Children′s Hospital from January 2016 to January 2018 were selected as the subjects. According to the digital method,all cases were divided into treatment group (101 cases) and control group (101 cases) randomly. The patients in the control group were given conventional treatment ( anti-infection and symptomatic thera-py) . The treatment group was treated with bronchoalveolar lavage on the basis of conventional treatment. The basic situation,the respiratory function before and after the treatment,the inflammation index,the curative effect and the prognosis of two groups were analyzed. Results There were no significant differences between the two groups in gender,age,course pre-admission,pediatric critical illness score,respiratory function and in-flammation index ( P>0. 05 ) . The respiratory function indexes of the treatment group were obviously im-proved 2 hours after the treatment and the PaO2 ,PaO2/FiO2 and SaO2 were significantly higher than those of the control group[PaO2:(82. 4 ± 6. 4) mmHg(1 mmHg=0. 133 kPa) vs. (74. 0 ± 5. 5) mmHg, PaO2/FiO2:(360. 2 ± 21. 3) mmHg vs. (332. 6 ± 23. 5) mmHg,SaO2:(94. 9 ± 8. 2)％ vs. (88. 6 ± 10. 3)％], while the PaCO2 were significantly lower than the control group [ ( 37. 3 ± 10. 3 ) mmHg vs. ( 45. 8 ± 5. 5 ) mmHg],and the differences were statistically significant (P<0. 05). Five days after treatment,the WBC, PCT and CRP of treatment group were significantly lower than those in the control group[WBC:(8. 5 ± 2. 4) × 109/L vs. (11. 7 ± 3. 5) × 109/L,PCT:(1. 2 ± 0. 7) μg/L vs. (2. 3 ± 0. 9) μg/L,CRP:(9. 1 ± 3. 2) mg/L vs. (16. 5 ± 4. 7) mg/L,P<0. 05,respectively]. The total effective rate in the treatment group was significantly higher than that in the control group[93. 1％(94/101)vs. 81. 2％(82/101)]. Mechanical venti-lation duration and PICU stay in treatment group were significantly shorter than those in the control group [(148. 5 ±30. 6)h vs. (159. 6 ±47. 3)h,(220. 8 ±49. 7)h vs. (330. 7 ±94. 6)h]. The positive rate of patho-genic bacteria was significantly higher than that in the control group [79. 2％(80/101)vs. 62. 4％(63/101), P<0. 05],but there was no significant difference in the 28 days mortality of the two groups[5. 0％(5/101) vs. 5. 9％(6/101),P>0. 05]. Conclusion The bronchoalveolar lavage can improve the respiratory func-tion,reduce the inflammatory reaction,shorten mechanical ventilation duration and PICU stay in children with severe pneumonia undergoing mechanical ventilation obviously. It is worth popularizing in the PICU because of the improvement of curative effect in these children.

Objective: To carry out mutation analysis for patients with myelodysplastic syndromes (MDS) and a normal karyotype. Methods: Targeted capture and next-generation sequencing (NGS) was carried out using a customized 49-gene panel. FLT3 internal tandem duplication (FLT3-ITD), CALR, NPM1 and CEBPA mutations were detected by PCR and Sanger sequencing. Results: Sixty two patients (80.5%) were found to harbor at least one mutation. Each patient has carried 2.21 mutations in average. Coexistence of ≥ 3 mutations was common (43.7%). The most commonly mutated genes were RUNX1 (23.4%, 18/77), ASXL1 (18.2%, 14/77), NPM1 (15.6%, 12/77), U2AF1 (15.6%, 12/77), DNMT3A (11.7%, 9/77). Patients with SF3B1 mutations were significantly older than those with ASXL1 mutations (P=0.023). Mutations of the DNMT3A gene were significantly associated with the blood platelet level compared with BCOR mutations (P=0.02). No significant difference was found in the number and rate of mutations between those under or above 60-year-old. Among 67 patients with clinical follow-up, 20 (29.8%) has transformed to acute myeloid leukemia, and the time of transformation has ranged from 1 to 44 months, with a average of 5.3 months. RUNX1, U2AF1 and FLT3 mutations are associated with leukemic transformation. Conclusion Coexistence of ≥ 3 mutations are frequent among patients with normal-karyotype MDS. Certain mutations are associated with age and leukemic transformation.