Objective To prepare Zanthoxylum alkaloid thermosensitive hydrogel, optimize the preparation process and conduct related performance studies. Methods Zanthoxylum alkaloids were obtained by reflux extraction, followed by enrichment and purification using macroporous adsorption resin. Poloxamer 407 and Poloxamer 188 were used as substrates to prepare the thermosensitive hydrogel of Zanthoxylum alkaloids, and the preparation process was optimized by orthogonal design. The quality of the hydrogel was systematically evaluated based on its gelation temperature, gelation time, Fourier transform infrared （FTIR） spectroscopy, scanning electron microscopy （SEM） images, mechanical properties, and in vitro release profile. Results The optimal preparation conditions for the Zanthoxylum alkaloid thermosensitive hydrogel were: 20% （g/ml） poloxamer 407, 2% （g/ml） poloxamer 188 and 100 μg/ml Zanthoxylum alkaloid. The gelation temperature was 32.6℃, and the average gelling time was 143.3 s. The hydrogel appeared as a transparent liquid at room temperature and was transformed into a semi-solid gel state when the temperature exceeded 33℃. Experimental results confirmed the successful preparation of poloxamer 407 and poloxamer 188 thermosensitive hydrogel loaded with Zanthoxylum alkaloids, which exhibited good bio adhesion, self-healing properties, and tensile strength. Conclusion The Zanthoxylum alkaloid thermosensitive hydrogel demonstrated favorable mechanical properties and a sustained-release effect, showing promising potential for further development and application.

Objective:To evaluate the effects of chlorinated organophosphate flame retardants (Cl-OPFRs) via respiratory and digestive tract exposure on multiple organs in mice.Methods:A short-term repeated exposure model of tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP) and tris(1, 3-dichloro-2-propyl) phosphate (TDCIPP) in mice was established through intratracheal instillation and oral gavage administration. The exposure doses were 0.7, 1 and 2 mg·kg -1·day -1, respectively, with continuous administration for 14 days. The organs of the heart, liver, spleen, lung, kidney, stomach, large intestine, small intestine, bladder and testis were collected and weighed to calculate the organ coefficients. The pathological and histological changes were observed by hematoxylin-eosin staining to quantitatively assess the effects of the three Cl-OPFRs on the various organs by using the pathology score. Results:Analysis of organ coefficients in tracheal drip-treated mice showed that the organ coefficients in the testes of the TCEP, TCIPP and TDCIPP groups were lower than those in the control group ( PTCEP-testis=0.045, PTCIPP-testis=0.012 and PTDCIPP-testis<0.001). The organ coefficients were lower in the lungs and small intestines of the TCEP group ( PTCEP-lung=0.006, PTCEP-small intestine=0.042). The organ coefficients for the stomach and large intestine were higher in the TDCIPP group ( PTDCIPP-stomach=0.014, PTDCIPP-large intestine=0.049). Analyses of gavage-contaminated mice showed that the organ coefficients for liver, stomach and small intestine in the TCEP and TDCIPP groups were higher than those in the control group ( PTCEP-liver=0.007, PTCEP-stomach=0.003, PTCEP-small intestine<0.001, PTDCIPP-liver=0.001, PTDCIPP-stomach=0.004, and PTDCIPP-small intestine<0.001). Histopathological analyses of the organs of tracheal drip dyed mice showed significant pathological damage in the lung tissue of the TCIPP group, mainly in the form of thickening of the interstitium, infiltration of inflammatory cells and alveolar collapse. The results of the analysis of gavage poisoned mice showed that TCIPP exposure could lead to blurring of the red and white medullary boundaries of spleen tissues, destruction of white medullary structures, etc., and induce small intestinal cryptitis. TDCIPP induced significant pathological damage to the liver tissues of mice, which mainly included cytoplasmic washout, infiltration of inflammatory cells, acute inflammation, and other injurious effects. Significant pathological damage to the intestinal tissues of mice was also observed. Conclusions:This study demonstrates that the toxic effects of Cl-OPFRs are significantly associated with exposure routes and compound specificity. Respiratory exposure predominantly induces TCIPP-mediated pulmonary injury, while digestive exposure causes TDCIPP-driven hepatointestinal toxicity. These findings provide preliminary evidence for the toxicity screening of Cl-OPFRs.

Objective:To evaluate the effects of chlorinated organophosphate flame retardants (Cl-OPFRs) via respiratory and digestive tract exposure on multiple organs in mice.Methods:A short-term repeated exposure model of tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP) and tris(1, 3-dichloro-2-propyl) phosphate (TDCIPP) in mice was established through intratracheal instillation and oral gavage administration. The exposure doses were 0.7, 1 and 2 mg·kg -1·day -1, respectively, with continuous administration for 14 days. The organs of the heart, liver, spleen, lung, kidney, stomach, large intestine, small intestine, bladder and testis were collected and weighed to calculate the organ coefficients. The pathological and histological changes were observed by hematoxylin-eosin staining to quantitatively assess the effects of the three Cl-OPFRs on the various organs by using the pathology score. Results:Analysis of organ coefficients in tracheal drip-treated mice showed that the organ coefficients in the testes of the TCEP, TCIPP and TDCIPP groups were lower than those in the control group ( PTCEP-testis=0.045, PTCIPP-testis=0.012 and PTDCIPP-testis<0.001). The organ coefficients were lower in the lungs and small intestines of the TCEP group ( PTCEP-lung=0.006, PTCEP-small intestine=0.042). The organ coefficients for the stomach and large intestine were higher in the TDCIPP group ( PTDCIPP-stomach=0.014, PTDCIPP-large intestine=0.049). Analyses of gavage-contaminated mice showed that the organ coefficients for liver, stomach and small intestine in the TCEP and TDCIPP groups were higher than those in the control group ( PTCEP-liver=0.007, PTCEP-stomach=0.003, PTCEP-small intestine<0.001, PTDCIPP-liver=0.001, PTDCIPP-stomach=0.004, and PTDCIPP-small intestine<0.001). Histopathological analyses of the organs of tracheal drip dyed mice showed significant pathological damage in the lung tissue of the TCIPP group, mainly in the form of thickening of the interstitium, infiltration of inflammatory cells and alveolar collapse. The results of the analysis of gavage poisoned mice showed that TCIPP exposure could lead to blurring of the red and white medullary boundaries of spleen tissues, destruction of white medullary structures, etc., and induce small intestinal cryptitis. TDCIPP induced significant pathological damage to the liver tissues of mice, which mainly included cytoplasmic washout, infiltration of inflammatory cells, acute inflammation, and other injurious effects. Significant pathological damage to the intestinal tissues of mice was also observed. Conclusions:This study demonstrates that the toxic effects of Cl-OPFRs are significantly associated with exposure routes and compound specificity. Respiratory exposure predominantly induces TCIPP-mediated pulmonary injury, while digestive exposure causes TDCIPP-driven hepatointestinal toxicity. These findings provide preliminary evidence for the toxicity screening of Cl-OPFRs.

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.

Analyzing the distribution characteristics of allergen sIgE in the serum of patients with respiratory and skin mucosal diseases in Shanghai City, and to provide epidemiological characteristics and diagnostic basis for the prevention and treatment of allergic respiratory and dermo-mucous diseases in Shanghai City. Adopting cross-sectional research, a total of 3 822 patients who received treatment in Tongren Hospital, Shanghai Jiao Tong University School of Medicine from July 2022 to July 2023 due to respiratory diseases or skin and dermo-mucous symptoms were included. Among them, there were 1 456 males and 2 366 females, with an age range of 1-97 years old. The median age (interquartile range) was 33 (27, 44) years old. The sIgE was detected by using immunoblotting. Statistical analysis was conducted using SPSS 22.0 software, and the comparison of count data (rates) between groups was conducted using χ 2 test. The results showed that a total of 3 377 (88.4%) cases among 3 822 patients were at least one allergen sIgE positive, and 72.9% (2 788/3 822) of them were multiple allergies sIgE positive. The top five allergen sIgE positive rates were Dermatophagoides pteronyssinus (37.9%, 1 447/3 822), Dermatophagoides farinae (32.1%, 1 225/3 822), milk (31.7%, 1 211/3 822), fungi (28.3%, 1 080/3 822), and Blomia tropicdis (23.8%, 909/3 822), with only milk was a kind of food allergen. The highest positive rates within the respiratory system disease group or dermo-mucous disease group were also these five allergens, without any difference in disease categories. The positive rates of cat dandruff, Humulusscandens, and juniper/birch in the respiratory system disease group were significantly higher than those in the skin and mucous membrane disease group, while the positive rates of shrimp/crab were relatively low (11.3% vs 14.9%, χ 2=9.616, P=0.002). Whether in the respiratory system disease group or the dermo-mucous disease group, the positive rates of Dermatophagoides pteronyssinus in male patients were significantly higher than those of females(42.6% vs 35.7%,41.0% vs 34.4%), with statistical significance ( χ 2=12.515, P<0.001; χ 2=5.143, P=0.023), And the three allergens, Dermatophagoides farinae, cat dander, and egg white allergens are also characterized by this feature.In addition, the positive rates of milk(33.8% vs 30.1%, χ 2=3.911, P=0.048), shrimp/crab(13.2% vs 10.0%, χ 2=6.423, P=0.014) in the respiratory system disease group were higher in males than in females, while in the dermo-mucous disease group, dog dander(20.5% vs 14.6%, χ 2=6.726, P=0.010) and peanuts/soybeans(10.5% vs 6.9%, χ 2=4.698, P=0.030) showed this phenomenon. In both the respiratory system disease group and the dermo-mucous disease group, there were 6 types of inhaled allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blomia tropicdis, cat dandruff, dog dander, fungi) and 4 types of food allergens (egg yolks, egg white allergens, milk, shrimp/crab). However, the positivity rate of Aspergillus fumigatus (7.2% vs 9.3% vs 10.5% vs 15.7%, χ 2=10.996, P=0.012)in the respiratory disease group and cockroaches(4.2% vs 11.3% vs 9.6% vs 16.4%, χ 2=10.237, P=0.017) in the skin and mucosal disease group was the lowest in the underage group. There are seasonal differences in the positivity rates of allergens, with most allergens having significantly higher positivity rates in summer and autumn. In conclusion, the most common allergens sIgE positive in patients with respiratory and dermo-mucous diseases in Shanghai City are Dermatophagoides pteronyssinus, Dermatophagoides farinae, milk, fungi, and Blomia tropicdis. The trend of allergen sIgE prevalence in the two major categories of diseases is basically consistent. Allergen sIgE distribution varies among patient populations of different gender, age or season, and clinical prevention and treatment can be based on the results of serum allergen testing.

Analyzing the distribution characteristics of allergen sIgE in the serum of patients with respiratory and skin mucosal diseases in Shanghai City, and to provide epidemiological characteristics and diagnostic basis for the prevention and treatment of allergic respiratory and dermo-mucous diseases in Shanghai City. Adopting cross-sectional research, a total of 3 822 patients who received treatment in Tongren Hospital, Shanghai Jiao Tong University School of Medicine from July 2022 to July 2023 due to respiratory diseases or skin and dermo-mucous symptoms were included. Among them, there were 1 456 males and 2 366 females, with an age range of 1-97 years old. The median age (interquartile range) was 33 (27, 44) years old. The sIgE was detected by using immunoblotting. Statistical analysis was conducted using SPSS 22.0 software, and the comparison of count data (rates) between groups was conducted using χ 2 test. The results showed that a total of 3 377 (88.4%) cases among 3 822 patients were at least one allergen sIgE positive, and 72.9% (2 788/3 822) of them were multiple allergies sIgE positive. The top five allergen sIgE positive rates were Dermatophagoides pteronyssinus (37.9%, 1 447/3 822), Dermatophagoides farinae (32.1%, 1 225/3 822), milk (31.7%, 1 211/3 822), fungi (28.3%, 1 080/3 822), and Blomia tropicdis (23.8%, 909/3 822), with only milk was a kind of food allergen. The highest positive rates within the respiratory system disease group or dermo-mucous disease group were also these five allergens, without any difference in disease categories. The positive rates of cat dandruff, Humulusscandens, and juniper/birch in the respiratory system disease group were significantly higher than those in the skin and mucous membrane disease group, while the positive rates of shrimp/crab were relatively low (11.3% vs 14.9%, χ 2=9.616, P=0.002). Whether in the respiratory system disease group or the dermo-mucous disease group, the positive rates of Dermatophagoides pteronyssinus in male patients were significantly higher than those of females(42.6% vs 35.7%,41.0% vs 34.4%), with statistical significance ( χ 2=12.515, P<0.001; χ 2=5.143, P=0.023), And the three allergens, Dermatophagoides farinae, cat dander, and egg white allergens are also characterized by this feature.In addition, the positive rates of milk(33.8% vs 30.1%, χ 2=3.911, P=0.048), shrimp/crab(13.2% vs 10.0%, χ 2=6.423, P=0.014) in the respiratory system disease group were higher in males than in females, while in the dermo-mucous disease group, dog dander(20.5% vs 14.6%, χ 2=6.726, P=0.010) and peanuts/soybeans(10.5% vs 6.9%, χ 2=4.698, P=0.030) showed this phenomenon. In both the respiratory system disease group and the dermo-mucous disease group, there were 6 types of inhaled allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blomia tropicdis, cat dandruff, dog dander, fungi) and 4 types of food allergens (egg yolks, egg white allergens, milk, shrimp/crab). However, the positivity rate of Aspergillus fumigatus (7.2% vs 9.3% vs 10.5% vs 15.7%, χ 2=10.996, P=0.012)in the respiratory disease group and cockroaches(4.2% vs 11.3% vs 9.6% vs 16.4%, χ 2=10.237, P=0.017) in the skin and mucosal disease group was the lowest in the underage group. There are seasonal differences in the positivity rates of allergens, with most allergens having significantly higher positivity rates in summer and autumn. In conclusion, the most common allergens sIgE positive in patients with respiratory and dermo-mucous diseases in Shanghai City are Dermatophagoides pteronyssinus, Dermatophagoides farinae, milk, fungi, and Blomia tropicdis. The trend of allergen sIgE prevalence in the two major categories of diseases is basically consistent. Allergen sIgE distribution varies among patient populations of different gender, age or season, and clinical prevention and treatment can be based on the results of serum allergen testing.

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.

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.