Network pharmacology and molecular docking were employed to predict the mechanism of Zhizhu Decoction in regulating macrophage polarization to reduce adipose tissue inflammation in obese children, and animal experiments were then carried out to validate the prediction results. The active ingredients and targets of Zhizhu Decoction were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The inflammation related targets in the adipose tissue of obese children were searched against GeneCards, OMIM, and DisGeNET, and a drug-disease-target network was established. STRING was used to construct a protein-protein interaction(PPI) network and screen for core targets. R language was used to carry out Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses. AutoDock was used for the molecular docking between core targets and active ingredients. 24 SPF grade 6-week C57B/6J male mice were adaptively fed for 1 week, and 8 mice were randomly selected as the blank group. The remaining 16 mice were fed with high-fat diet for 8 weeks to onstruct a high-fat diet induced mouse obesity model. After successful modeling, the 16 mice were randomly divided into model group and Zhizhu Decoction group, with 8 mice in each group. Zhizhu Decoction group was intervened by gavage for 14 days, once a day. Blank group and model group were given an equal amount of sterile double distilled water(ddH_2O) by gavage daily. After the last gavage, serum and inguinal adipose tissue were collected from mice for testing. The morphology of inguinal adipose tissue was observed by hematoxylin-eosin(HE) staining, the levels of inflammatory factors interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α)were detected by enzyme-linked immunosorbent assay(ELISA), and the protein expression of macrophage marker molecule nitric oxide synthase(iNOS) and epidermal growth factor like hormone receptor 1(F4/80) was detected by immunofluorescence staining. Network pharmacology predicted luteolin, naringenin, and nobiletin as the main active ingredients in Zhizhu Decoction and 15 core targets. KEGG pathway enrichment analysis revealed involvement in the key signaling pathway of nuclear factor κB(NF-κB). Molecular docking showed that the active ingredients of Zhizhu Decoction bound well to the core targets. Animal experiment showed that compared with the model group, Zhizhu Decoction reduced the distribution of inflammatory cytokines in the inguinal adipose tissue of mice, lowered the levels of TNF-α and IL-6 in the serum(P<0.05, P<0.01), and down-regulated the expression of iNOS and F4/80(P<0.05). The results showed that the active ingredients in Zhizhu Decoction, such as luteolin, naringenin, and nobiletin, inhibit the aggregation of macrophages in adipose tissue, downregulate their classic activated macrophage(M1) polarization, reduce the expression of inflammatory factors IL-6 and TNF-α, and thus improve adipose tissue inflammation in obese mice.
Animals ; Drugs, Chinese Herbal/pharmacology* ; Molecular Docking Simulation ; Adipose Tissue/immunology* ; Mice ; Male ; Humans ; Network Pharmacology ; Macrophages/immunology* ; Mice, Inbred C57BL ; Child ; Protein Interaction Maps/drug effects* ; Obesity/genetics* ; Inflammation/drug therapy*

Since the promulgation of the first Drug Administration Law of the People's Republic of China 40 years ago in 1984, China has undergone four main stages in the traditional Chinese medicine(TCM) regulation: the initial establishment of TCM regulation rules(1984-1997), the formation of a modern TCM regulatory system(1998-2014), the reform of the review and approval system for new TCM drugs(2015-2018), and the construction of a scientific regulation system for TCM(2019-2024). Over the past five years, a series of milestone achievements of TCM regulation in China have been achieved in the six aspects, including its strategic objectives and the establishment of a science-based regulatory system, the reform of the review and approval system for new TCM drugs, the optimization and improvement of the TCM standard system and its formation mechanism, comprehensive enhancement of regulatory capabilities for TCM safety, international harmonization of TCM regulation and its role in promoting innovation. Looking ahead, centered on advancing TCMRS to establish a sound regulatory framework tailored to the unique characteristics of TCM, TCM regulation will evolve into new reform patterns, advancing and extending across eight critical fronts, including the legal framework and policy architecture, the review and approval system for new TCM drugs, the quality standard and management system of TCM, the comprehensive quality & safety regulation and traceability system, the research and transformation system for TCMRS, AI-driven innovations in TCM regulation, the coordination between high-quality industrial development and high-level regulation, and the leadership in international cooperation and regulatory harmonization. In this way, a unique path for the development of modern TCM regulation with Chinese characteristics will be pioneered.
Humans ; China ; Drugs, Chinese Herbal/standards* ; History, 20th Century ; History, 21st Century ; Medicine, Chinese Traditional/trends*

Objective The prevalence of drug-resistant Mycobacterium tuberculosis (Mtb) strains is exacerbating the global burden of tuberculosis (TB), highlighting the urgent need for new treatment strategies for TB. Methods The recombinant adenovirus vaccine expressing cyclic di-adenosine monophosphate (c-di-AMP) phosphodiesterase B (CnpB) (rAd-CnpB), was administered to normal mice via mucosal immunization, either alone or in combination with drug therapy, to treat Mtb respiratory infections in mice.Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of antibodies in serum and bronchoalveolar lavage fluid (BALF). Real-time quantitative PCR was performed to assess the transcription levels of cytokines interferon γ(IFN-γ) and interleukin 10(IL-10) in mouse lungs. Flow cytometry was used to determine the proportions of CD4⁺ and CD8⁺ T cell subsets in the lungs and spleens. ELISA was employed to measure the levels of cytokines IFN-γ, IL-2, IL-10, inflammatory factors IL-6, and tumor necrosis factor α (TNF-α) secreted by spleen cells following antigen stimulation. The bacteria loads in the lungs and spleens of Mtb-infected mice were enumerated by plate counting methods. Resluts Intranasal immunization with rAd-CnpB induced high titers of IgG in mouse serum and the production of IgG and IgA in BALF, along with alterations in T lymphocyte subsets in the lungs and spleens. Administration of rAd-CnpB, either alone or in combination with drugs, to Mtb-infected mice significantly increased serum IgG levels as well as IgA and IgG levels in BALF. rAd-CnpB immunization promoted the secretion of CnpB-specific cytokines and inflammatory factors by splenocytes in Mtb-infected mice. However, rAd-CnpB immunotherapy, either alone or combined with drugs, did not significantly affect the bacterial loads in the lungs and spleens of mice with Mtb respiratory infections. Conclusion Mucosal immunization with rAd-CnpB induced significant mucosal, humoral and cellular immune responses in mice, and significantly enhanced CnpB-specific cellular immune responses in Mtb-infected mice.
Animals ; Adenoviridae/immunology* ; Mycobacterium tuberculosis/genetics* ; Mice ; Female ; Phosphoric Diester Hydrolases/genetics* ; Tuberculosis Vaccines/administration & dosage* ; Tuberculosis/prevention & control* ; Mice, Inbred BALB C ; Cytokines ; Lung/microbiology* ; Immunization ; Bronchoalveolar Lavage Fluid/immunology* ; Immunity, Mucosal

OBJECTIVE: Recent studies have overturned the traditional concept of the lung as a "sterile organ" revealing that pulmonary microbiota dysbiosis and abnormal surfactant proteins (SPs) expression are involved in the progression of silicosis. This study aimed to investigate the relationship between abnormal SPs expression and dysbiosis of lung microbiota in silica-induced lung fibrosis, providing insights into mechanisms of silicosis. METHODS: Lung pathology, SPs expression, and microbiota composition were evaluated in silica-exposed mice. A mouse model of antibiotic-induced microbiota depletion was established, and alveolar structure and SPs expression were assessed. The roles of the lung microbiota and SPs in silicosis progression were further evaluated in mice with antibiotic-induced microbiota depletion, both with and without silica exposure. RESULTS: Silica exposure induced lung inflammation and fibrosis, along with increased expression of SP-A expression. Antibiotics (Abx)-induced microbiota depletion elevated SP-A and SP-D expression. Furthermore, silica exposure altered lung microbiota composition, enriching potentially pathogenic taxa. However, antibiotic-induced microbiota depletion prior to silica exposure reduced silica-mediated lung fibrosis and inflammation. CONCLUSION Lung microbiota is associated with silica-induced lung injury. Overproduction of SP-A and SP-D, induced by Abx-induced microbiota depletion, may enhance the resistance of mouse lung tissue to silica-induced injury.
Animals ; Silicosis/prevention & control* ; Lung/metabolism* ; Mice ; Anti-Bacterial Agents/pharmacology* ; Microbiota/drug effects* ; Silicon Dioxide/toxicity* ; Mice, Inbred C57BL ; Male ; Pulmonary Surfactant-Associated Proteins/genetics*

Objective To investigate the effects of DNA demethylation drugs combined with histone deacetylase in-hibitors on fragile X mental retardation 1 neighbor protein (FMR1NB) expression and its promoter methylation in human oral cancer cells and try to find a strategy of weakening the heterogeneity of FMR1NB expression.Methods Human oral cancer cell lines Cal27 and SCC-9 were treated with decitabine (DAC) , an inhibitor of DNA meth-yltransferase, combined with trichostatin A (TSA) and valproic acid (VPA), inhibitors of histone deacetylase.Then reverse transcription-polymerase chain reaction (RT-PCR) , quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the expression of FMR1 NB and pyrosequencing was used to detect the methylation of FMR1NB promoter.Results Compared with the blank control group, DAC and its combination with TSA and VPA significantly induced the expression of FMR1NB mRNA and protein in Cal27 and SCC-9 cells.Compared with DAC alone group, FMR1NB mRNA expression of each DAC-combined drug groups significantly increased, but FMR1NB protein did not significantly change in Cal27 cells; for SCC-9 cells, except for DAC+TSA group, the mRNA and protein levels of FMR1NB significantly increased in all other groups.In addition, there was no signifi-cant difference in the expression of FMR1 NB mRNA and protein between the three-combined drugs group and two-combined drugs groups.Further methylation assay showed that the methylation level of the overall FMR1NB promot-er and its each CpG site measured were reduced to varying degrees in all treatment groups except for three-combina-tion drug group of SCC-9.Conclusion DAC and its combination with TSA and VPA can enhance the expression of FMR1NB by mediating the demethylation of FMR1NB promoter, wherein the enhanced expression effect of the com-bination of the two drugs is stronger, suggesting that they have the potential to weaken the heterogeneity of FMR1NB expression and improve the immunotherapy effect of oral cancer.

Objective To compare the biomechanical stability of three cross-bridge headless compression screws and lock-ing plates in the fixation of Mason type Ⅲ radial head fractures by finite element method.Methods Using reverse modeling technology,the radial CT data and internal fixation data of a healthy 25-year-old male were imported into the relevant software.Three-dimensional finite element model of 3 cross-bridge headless compression screws and locking plates for Mason Ⅲ radial head fractures were established,and the radial head was loaded with 100 N axial loading.The maximum displacement,maxi-mum Von Mises stress and stress distribution of the two groups were compared.Results The maximum displacements of the three cross-bridge screws group and locking plate group were 0.069 mm and 0.087 mm respectively,and the Von Mises stress peaks were 18.59 MPa and 31.85 MPa respectively.The stress distribution of the three screws group was more uniform.Con-clusion Both internal fixation methods can provide good fixation effect.CoMPared with the locking plate fixation method,the 3 cross-bridge headless compression screws fixation is more stable and the stress distribution is more uniform.

Objective To evaluate the bioequivalence and safety of ezetimibe tablets in healthy Chinese subjects.Methods The study was designed as a single-center,randomized,open-label,two-period,two-way crossover,single-dose trail.Subjects who met the enrollment criteria were randomized into fasting administration group and postprandial administration group and received a single oral dose of 10 mg of the subject presparation of ezetimibe tablets or the reference presparation per cycle.The blood concentrations of ezetimibe and ezetimibe-glucuronide conjugate were measured by high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS),and the bioequivalence of the 2 preparations was evaluated using the WinNonlin 7.0 software.Pharmacokinetic parameters were calculated to evaluate the bioequivalence of the 2 preparations.The occurrence of all adverse events was also recorded to evaluate the safety.Results The main pharmacokinetic parameters of total ezetimibe in the plasma of the test and the reference after a single fasted administration:Cmax were(118.79±35.30)and(180.79±51.78)nmol·mL-1;tmax were 1.40 and 1.04 h;t1/2 were(15.33±5.57)and(17.38±7.24)h;AUC0-t were(1 523.90±371.21)and(1 690.99±553.40)nmol·mL-1·h;AUC0-∞ were(1 608.70±441.28),(1 807.15±630.00)nmol·mL-1·h.The main pharmacokinetic parameters of total ezetimibe in plasma of test and reference after a single meal:Cmax were(269.18±82.94)and(273.93±87.78)nmol·mL-1;Tmax were 1.15 and 1.08 h;t1/2 were(22.53±16.33)and(16.02±5.84)h;AUC0_twere(1 463.37±366.03),(1 263.96±271.01)nmol·mL-1·h;AUC0-∞ were(1 639.01±466.53),(1 349.97±281.39)nmol·mL-1·h.The main pharmacokinetic parameters Cmax,AUC0-tand AUC0-∞ of the two preparations were analyzed by variance analysis after logarithmic transformation.In the fasting administration group,the 90％CI of the log-transformed geometric mean ratios were within the bioequivalent range for the remaining parameters in the fasting dosing group,except for the Cmax of ezetimibe and total ezetimibe,which were below the lower bioequivalent range.The Cmax of ezetimibe,ezetimibe-glucuronide,and total ezetimibe in the postprandial dosing group was within the equivalence range,and the 90％CI of the remaining parameters were not within the equivalence range for bioequivalence.Conclusion This test can not determine whether the test preparation and the reference preparation of ezetimibe tablets have bioequivalence,and further clinical trials are needed to verify it.

Objective To address the quality problems caused by high porosity in the preparation of dental cobalt-chrome alloy prosthetics based on selective laser melting(SLM)technology,we investigated the influence mechanism of different forming process parameters on the microstructure and properties of the materials.Moreover,the range of form-ing process parameters that can effectively reduce defects was precisely defined.Methods The effects of laser power,scanning speed,and scanning distance on the pore properties,surface roughness,and hardness of dental cobalt-chrome al-loy were investigated by adjusting the printing parame-ters in the process of SLM.Through metallographic anal-ysis,image analysis,and molten pool simulation,the pore formation mechanism was revealed,and the relation-ship between the porosity and energy density of SLM dental cobalt-chrome alloy was elucidated.Results When the linear energy density was higher than 0.18 J/mm,the po-rosity defect easily appeared at the bottom of the molten pool.When the laser energy density was lower than 0.13 J/mm,defects occurred in the gap of the molten pool due to insufficient melting of powder.In particular,when the linear energy density exceeded the threshold of 0.30 J/mm or was below 0.12 J/mm,the porosity increased significantly to more than 1%.In addition,we observed a negative correlation between free surface roughness and energy density and an inverse re-lationship between macroscopic hardness and porosity.Conclusion On the basis of the conditions of raw materials and molding equipment used in this study,the key process parameters of SLM of molding parts with porosity lower than 1%were successfully determined.Specifically,these key parameters included the line energy density,which ranged from 0.13 J/mm to 0.30 J/mm,and the scan spacing should be strictly controlled below 90 μm.

Liver size is regulated by circadian clock and exhibits a diurnal rhythm. Pregnane X receptor (PXR) and peroxisome proliferator-activated receptor α (PPARα), members of nuclear receptor superfamily, are important regulators of liver size. We previously demonstrated that mPXR agonist pregnenolone 16α-carbonitrile (PCN) and mPPARα agonist pirinixic acid (WY-14643) promoted liver enlargement and liver regeneration after partial hepatectomy. However, whether PXR or PPARα activation-induced liver enlargement exhibits diurnal rhythm with normal liver diurnal oscillations remains unclear. The aim of this study was to investigate the diurnal rhythm of PXR or PPARα activation-induced liver enlargement. Male C57BL/6 mice were intraperitoneally injected with corn oil, PCN or WY-14643 for three days, and liver samples were weighed and collected at various time points for analysis. The animal experiment protocol was reviewed and approved by Institutional Animal Care and Use Committee of Sun Yat-sen University (approval No. SYSU-IACUC-2023-001613, SYSU-IACUC-2023-001783). The results showed that PXR or PPARα activation at various time points significantly induced liver enlargement, and liver size maintained normal diurnal oscillations during PXR or PPARα activation-induced hepatomegaly, without significant effects on the expression of core clock genes. This study reveals PXR or PPARα activation-induced liver enlargement exhibits diurnal rhythm with normal liver diurnal oscillations, and provides novel data for nuclear receptor-induced liver enlargement and liver diurnal rhythm.

Objective To develop a GPU-based Monte Carlo dose calculation module for helical tomotherapy(TOMO),and integrate it into the commercial software ArcherQA to achieve fast and accurate dose verification in clinic.Methods The TOMO treatment head was modeled using TOPAS to obtain phase space files,and a fast weight tuning algorithm was used to simulate particle transport in multi-leaf collimator for improving computational efficiency,and finally,GPU-based Monte Carlo algorithms in ArcherQA were used to simulate particle transport in patients.To verify the model accuracy,the ArcherQA calculated results in water tank were compared with measured data for different open fields.In addition,multiple comparisons among ArcherQA results,TPS results and ArcCHECK results were conducted on 15 clinical cases(5 cases in the head and neck,5 cases in the chest and abdomen,and 5 cases in the whole body).Results In the water tank tests for 40 cm×5.0 cm,40 cm×2.5 cm and 40 cm× 1.0 cm radiation fields,the average global relative errors of the percentage depth dose,transverse dose distribution,and longitudinal dose distribution calculated by ArcherQA with the corresponding measured values were 0.72％,0.66％,and 0.54％,respectively.Over 98％of the voxels had a global relative error of less than 1％.As for 15 clinical cases,in 2％/2 mm criteria,the mean Gamma passing rate was 98.1％between ArcherQA and TPS,99.1％between TPS and ArcCHECK,and 99.4％between ArcherQA and ArcCHECK.The uncertainty of the simulation maintained less than 1％,and the average time taken for calculation based on patient CT vs ArcCHECK phantom was 87 s vs 64 s.Conclusion ArcherQA can be used for independent dose validation for TOMO plans for it can provide fast and accurate dose calculations.