BACKGROUND:We have successfully established an animal model of small ear pig in southern Yunnan province with internal tension relieving technique combined with autologous Achilles tendon for anterior cruciate ligament reconstruction,and verified the stability and reliability of the model.However,whether internal tension relieving technique can promote the ligamentalization process of autologous Achilles tendon graft has not been studied. OBJECTIVE:To investigate the differences in the process of ligamentalization between conventional reconstruction and internal reduction reconstruction of the anterior cruciate ligament by gross view,histology and electron microscopy. METHODS:Thirty adult female small ear pigs in southern Yunnan province were selected.Anterior cruciate ligament reconstruction was performed on the left knee joint with the ipsilateral knee Achilles tendon(n=30 in the normal group),and anterior cruciate ligament reconstruction was performed on the right knee joint with the ipsilateral knee Achilles tendon combined with the internal relaxation and enhancement system(n=30 in the relaxation group).The autogenous right forelimb was used as the control group;the anterior cruciate ligament was exposed but not severed or surgically treated.At 12,24,and 48 weeks after surgery,10 animals were sacrificed,respectively.The left and right knee joint specimens were taken for gross morphological observation to evaluate the graft morphology.MAS score was used to evaluate the excellent and good rate of the ligament at each time point.Hematoxylin-eosin staining was used to evaluate the degree of ligament graft vascularization.Collagen fibers and nuclear morphology were observed,and nuclear morphology was scored.Ultrastructural remodeling was evaluated by scanning electron microscopy and transmission electron microscopy. RESULTS AND CONCLUSION:(1)The ligament healing shape of the relaxation group was better at various time points after surgery,and the excellent and good rate of MAS score was higher(P<0.05).Moreover,the relaxation group could obtain higher ligament vascularization score(P<0.05).(2)The arrangement of collagen bundles and fiber bundles in the two groups gradually tended to be orderly,and the transverse fiber connections between collagen gradually increased and thickened,suggesting that the strength and shape degree of the grafts were gradually improved,but the ligament remodeling in the relaxation group was always faster than that in the normal group at various time points after surgery.(3)The diameter,distribution density,and arrangement degree of collagen fibers in the relaxation group were better than those in the normal group at all time points,especially in the comparison of collagen fiber diameter between and within the relaxation group(P<0.05).

OBJECTIVE To analyze the characteristics of pediatric medicines with priority review and approval for marketing in China， providing a reference for promoting enterprise R&D and production， as well as improving the supply guarantee mechanism for pediatric medicines. METHODS Based on publicly available data sources such as List of Approved Information for Pediatric Medications Subject to Priority Review and Approval， Pharnexcloud biomedical database， and National Medical Insurance Drug Directory， this study conducted a comprehensive analysis of the main characteristics of pediatric medicines with priority review and approval for marketing. RESULTS As of June 30， 2024， a total of 68 pediatric medicines had been approved through the priority review and approval process， covering 12 therapeutic areas， with oral dosage forms accounting for 64.71%. The median time from application to inclusion in priority review was 35.50 days， with an average of 41.69 days. The median time from inclusion in priority review to market approval was 1.24 years， with an average of 1.42 years. This included 12 domestic new medicines， 21 domestic generic medicines， 35 imported medicines， as well as 29 pediatric-specific medicines and 21 orphan medicines. Additionally， 31 of these medicines had been included in the medical insurance catalog， representing a proportion of 45.59%. CONCLUSIONS Currently， a trend of differentiated competition is emerging between domestic and imported pediatric medicines. The therapeutic areas for pediatric medicines are continuously expanding， and the dosage forms are becoming more tailored to children’s needs. However， there are still issues such as slow progress in new medicine development， insufficient stability in the medicine review and approval process， and a need to increase the proportion of medicines included in medical insurance.

ObjectiveTo identify the active constituents of Kaixuan Jiedu core prescription （KXJD） and investigate its effective components and therapeutic targets in the treatment of common psoriasis. MethodsUltra-performance liquid chromatography-high resolution mass spectrometry （UPLC-Q-TOF MS） was used to identify and analyze the chemical components of KXJD and its blood-entering chemical components. The chemical components of the single decoction were further identified to clarify the source of the chemical components in KXJD. Then， all identified blood-entering compounds were screened for effective active ingredients through the Swiss ADME database. The active ingredient targets of KXJD were searched on the Swiss Target Prediction platform. The targets of common psoriasis were searched in OMIM， GEO， GeneCards， and DISGNET databases to obtain drug-disease intersection targets. The protein-protein interaction network of intersection targets was constructed using STRING， and then the core blood-entering component-intersection target network of KXJD was constructed. The core target proteins in the network were selected for molecular docking with the core components of KXJD. Small molecules and proteins were pretreated， and appropriate docking sites were selected. AutoDock Vina software was used for continuous local search and repeated iterations to find molecular docking conformations. PyMOL software and LigPlot+ software were used for analysis and visualization. Subsequently， the verification was carried out through animal experiments. SPF-grade male C57 mice were randomly divided into a blank group， a model group， a positive drug methotrexate group， and a KXJD group. In the model group， the methotrexate group， and the KXJD group， imiquimod was applied to the backs of the mice for modeling. The blank group and the model group were administered normal saline by gavage， while the methotrexate group and the KXJD group were respectively administered 1 mg·kg^-1 suspension and 30.42 g·kg^-1 decoction of traditional Chinese medicine by gavage. Five days after administration， the mice were sacrificed， and samples were collected. Hematoxylin-eosin （HE） staining was used to observe the skin tissue samples of mice， and the effect of KXJD on the pathological manifestations of psoriasis mice was analyzed. The expression areas of tumor necrosis factor-α （TNF-α）， cyclooxygenase 2 （PTGS2）， interleukin （IL）-1β， and IL-6 in the skin tissue of mice were detected by immunohistochemistry （IHC）. The mRNA expressions of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of mice were detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）. ResultsIn this study， 208 compounds in KXJD were identified by UPLC-Q-TOF MS， and 44 compounds were detected in serum， including 28 prototype components and 16 metabolites. 12 blood-entering active components were screened， and 1 153 active component targets and 1 076 psoriasis-related targets were identified. Eighty-five targets in the intersection set were drug-disease common targets. PPI network analysis showed that TNF-α， IL-1β， IL-6， PTGS2， and ALB were the key target proteins. The results of molecular docking showed that the binding ability of （+）-hexylphenylglycolic acid to key target proteins such as PTGS2 was stable， and PTGS2 showed high stability with a variety of core compounds. Compared with those in the blank group， the stratum corneum and epidermis in the model group mice were significantly thickened， and the pathological Baker score of the mice's skin in the model group was significantly higher than that of the blank group （P<0.01）. The expression areas of PTGS2， TNF-α， IL-1β， and IL-6 proteins in the skin tissue of the model group mice were significantly increased （P<0.01）， and the expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the model group mice were significantly elevated （P<0.01）. Compared with the model group， the pathological Baker scores of the methotrexate group and the KXJD group were both decreased （P<0.01）， and the expression areas in the skin tissue of the methotrexate group and the KXJD group were significantly reduced （P<0.05， P<0.01）. The expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the methotrexate group and the KXJD group were significantly decreased （P<0.01）. ConclusionKXJD can effectively improve the skin lesions of psoriasis model mice and reduce the expression of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of psoriasis model mice. PTGS2 has a stable binding ability with a variety of compounds in the decoction， which may be a key target for the treatment of psoriasis. The compound （+）-hexylphenylglycolic acid may play a key role.

ObjectiveTo identify the active constituents of Kaixuan Jiedu core prescription （KXJD） and investigate its effective components and therapeutic targets in the treatment of common psoriasis. MethodsUltra-performance liquid chromatography-high resolution mass spectrometry （UPLC-Q-TOF MS） was used to identify and analyze the chemical components of KXJD and its blood-entering chemical components. The chemical components of the single decoction were further identified to clarify the source of the chemical components in KXJD. Then， all identified blood-entering compounds were screened for effective active ingredients through the Swiss ADME database. The active ingredient targets of KXJD were searched on the Swiss Target Prediction platform. The targets of common psoriasis were searched in OMIM， GEO， GeneCards， and DISGNET databases to obtain drug-disease intersection targets. The protein-protein interaction network of intersection targets was constructed using STRING， and then the core blood-entering component-intersection target network of KXJD was constructed. The core target proteins in the network were selected for molecular docking with the core components of KXJD. Small molecules and proteins were pretreated， and appropriate docking sites were selected. AutoDock Vina software was used for continuous local search and repeated iterations to find molecular docking conformations. PyMOL software and LigPlot+ software were used for analysis and visualization. Subsequently， the verification was carried out through animal experiments. SPF-grade male C57 mice were randomly divided into a blank group， a model group， a positive drug methotrexate group， and a KXJD group. In the model group， the methotrexate group， and the KXJD group， imiquimod was applied to the backs of the mice for modeling. The blank group and the model group were administered normal saline by gavage， while the methotrexate group and the KXJD group were respectively administered 1 mg·kg^-1 suspension and 30.42 g·kg^-1 decoction of traditional Chinese medicine by gavage. Five days after administration， the mice were sacrificed， and samples were collected. Hematoxylin-eosin （HE） staining was used to observe the skin tissue samples of mice， and the effect of KXJD on the pathological manifestations of psoriasis mice was analyzed. The expression areas of tumor necrosis factor-α （TNF-α）， cyclooxygenase 2 （PTGS2）， interleukin （IL）-1β， and IL-6 in the skin tissue of mice were detected by immunohistochemistry （IHC）. The mRNA expressions of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of mice were detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）. ResultsIn this study， 208 compounds in KXJD were identified by UPLC-Q-TOF MS， and 44 compounds were detected in serum， including 28 prototype components and 16 metabolites. 12 blood-entering active components were screened， and 1 153 active component targets and 1 076 psoriasis-related targets were identified. Eighty-five targets in the intersection set were drug-disease common targets. PPI network analysis showed that TNF-α， IL-1β， IL-6， PTGS2， and ALB were the key target proteins. The results of molecular docking showed that the binding ability of （+）-hexylphenylglycolic acid to key target proteins such as PTGS2 was stable， and PTGS2 showed high stability with a variety of core compounds. Compared with those in the blank group， the stratum corneum and epidermis in the model group mice were significantly thickened， and the pathological Baker score of the mice's skin in the model group was significantly higher than that of the blank group （P<0.01）. The expression areas of PTGS2， TNF-α， IL-1β， and IL-6 proteins in the skin tissue of the model group mice were significantly increased （P<0.01）， and the expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the model group mice were significantly elevated （P<0.01）. Compared with the model group， the pathological Baker scores of the methotrexate group and the KXJD group were both decreased （P<0.01）， and the expression areas in the skin tissue of the methotrexate group and the KXJD group were significantly reduced （P<0.05， P<0.01）. The expression levels of PTGS2， TNF-α， IL-1β， and IL-6 mRNA in the skin tissue of the methotrexate group and the KXJD group were significantly decreased （P<0.01）. ConclusionKXJD can effectively improve the skin lesions of psoriasis model mice and reduce the expression of TNF-α， IL-1β， IL-6， and PTGS2 in the skin tissue of psoriasis model mice. PTGS2 has a stable binding ability with a variety of compounds in the decoction， which may be a key target for the treatment of psoriasis. The compound （+）-hexylphenylglycolic acid may play a key role.

This study aimed to compare the ameliorative effects of Lycii Fructus and Chrysanthemi Flos at different ratios on retinal damage in mice and to elucidate the underlying mechanisms. A retinal injury model was established by intraperitoneal injection of sodium iodate(NaIO_3) solution. The mice were divided into the following groups: blank group, model group, positive drug(AREDS 2) group, low-and high-dose groups of Lycii Fructus and Chrysanthemi Flos at 1∶1, low-and high-dose groups at 3∶1, and low-and high-dose groups at 1∶3. Administration was carried out 15 days after modeling. The visual acuity of the mice was assessed using the black-and-white box test. The fundus was observed using an optical coherence tomography device, and retinal thickness was measured. HE staining was used to observe the morphology and pathological changes of the retina. The levels of oxidative factors in serum and ocular tissues were measured using assay kits. The levels of inflammatory factors in serum and ocular tissues were detected by enzyme-linked immunosorbent assay(ELISA), and the expression of Nrf2, HO-1, and NF-κB proteins in ocular tissues was analyzed by Western blot. The results showed that after administration of Lycii Fructus and Chrysanthemi Flos at different ratios, the model group showed improved retinal thinning and disordered arrangement of retinal layers, elevated content of SOD and GSH in the serum and ocular tissues, and reduced levels of MDA, TNF-α, IL-1β, and IL-6. Lycii Fructus and Chrysanthemi Flos at 1∶1 and 1∶3 showed better improvement effects. The combination significantly upregulated the expression levels of Nrf2 and HO-1 and downregulated the expression of NF-κB p65. These results indicate that Lycii Fructus and Chrysanthemi Flos at different ratios can improve retinal damage, reduce oxidative stress, and alleviate inflammation in both the body and ocular tissues of mice. The mechanism may be related to the regulation of the Nrf2/HO-1 and NF-κB signaling pathways in ocular tissues. These findings provide a theoretical basis for the clinical application of Lycii Fructus and Chrysanthemi Flos in the treatment of dry age-related macular degeneration.
Animals ; Mice ; Retina/injuries* ; Male ; Lycium/chemistry* ; Drugs, Chinese Herbal/administration & dosage* ; Chrysanthemum/chemistry* ; NF-kappa B/genetics* ; Humans ; Retinal Diseases/metabolism* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress/drug effects* ; Flowers/chemistry* ; Heme Oxygenase-1/genetics*

This study employed bioinformatics to screen the feature genes related to efferocytosis in diabetic kidney disease(DKD) and explores traditional Chinese medicine(TCM) regulating these feature genes. The GSE96804 and GSE30528 datasets were integrated as the training set, and the intersection of differentially expressed genes and efferocytosis-related genes(ERGs) was identified as DKD-ERGs. Subsequently, correlation analysis, protein-protein interaction(PPI) network construction, enrichment analysis, and immune infiltration analysis were performed. Consensus clustering was conducted on DKD patients based on the expression levels of DKD-ERGs, and the expression levels, immune infiltration characteristics, and gene set variations between different subtypes were explored. Eight machine learning models were constructed and their prediction performance was evaluated. The best-performing model was evaluated by nomograms, calibration curves, and external datasets, followed by the identification of efferocytosis-related feature genes associated with DKD. Finally, potential TCMs that can regulate these feature genes were predicted. The results showed that the training set contained 640 differentially expressed genes, and after intersecting with ERGs, 12 DKD-ERGs were obtained, which demonstrated mutual regulation and immune modulation effects. Consensus clustering divided DKD into two subtypes, C1 and C2. The support vector machine(SVM) model had the best performance, predicting that growth arrest-specific protein 6(GAS6), S100 calcium-binding protein A9(S100A9), C-X3-C motif chemokine ligand 1(CX3CL1), 5'-nucleotidase(NT5E), and interleukin 33(IL33) were the feature genes of DKD. Potential TCMs with therapeutic effects included Astragali Radix, Trionycis Carapax, Sargassum, Rhei Radix et Rhizoma, Curcumae Radix, and Alismatis Rhizoma, which mainly function to clear heat, replenish deficiency, activate blood, resolve stasis, and promote urination and drain dampness. Molecular docking revealed that the key components of these TCMs, including β-sitosterol, quercetin, and sitosterol, exhibited good binding activity with the five target genes. These results indicated that efferocytosis played a crucial role in the development and progression of DKD. The feature genes closely related to both DKD and efferocytosis, such as GAS6, S100A9, CX3CL1, NT5E, and IL33, were identified. TCMs such as Astragali Radix, Trionycis Carapa, Sargassum, Rhei Radix et Rhizoma, Curcumae Radix, and Alismatis Rhizoma may provide a new therapeutic strategy for DKD by regulating efferocytosis.
Humans ; Computational Biology ; Diabetic Nephropathies/physiopathology* ; Protein Interaction Maps ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal ; Phagocytosis/genetics* ; Efferocytosis

OBJECTIVE: To analyze the MYH9 gene sequence of a patient with hereditary thrombocytopenia and diffuse large B-cell lymphoma and his family members, and to explore the relationship between MYH9 gene and tumors. METHODS: Peripheral blood samples were collected from the patients and their family members for complete blood count analysis. The platelet morphology was observed under microscope. The MYH9 gene sequence was analyzed by Whole Exon Sequencing and Sanger Sequencing. RESULTS: The mutation site c.279C>A:p.(Asn93Lys) in exon 2 of the MYH9 gene were found in patient and his family members, both presenting as thrombocytopenia. The platelet count was significantly increased after the administration of Avatrombopag. CONCLUSION A novel mutation of MYH9 was found in this study, and the case was sensitive to Avatrombopag, by exploring the relationship between the MYH9 gene and tumors, suggesting that the MYH9 gene may be associated with the development of diffuse large B-cell lymphoma.
Humans ; Myosin Heavy Chains/genetics* ; Thrombocytopenia/genetics* ; Mutation ; Male ; Lymphoma, Non-Hodgkin/genetics* ; Lymphoma, Large B-Cell, Diffuse/genetics* ; Molecular Motor Proteins/genetics* ; Pedigree

BACKGROUND: The association of systemic inflammatory response index (SIRI) with prognosis of coronary artery disease (CAD) patients has never been investigated in a large sample with long-term follow-up. This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States. METHODS: A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 were included in this study. Cox proportional hazards model, restricted cubic spline (RCS), and receiver operating characteristic curve (ROC) were performed to investigate the association of SIRI with all-cause and cause-specific mortality. Piece-wise linear regression and sensitivity analyses were also performed. RESULTS: During a median follow-up of 7.7 years, 1454 all-cause mortality occurred. After adjusting for confounding factors, higher lnSIRI was significantly associated with higher risk of all-cause (HR = 1.16, 95% CI: 1.09-1.23) and CVD mortality (HR = 1.17, 95% CI: 1.05-1.30) but not cancer mortality (HR = 1.17, 95% CI: 0.99-1.38). The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI, respectively. ROC curves showed that lnSIRI had robust predictive effect both in short and long terms. CONCLUSIONS SIRI was independently associated with all-cause and CVD mortality, and the dose-response relationship was J-shaped. SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.

Acute pancreatitis (AP) is a life-threatening gastrointestinal disorder for which no effective pharmacological treatments are currently available. One of the pharmacological targets that merits further research is the neurokinin 1 receptor (NK1R), which is found on pancreatic acinar cells and responds to the neuropeptide substance P (SP) that participates in AP. Although a few studies have stated the involvement of SP/NK1R in neurogenic inflammation in AP development, the regulatory mechanism remains unclear. In this study, we found that following activation of NK1R by SP, β-arrestin1, a scaffold protein of NK1R, down-regulated transcription of Adss, Adsl, and Ampd in the purine nucleotide cycle, thereby inhibiting mitochondrial function through fumarate depletion. Interestingly, we identified magnolol as a new and natural NK1R inhibitor with a non-nitrogenous biphenyl core structure. It exhibited a beneficial effect on AP by restoring purine nucleotide cycle metabolic enzymes and fumarate levels. Our study not only provides new therapeutic strategies, leading compounds, and drug translation possibilities for AP, but also provides important clues for the study of downstream mechanisms driven by SP in other diseases.