ObjectiveTo explore the correlation between the occurrence of cardiovascular events in rheumatoid arthritis（RA） and traditional Chinese medicine（TCM） syndrome. MethodsThe cross-sectional study selected 6713 RA patients from 122 centres nationwide， in which general information such as name， gender， age， height， body weight， and course of disease were collected by completing a questionnaire； patients were classified into eight types of syndrome according to the information of their four examinations，i.e. wind-dampness obstruction syndrome， cold-dampness obstruction syndrome， dampness-heat obstruction syndrome， phlegm-stasis obstruction syndrome， stasis-blood obstructing collateral syndrome， qi-blood deficiency syndrome， liver-kidney insufficiency syndrome， and qi-yin deficiency syndrome. According to the occurrence of cardiovascular events， they were divided into the occurrence group and the non-occurrence group， and the condition assessment data and laboratory examination indexes were recorded. The test of difference between groups was used to analyse the possible risk factors for the occurrence of RA cardiovascular events， and binary logistic regression was used to analyse the correlation between TCM syndromes and RA cardiovascular events. ResultsA total of 6713 RA patients were included， including 256 cases in occurrence group and 6457 in non-occurrence group. There was no statistically significant difference between groups in terms of height， gender， insomnia， appetite， white blood cell（WBC）， hemoglobin（HGB）， platelets（PLT）， rheumatoid factor（RF）， anti-cyclic peptide containing citrulline（CCP）， alanine aminotransferase（ALT）， aspartate aminotransferase（AST）， γ-glutamyl transpeptidase（GGT）， urea creatinine（CREA）， and glucose（GLU）（P＞0.05）. The TCM syndromes between groups showed significant statistic differences（P＜0.05）. Patients in occurrence group had longer disease duration， heavier body weight， and older age； more severe conditions such as disease activity（DAS-28）， number of painful joints（TJC）， number of swollen joints（SJC）， health questionnaire scores（HAQ）， visual analog scores（VAS）， restlessness， and fatigue； higher blood sedimentation rate（ESR）， low-density lipoprotein（LDL-C）， triglyceride（TG）， total cholesterol（TC）， D-Dimer， and lower high-density lipoprotein（HDL-C）（P＜0.05）. The distribution of syndrome types showed that dampness-heat obstruction syndrome accounted for the largest proportion of patients in both groups and was higher in RA cardiovascular events. Logistic regression analysis showed that the occurrence of RA cardiovascular events was strongly associated with dampness-heat obstruction syndrome［OR=5.937， 95%CI （4.434， 7.949）， P＜0.001］. ConclusionThe occurrence of RA cardiovascular events were associated with TCM syndromes， and the probability of cardiovascular events in the RA patients with dampness-heat obstruction syndrome was 5.937 times higher than patients with other TCM syndromes.

Objective:To explore whether multi-parametric MRI (mpMRI) combined with 68Ga-prostate specific membrane antigen (PSMA) PET/CT can improve the detection efficiency of clinically significant prostate cancer (csPCa). Methods:Clinical and imaging data of 152 patients (age (68.5±8.5) years) who underwent mpMRI and 68Ga-PSMA PET/CT examination for suspected prostate cancer in the First Affiliated Hospital of the Air Force Medical University from January 2021 to November 2022 were retrospectively analyzed, with the histopathological results from transrectal ultrasound guided biopsy as reference. Lesions with Gleason scores (GS) ≥3+ 4 from the biopsy were diagnosed with csPCa, and lesions with negative biopsy or GS 6 were diagnosed with non-csPCa. MpMRI was evaluated independently by two radiologists according to the Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. The radioactive uptake of 68Ga-PSMA PET/CT in prostate lesions was evaluated by SUV max. The independent-sample t test, Mann-Whitney U test and χ2 test were used to compare differences between the two groups, and then multivariate logistic regression analysis was performed. ROC curves analysis was used to analyze the diagnostic efficacies of individual and combined factors and Delong test was used. Results:There were 85 csPCa and 67 non-csPCa confirmed. Prostate specific antigen (PSA), PI-RADS score and SUV max were significantly different between the csPCa group and the non-csPCa group ( χ2=68.06, U values: -7.66, -8.98, all P<0.001). Multivariate logistic regression analysis indicated that PI-RADS score (odds ratio ( OR)=3.424, 95% CI: 1.651-7.100) and SUV max ( OR=1.931, 95% CI: 1.403-2.658) were independent predictors of csPCa (both P<0.001). ROC curves analysis revealed that the cut-off value for diagnosing csPCa was 4 for PI-RADS score and 5.6 for SUV max. The accuracy of mpMRI and PET/CT alone in csPCa diagnosis was 80%(122/152) (AUC of 0.789(95% CI: 0.711-0.866) with the sensitivity and specificity of 91%(77/85) and 67%(45/67)), and 87%(132/152) (AUC of 0.876(95% CI: 0.817-0.936) with the sensitivity and specificity of 81%(69/85) and 94%(63/67)), respectively. Several joint models incorporating 68Ga-PSMA PET/CT with mpMRI data were investigated, the model of PI-RADS 5 or PI-RADS 3-4 and SUV max>5.6 showed better performance than mpMRI and PET/CT alone and other joint models ( z values: 2.01-3.64, all P<0.05), with the accuracy of 91%(138/152) (AUC of 0.910(95% CI: 0.857-0.962) with the sensitivity and specificity of 89%(76/85) and 93%(62/67)). Conclusion:MpMRI combined with 68Ga-PSMA PET/CT can significantly improve the detection efficiency of csPCa, with the principal effect being improved in risk stratification of PI-RADS 3-4 lesions in mpMRI.

ObjectiveTo observe the clinical characteristics and influencing factors of adverse events of Osteoking and provide a basis for its rational use in clinical practice. MethodA prospective and multicenter Cohort study with large samples was conducted to observe the effects of Osteoking in the treatment of 922 patients with knee osteoarthritis from 20 hospitals from May 1， 2020 to December 31， 2021. Patients who were treated with Osteoking were set as the exposed cohort， and those who were not treated with Osteoking were set as the non-exposed cohort. The gender， age， body mass index （BMI）， occupation， allergy history， past medical history， hospital information， medication， and the occurrence of adverse events of the patients were recorded， and the incidence of adverse events was analyzed， as well as its characteristics and factors. ResultA total of 922 patients with knee osteoarthritis were involved， including 274 males （29.72%） and 648 females （70.28%）， from which 617 cases were in the exposed cohort， and 305 cases were in the non-exposed cohort. A total of 25 adverse events occurred in both cases， accounting for 2.71% of the total number of cases， with 17 cases in the exposed cohort （2.76%） and eight cases in the non-exposed cohort （2.62%）. There was no difference in the incidence rate between the two groups （P=0.907）. The age group with the highest incidence of adverse events was between 50 and 59 years old in the exposed cohort （4.61%）. The incidence rate in women was 3.49%， slightly higher than 1.07% in men， but there was no difference （P=0.156）. According to the systematic classification of adverse events， five cases were respiratory， thoracic， and mediastinal diseases， with an incidence rate of 0.81%. There were two cases of infection and infection diseases， two cases of skin and subcutaneous tissue diseases， two cases of heart-related diseases， two cases of symptoms and signs （not otherwise classified）， and two cases of eye organ diseases， and the incidence rate was 0.32%. There was one case of systemic disease， one case of neuropathy， one case of heart organ disease， and one case of vascular hypotension disease， and the incidence rate was 0.16%. During the trial， a total of seven adverse reactions occurred. Among them， there were two cases of dry pharynx， two cases of dizziness， one case of drowsiness， one case of hypotension， and one case of eye discharge， with an incidence rate of 1.13%. Through binary Logistic regression analysis， it was found that among the factors that may affect the occurrence of adverse events in the exposed group， traditional Chinese medicine hospitals were the protective factors for the occurrence of adverse events （OR=0.200， P=0.002）， while gender， age， BMI， occupation， allergy history， past medical history， and hospital level cannot be considered to have an impact on the occurrence of adverse events. ConclusionOsteoking can be used to treat knee osteoarthritis of patients of all ages and genders by doctors from hospitals of different levels with higher safety， with occasional and mild adverse events， and seeing a doctor in a traditional Chinese medicine hospital can reduce the occurrence of adverse reactions.

OBJECTIVE To explore the characteristics of adverse drug reaction （ADR） induced by semaglutide and provide a reference for clinically safe medication. METHODS Using search terms such as “semaglutide” and “adverse reactions” in both Chinese and English， the case reports about ADRs caused by semaglutide were searched and analyzed from PubMed， Web of Science， SpringerLink， CNKI， Chinese Medical Journal Full-text Database， Wanfang Medical Network and VMIS. RESULTS Overall 14 literature were included， involving 17 patients. Among 17 patients， 9 were female and 8 were male， with the age ranging from 25 to 80 years. Eight patients were given two or more drugs， and eight patients took 0.25 mg as the initial dose； the ADR occurred most frequently within 6 months （94.12%）. Sixteen patients’ symptoms improved or recovered after drug withdrawal and symptomatic treatment. Eleven patients did not mention whether to continue to use semaglutide in the future. Nine patients underwent ADR correlation evaluation， and 1， 3， 1 and 4 cases were determined to be “definite”，“ probable”，“ possible”， and “doubtful” respectively. Semaglutide-induced ADRs involved multiple organs or systems， most of which were the digestive system （35.29%）， followed by skin tissue （29.41%）. Among them， acute gastric dilation， severe liver injury， calculous cholecystitis， bullous pemphigoid， eosinophilic fasciitis， acute kidney injury， acute interstitial nephritis， depression and acute hemolytic anemia were not mentioned in the instruction. CONCLUSIONS ADRs caused by semaglutide can occur in all ages， mainly within 6 months after medication， and mainly involve the digestive system， skin tissue， etc. Great attention should be paid to pharmaceutical care for those patients with liver and kidney dysfunction， neuropsychiatric diseases， glucose-6-phosphate dehydrogenase deficiency， etc. When ADR occurs， drug withdrawal and symptomatic treatment should be performed promptly to ensure patients’ medication safety.

OBJECTIVE To introduce a case of interstitial pneumonia induced by vedolizumab （VDZ）， summarize and analyze the characteristics of the occurrence of VDZ-associated lung toxicity， and provide a reference for the clinically safe use of drugs. METHODS From the perspective of clinical pharmacists， the diagnosis and treatment of a case of VDZ-induced interstitial pneumonia were retrospectively analyzed， and the association of adverse drug reactions （ADR） was analyzed. Retrieving from Chinese and English databases such as CNKI， VIP， PubMed and Web of Science， case reports of VDZ-associated lung toxicity were summarized and analyzed. RESULTS The patient developed interstitial pneumonia during the use of VDZ and empirical anti- infective therapy with antibiotics was ineffective. After withdrawal of VDZ and treatment with methylprednisolone， symptoms and imaging examinations improved， but interstitial pneumonia still existed. According to Naranjo’s ADR evaluation scale and based on China Adverse Drug Reaction Reporting and Monitoring Manual， the association between VDZ and interstitial pneumonia was “very likely”. Results of the literature analysis showed that among 29 involved patients （including the patient reported in this article）， there were 19 males and 10 females， with an average age of （49.24±17.06） years. Lung toxicity mainly included VDZ- associated pneumonia， eosinophilic pneumonia， pulmonary granulomas or necrobiotic nodules， interstitial lung injury， etc.， which mostly occurred ≤24 weeks after medication （58.62%）. The main clinical manifestations included cough， dyspnea and fever. The vast majority of patients improved or recovered after drug withdrawal and/or glucocorticoid treatment， but one patient died of respiratory failure. CONCLUSIONS Lung toxicity is a rare ADR of VDZ with insidious onset and nonspecific symptoms. Once patients experience symptoms such as cough and dyspnea， early diagnosis，timely drug withdrawal，and symptomatic treatment measures such as glucocorticoid should be taken to ensure medication safety.

The MADS-box gene family is a very important transcriptional regulator gene, which plays a role in the whole growth and development process of plants. The APETALA1 (AP1) gene is considered to play an important regulatory role in the transformation of plant flowering, but also to control the characteristic development of floral organs. Lonicera macranthoides is used as medicine with dry buds and early flowers. Therefore, studying the potential mechanism of AP1 gene in regulating flower organ development can provide a basis for improving its medicinal value by molecular means. To explore the potential mechanism of the AP1 gene in the regulation of floral organ development in L. macranthoides, the full-length cDNA of the AP1 was cloned by reverse transcription PCR (RT-PCR) and named LmMADS4. The results show that the CDS of the LmMADS4 gene is 729 bp and encodes 242 amino acids, and the LmMADS4 protein contains no signal peptide and no transmembrane structure, which is an unstable hydrophilic protein. Through homologous sequence alignment and phylogenetic analysis, LmMADS4 and L. japonica MADS27 protein cluster into one class and are closely related. Finally, the expression pattern and protein interaction pattern of LmMADS4 were analyzed by real-time reverse transcription-PCR (qRT-PCR) and yeast two-hybrid technology. The qRT-PCR showed that LmMADS4 gene was differentially expressed in the stems, leaves and flower bud at different developmental stages, including bud type variety Longhua and common variety Baiyun; and LmMADS4 gene was highly expressed in the flower buds, and with the development of flower buds, LmMADS4 gene was continuously up-regulated in the flower bud variety Longhua, however, the expression level of LmMADS4 in the Baiyun terminal flower bud was lower than that in the late flower bud, but the difference was not significant. The yeast two-hybrid results showed that the bait vector pGBKT7-LmMADS4 was not toxic to yeast strains and had no self-activating activity. LmMADS4 protein interacted with LmSVP1, LmSVP3 and LmSOC1s proteins. This study can provide a theoretical basis for exploring the mechanism of long flower bud stage and corolla non-unfolding at the molecular level and variety improvement of L. macranthoides.

Objective:To summarize the clinical characteristics of multisystem inflammatory syndrome in children（MIS-C）related to SARS-CoV-2 and analyze the risk factors for hypotension.Methods:The clinical data of children with MIS-C who visited Beijing Children's Hospital from January 2023 to March 2023 were retrospectively collected,and the clinical characteristics and risk factors for hypotension were analyzed.Results:Thirty-six patients were included,the median age was 3.1 (2.3,5.8) years; 61.1% were boys.All cases had a history of SARS-CoV-2 infection between 1 and 9 weeks before onset.Clinical symptoms included fever (100.0%); rash (94.4%); bilateral conjunctival congestion (88.8%); lips/oral cavity changes (100.0%); swollen hands and foot (61.1%); cervical lymphadenopathy (88.8%); acute gastrointestinal symptoms (61.1%) of diarrhea,abdominal pain and vomiting; neurologic manifestations (33.3%) of lethargy,headache,and convulsions; respiratory symptoms(41.6%) of cough,sore throat and shortness of breath.Nineteen (52.8%) cases developed hypotension and needed vasoactive drugs support to maintain blood pressure.Mechanical ventilation was required in four(11.1%) cases,and one patient was intubated and treated with continuous renal replacement therapy.The level of ferritin in hypotension group was significantly higher than those in normal blood pressure group( P＜0.05),while the levels of platelet count,serum sodium and potassium in hypotension group were significantly lower than those in normal blood pressure group( P＜0.05).Logistic regression multivariable analysis found the elevated serum ferritin ( OR=20.000,95% CI:2.750-145.481, P=0.003) was an independent risk factor for hypotension. Conclusions:MIS-C may be observed following SARS-CoV-2 infection.Various symptoms and signs,including fever,multiple organ dysfunction,and hypotension,may occur in children with MIS-C.Elevated ferritin is a risk factor for hypotension.

AIM To investigate the protective effects and the mechanism of the Liuwei Dihuang Pills on mouse brain microvascular endothelial(bEnd.3)cells damaged by β-Amyloid protein1-40(Aβ1-40).METHODS CCK8 method was used to detect the effects of Aβ1-40 and medicated serum of Liuwei Dihuang Pills(MSLDP)on cell activity,and to screen the appropriate concentration.bEnd.3 cells of the control group,the Aβ1-40 group,the MSLDP+Aβ1-40 group and the MSLDP group had their low density lipoprotein-associated protein 1(LRP1),receptor for advanced glycation end products(RAGE),matrix metalloproteinase-2(MMP-2),MMP-9,scaffold protein zonule protein-1(ZO-1)detected by Western blot.bEnd.3 cells assigned into the control group,the Aβ1-40 group,the FPS-ZM1(RAGE inhibitor)+Aβ1-40 group and the FPS-ZM1+Aβ1-40+MSLDP group had their expressions of RAGE,MMP-9,MMP-2 and ZO-1 detected by Western blot as well.RESULTS The cell activity of bEnd.3,was dose-dependently decreased by Aβ1-40(P<0.01),but was protected by MSLDP(P<0.05,P<0.01).And 10 μmol/L Aβ1-40 and 10%MSLDP were selected for subsequent experiments.Compared with the control group,the Aβ1-40 group displayed increased protein expressions of RAGE,MMP-2 and MMP-9(P<0.01),decreased protein expressions of LRP1,ZO-1 and BDNF(P<0.05,P<0.01),and decreased fluorescence intensities of LRP1 and ZO-1(P<0.01).Compared with the Aβ1-40 group,the MSLDP group shared decreased expressions of RAGE,MMP-2,MMP-9 proteins and RAGE fluorescence intensity(P<0.05,P<0.01),and increased expressions of LRP1,ZO-1 and BDNF proteins,and the fluorescence intensity of LRP1 and ZO-1(P<0.05,P<0.01);the Aβ1-40+FPS-ZM1 group displayed decreased protein expressions of MMP-2,MMP9 and RAGE(P<0.05,P<0.01),and increased ZO-1 protein expression(P<0.05);and the Aβ1-40+FPS-ZM1+ MSLDP group displayed an even more decreased protein expressions of MMP-2,MMP9 and RAGE(P<0.01),increased ZO-1 protein expression(P<0.01)due to the the combination use of FPS-ZM1 and MSLDP.CONCLUSION Liuwei Dihuang Pills can protect the tight junction of bEnd.3 injured by Aβ1-40 and neurovascular units from Alzheimer's disease by alleviating the dysfunction of the blood-brain barrier via RAGE-mediated MMP-2/MMP-9 pathway inhibition.

Objective To detect the changes of mitophagy level in rats with endplate cartilage degeneration induced by spinal instability,and explore the role of PINK1/Parkin-mediated mitophagy in endplate cartilage and intervertebral disc degeneration.Methods The rat spinal instability model was established by surgically removing the superspinal and interspinal ligaments of L2 to L5,and cleaning the bilateral articular processes of the L2 to L5.Eighteen SD rats were divided into the normal group,the degenerative group,and the carbonyl cyanide 3-chlorophenylhydrazone(CCCP)group,with 6 rats in each group.The rats in the normal group had no special treatment,the rats in the degenerative group constructed a rat spinal instability model,and the rats in the CCCP group were injected with 5 μL of CCCP(10 μmol/L)in the intervertebral disc after the construction of spinal instability model.The changes of histomorphology in the endplate cartilage and intervertebral disc were abserved by HE staining,and the change of extracellular matrix of endplate cartilage was observed by safranin O-fast green staining.RT-PCR detected the mRNA expression of type Ⅱ collagen(COL-2A),aggrecan(ACAN),PINK1 and Parkin in each group.The changes of the protein expression levels of COL-2A,ACAN,PINK1,Parkin and mitochondrial membrane proteins of Tomm20 and Timm23 were detected by Western blot.Results Compared with the normal group,the intervertebral disc nucleus pulposus of rats in the degenerative group was significantly destroyed and the secretion of extracellular matrix of endplate chondrocytes decreased;while the structure of intervertebral discs for rats in the CCCP group was more intact,and the secretion of extracellular matrix of endplate chondrocytes was significantly increased compared with that in the degenerative group.Compared with the normal group,the expression of COL-2A and ACAN in endplate cartilage tissues of rats in the degenerative group were significantly down-regulated(P<0.05),the expression of mitochon-drial autophagy-related genes of PINK1 and Parkin were significantly decreased(P<0.05),and the expression of mitochondrial membrane proteins of Tomm20 and Timm23 were increased(P<0.05).Compared with the degenerative group,the expression of COL-2A,ACAN,PINKI and Parkin in the endplate cartilage tissue of rats in the CCCP group were significantly up-regulated(P<0.05),and the protein levels of Tomm20 and Timm23 were significantly down-regulated(P<0.05).Conclusion Rat spinal instability leads to a decrease level of mitophagy mediated by PINK1/Parkin signaling pathway in endplate cartilage,thereby inducing endplate cartilage and intervertebral disc degeneration,and the activation of mitophagy can significantly reduce endplate cartilage and intervertebral disc degeneration.

OBJECTIVE: To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer (CRC) through network pharmacology and molecular docking combined with experimental verification. METHODS: Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway. RESULTS: The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase (Akt1, Akt2), cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-9 (MMP9), epidermal growth factor receptor (EGFR), cell division control protein 42 homolog (CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets (Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein (P<0.05). Furthermore, our research revealed that monotropein induced cell apoptosis by inhibiting Bcl-2 and increasing Bax, induced G₁-S cycle arrest in colorectal cancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9 (P<0.05), and might play an anticancer role through Akt signaling pathway. CONCLUSION Monotropein exerts its antitumor effects primarily by arresting the cell cycle, causing cell apoptosis, and inhibiting cell migration. This indicates a high potential for developing novel medication for treating CRC.
Humans ; Proto-Oncogene Proteins c-akt/metabolism* ; Cell Proliferation ; Matrix Metalloproteinase 9 ; Molecular Docking Simulation ; Cell Cycle ; ErbB Receptors ; Apoptosis ; Colorectal Neoplasms/pathology* ; Cell Line, Tumor