OBJECTIVE: To determine the role of Tripterygium wilfordii multiglycoside (TGW) in the treatment of psoriatic dermatitis from a cellular immunological perspective. METHODS: Mouse models of psoriatic dermatitis were established by imiquimod (IMQ). Twelve male BALB/c mice were assigned to IMQ or IMQ₊TGW groups according to a random number table. Histopathological changes in vivo were assessed by hematoxylin and eosin staining. Ratios of immune cells and cytokines in mice, as well as PAM212 cell proliferation in vitro were assessed by flow cytometry. Pro-inflammatory cytokine expression was determined using reverse transcription quantitative polymerase chain reaction. RESULTS: TGW significantly ameliorated the severity of IMQ-induced psoriasis-like mouse skin lesions and restrained the activation of CD45⁺ cells, neutrophils and T lymphocytes (all P<0.01). Moreover, TGW significantly attenuated keratinocytes (KCs) proliferation and downregulated the mRNA levels of inflammatory cytokines including interleukin (IL)-17A, IL-23, tumor necrosis factor α, and chemokine (C-X-C motif) ligand 1 (P<0.01 or P<0.05). Furthermore, it reduced the number of γ δ T17 cells in skin lesion of mice and draining lymph nodes (P<0.01). CONCLUSIONS TGW improved psoriasis-like inflammation by inhibiting KCs proliferation, as well as the associated immune cells and cytokine expression. It inhibited IL-17 secretion from γ δ T cells, which improved the immune-inflammatory microenvironment of psoriasis.
Male ; Animals ; Mice ; Tripterygium ; Psoriasis/drug therapy* ; Keratinocytes ; Skin Diseases/metabolism* ; Cytokines/metabolism* ; Imiquimod/metabolism* ; Dermatitis/pathology* ; Disease Models, Animal ; Mice, Inbred BALB C ; Skin/metabolism*

Objective To evaluate the bioequivalence of oral sidenafil citrate tablets manufactured(100 mg)test preparations and reference preparations in healthy subjects under fasting and fed conditions.Methods Using a single-dose,randomized,open-lable,two-period,two-way crossover design,36 healthy subjects respectively for fasting and fed study were enrolled,and randomized into two groups to receive a single dose of test 100 mg with 7-day washout period.Plasma concentration of sidenafil and N-demethylsildenafil was determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS)method.The pharmacokinetic parameters were calculated by Analyst 1.6.3(AB Scie)using non-compartmental model,and bioequivalence evaluation was performed for the two preparations.Relevant safety evaluations were performed during the trial.Results The main pharmacokinetic parameters of sidenafil after a single oral dose of sidenafil citrate tablets under fasting condition for test and reference were as follows:Cmax were(494.69±230.94)and(558.78±289.83)ng·mL-1,AUC0-t were(1 336.21±509.78)and(1 410.82±625.99)h·ng·mL-1,AUC0-were(1 366.49±512.16)and(1 441.84±628.04)h·ng·mL-1,respectively.The main pharmacokinetic parameters of sidenafil under fed condition for T and R were as follows:Cmax were(381.89±126.53)and(432.47±175.91)ng·mL-1,AUC0-t were(1 366.34±366.99)and(1 412.76±420.37)h·ng·mL-1,AUC0-were(1 403.28±375.32)and(1 454.13±429.87)h·ng·mL-1,respectively.The results demonstrated the bioequivalence of sidenafil citrate tablets between T and R.The incidence of adverse events in fasting and fed tests were 33.33％and 25.00％,respectively.No serious adverse event was reported.Conclusion The test and reference formulation of sidenafil citrate tablets were equivalent and was safe.

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators. Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),anti-infective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed. Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group. Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-α and IL-6 may partake the inflammatory process of DILI.

Objective: To explore the efficacy and potential mechanisms of the ethanol extract of Abelmoschus manihot (L.) Medic in contrast-induced nephropathy (CIN). Methods: CIN rat models and human renal proximal tubular cells (HK-2) with iopromide-induced injury were employed to mimic CIN conditions. The effect of Abelmoschus manihot extract on the rat models and HK-2 cells was evaluated. In rat models, kidney function, histology, oxidative stress and apoptosis were determined. In HK-2 cells, cell viability, apoptosis, mitochondrial membrane potential, and endoplasmic reticulum stress were assessed. Results: Abelmoschus manihot extract significantly improved structural and functional impairments in the kidneys of CIN rats. Additionally, the extract effectively mitigated the decline in cellular viability and reduced iopromide-induced oxidative stress and lipid peroxidation. Mechanistic investigations revealed that Abelmoschus manihot extract prominently attenuated acute endoplasmic reticulum stress-mediated apoptosis by downregulating GRP78 and CHOP protein levels. Conclusions: Abelmoschus manihot extract can be used as a promising therapeutic and preventive agent in the treatment of CIN.

Brasilicardin A, a diterpene glycoside isolated from pathogenic actinomycete Nocardia brasiliensis IFM 0406, has become a novel immunosuppressant candidate due to its significant immunosuppressive activity, low toxicity and unique mechanism of action. However, brasilicardin A and its analogues have become a research hotspot to the development of this promising immunosuppressant because of the low-yield production in the natural pathogenic producer and the synthetically challenging skeleton. According to the reported biosynthetic pathway of brasilicardin A, the function of involved diterpene synthase was analyzed by bioinformatics. Then the genes bra1-5 that synthesize the brasilicardin A skeleton were directionally amplified from the pathogenic strain N. brasiliensis IFM 0406, and heterologous expression was achieved successfully in Streptomyces albus R1. The compounds were isolated and purified by using various column chromatographies including silica gel column chromatography and semi-preparative HPLC. Six new brasilicardins were established and named brasilicardin H-M. The activity of brasilicardins was screened using lipopolysaccharide (LPS)-activated mouse primary macrophage inflammation model. Brasilicardin H-M exhibited good inhibitory activity on nitric oxide (NO) release with IC₅₀ values of 28.24 ± 3.70, 37.44 ± 2.00, 39.85 ± 4.02, 26.77 ± 4.40, 65.25 ± 1.48 and 15.24 ± 2.72 μmol·L^-1, respectively (indomethacin as the positive control with IC₅₀ value of 34.28 ± 4.10 μmol·L^-1). The results indicated that six compounds had potential anti-inflammatory activity. This study laid a foundation for the elucidation of the brasilicardin A biosynthetic pathway and evaluation of the structure-activity relationship as well as new drug developments.

Objective To evaluate and compare the success rate and short-term clinical prognosis of transfemoral transcatheter aortic valve replacement(TF-TAVR)for patients with pure aortic regurgitation(PAR)of different annulus sizes.Methods This study is a single center retrospective study,selecting symptomatic PAR patients who received TF-TAVR treatment at Zhongshan Hospital Fudan University from September 2019 to September 2023.Based on preoperative CT results,all patients were divided into three groups:Group A(aortic annulus circumference＜80 mm),Group B(80 mm≤aortic annulus circumference＜85 mm),and Group C(aortic annulus circumference&ge; 85 mm).The primary endpoint was success rate and 30d all-cause mortality,while the secondary endpoint was TAVR related complications.Results A total of 61 PAR patients were included in this study,including 27 in Group A,21 in Group B,and 13 in Group C.The overall success rate is 82.0％,and the 30 d all-cause mortality rate is 3.3％.The success rate of Group C patients was significantly lower(P=0.012),with higher rates of conversion to surgery and valve-in-valve implantation(P=0.022 and P=0.040).In terms of secondary endpoint events,there were no significant differences among the three groups in major bleeding events,major vascular complications,stroke,myocardial infarction,newly developed atrial fibrillation,implantation of new pacemakers,coronary artery occlusion,and postoperative moderate to severe perivalvular leakage(all P＞0.05).Conclusions The circumference of the aortic valve annulus is a key factor affecting the success rate of TF-TAVR in PAR,and PAR patients with an aortic valve annulus circumference less than 85mm may be more suitable for TF-TAVR.

Objective:To investigate the effect of feeder layer cells expressing interleukin(IL)-21 on the amplification of NK cells in vitro.Methods:The K562 cell line with IL-21 expression on its membrane was constructed by electroporation,and co-cultured with NK cells after inactivation.The proliferation of NK cells was observed.The killing function of the amplified NK cells in vitro was evaluated by the lactate dehydrogenase(LDH)and interferon-γ(IFN-y)release assay.A colorectal cancer xenograft model in NOD/SCID mice was established,and a blank control group,a NK cell group and an amplified NK cell group were set up to detect the tumor killing effect of amplified NK cells in vivo.Results:K562 cells expressing IL-21 on the membrane were successfully constructed by electroporation.After co-culturing with K562 cells expressing IL-21 on the membrane for 17 days,the NK cells increased to 700 times,which showed an enhanced amplification ability compared with control group(P＜0.001).In the tumor cell killing experiment in vitro,there was no significant difference in the killing activity on tumor cells between NK cells and amplified NK cells,and there was also no significant difference in mice in vivo.Conclusion:K562 cells expressing IL-21 on the membrane can significantly increase the amplification ability of NK cells in vitro,but do not affect the killing function of NK cells in vitro and in vivo.It can be used for the subsequent large-scale production of NK cells in vitro.

Objective To establish a scoring model for predicting the prognosis and drug sensitivity of colorectal cancer(CRC)based on the expression of disulfidptosis-related genes by bioinformatics analyses combined with the validation with CRC patient-derived organoids(CRC-PDOs).Methods NMF(non-negative Matrix Factorization)algorithm,Cox and LASSO regression analyses were used to identify disulfidptosis-related genes with predictive value for CRC prognosis,and disulfidptosis-related risk scoring formula was constructed.The differential genes and enrichment pathways among different clusters were analyzed by GO(Gene Ontology)and KEGG(Kyoto Encyclopedia of Genes and Genomes).The sensitivity of the high/low-risk clusters of CRC patients to chemotherapy drugs was predicted using the GDSC database and validated using CRC-PDOs.Results The results of NMF algorithm showed that CRC patients could be grouped into two clusters based on the disulfidptosis-related genes.COX regression analysis demonstrated that LRPPRC and SLC7A11 were the only two genes with significance to predict the prognosis of CRC patients(P=0.047,0.033).Low expression of SLC7A11 or high expression of LRPPRC in tumors of CRC patients was significantly correlated with overall survival(OS)(P=0.004,0.003).Based on LASSO regression analysis,the mortality risk scoring formula for disulfidptosis was as follows:Risk score=LRPPRC×(-0.670 5)+SLC7A11×0.311 2,and the GSE161158 dataset could be re-grouped into high-risk and low-risk clusters accordingly.There were 125 differentially expressed genes(DEGs)between the two clusters.According to the GO and KEGG results,the up-regulated genes in high-risk cluster were mainly enriched in immune regulation,such as leukocyte chemotaxis,granulocyte migration and toll-like receptor binding.Low-risk cluster was characterized by pathways associated with sulfide metabolism,such as sulfur compound transmembrane transporter activity.Based on the GDSC database,the expression level of SLC7A11 and LRPPRC could predict chemotherapy drug sensitivity.As a representative,the efficacy of chemotherapy drug(irinotecan)on inhibiting the growth of CRC-PDOs was shown to be linearly correlated with the relative gene expression levels of SLC7A11 and LRPPRC in CRC tissues of patients(P=0.007,0.040).Conclusion According to the results based on the bioinformatics analyses and drug sensitivity testing on CRC-PDOs,disulfidptosis risk score could predict the prognosis and drug sensitivity of CRC patients,with potential clinical application prospect.

Objective To investigate the clinical characteristics of female migraine patients with patent foramen ovale(PFO)and design a risk prediction model for PFO in female migraine patients(migraineur patients PFO risk prediction model,MPRPM).Methods Female migraine patients who visited Zhongshan Hospital,Fudan University from Jun 1,2019 to Dec 31,2022 were included.Preoperative information and follow-up results after discontinuation of medication were collected.Patients were divided into PFO-positive and PFO-negative groups based on transesophageal echocardiography results.A multivariate Logistic regression model and a random forest model were constructed,and the random forest model was validated multidimensionally.Key features were selected based on the mean decrease accuracy(MDA)to construct MPRPM.Results A total of 305 female patients were included in the study,with 204 patients in the PFO-positive group and 101 patients in the PFO-negative group.Multivariate Logistic regression analysis showed that age at migraine onset,attack frequency,severe impact on life during attacks,exercise-related headaches,menstruation-induced headaches,aura migraines,and a history of cryptogenic stroke were predictive factors for PFO positivity.The random forest model effectively predicted the incidence of PFO in female migraine patients,with an AUC of 0.895(95%CI:0.847-0.943).MPRPM demonstrated a sensitivity of 71.6%and specificity of 91.1%(AUC:0.862,95%CI:0.818-0.906,P<0.001).The optimal cut-off value was 2.5 points.Patients correctly classified by the model showed a higher rate of symptom improvement compared to incorrectly classified patients(94.3%vs.82.0%,P=0.023).Conclusion We identified predictive factors for PFO in migraine patients.MPRPM can provide guidance in the diagnostic process and therapeutic decision-making for female migraine patients,assist in patient triage,and reduce the healthcare burden.

Corydalis hendersonii(CH) is a Tibetan folk medicine with the functions of clearing heat, detoxifying, cooling blood, checking diarrhea, and lowering blood pressure. It is often used to treat high altitude polycythemia, vasculitis, peptic ulcer, and diarrhea. Nine compounds were separated from the ethanol extract of CH by silica gel, ODS, Sephadex LH-20 chromatography and semi-preparative HPLC. Their structures were identified as hendersine H(1),hendersine I(2), dehydrocheilanthifoline(3), protopine(4), izmirine(5), 6,7-methylenedioxy-1(2H)-isoquinolinone(6), icariside D_2(7), ethyl 4-(β-D-glucopyranosyloxy)-3-methoxybenzoate(8), 3-hydroxy-4-methoxybenzoic acid(9), respectively, by the spectroscopic data analysis and comparison with those in the literature. Among them, compounds 1 and 2 are new isoquinoline alkaloids, and compounds 7-9 are reported the first time for Corydalis. The hypoglycemic model of H9c2 cardiomyocytes and the inflammatory model of H9c2 cardiomyocytes induced by conditional supernatant were employed to determine the activities of the above compounds. The results showed that 20 μmol·L~(-1) compound 1 had a protective effect on H9c2 cardiomyocytes and 10 μmol·L~(-1) compounds 4 and 5 inhibited H9c2 cardiomyocyte inflammation induced by conditional supernatant.
Humans ; Corydalis/chemistry* ; Alkaloids/chemistry* ; Inflammation ; Spectrum Analysis ; Isoquinolines/pharmacology*