BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

Objective To investigate the changes and clinical significance of pyroptosis and inflammation in children with acute lymphoblastic leukemia after chemotherapy.Methods A retrospective analysis was con-ducted on the clinical data of 98 children with acute lymphoblastic leukemia who received chemotherapy in the pediatrics and hematology and oncology departments of the hospital from May 2023 to August 2024.Accord-ing to the results of blood culture,the selected children were divided into the Gram-positive bacteria group,the Gram-negative bacteria group,the fungal group and the non-bloodstream infection group,and drug sensitivity tests were conducted.After chemotherapy,the children were divided into the granulocytosis group and the non-granulocytosis group according to the granulocyte level.The relevant indicators were detected and com-pared by methods such as blood routine,flow microsphere array technology,enzyme-linked immunosorbent assay(ELISA),and Western blot.Results After chemotherapy,the pyroptosis related indicators caspase-1,caspase-4,caspase-5,caspase-11,interleukin(IL)-1 β,IL-18,the proportion of pyroptosis cells and the relative expression level of GSDMD protein in children of each infection type were significantly increased compared with those before chemotherapy(P＜0.05).After chemotherapy,the levels of IL-4,IL-6,IL-10 and interfer-on-γ(IFN-γ)in the granulocytosis group were significantly higher than those in the non-granulocytosis group(P＜0.05),and the granulocyte level was negatively correlated with the levels of IL-4,IL-6,IL-10 and IFN-γ(P＜0.05).There were statistically significant differences in the levels of IL-4,IL-6,IL-10 and IFN-γ in dif-ferent infection states after chemotherapy(P＜0.05).Conclusion The number of granulocytes and the levels of serum cytokines can serve as potential indicators of infection in children with leukemia.The regulation of pyroptosis may provide new strategies for the treatment of childhood leukemia.

Objective:To investigate the distribution characteristics of cognition-related lifestyles of elderly in communities and explore the integrated effects on early cognitive decline.Methods:The participants were from the Project of Prevention and Intervention of Neurodegenerative Disease for Elderly in China. A total of 2 537 older adults aged ≥60 years without dementia in the 2015 baseline survey and the 2017 follow-up survey were included. The information about their cognition-related lifestyles, including physical exercise, social interaction, leisure activity, sleep quality, smoking status, and alcohol consumption, were collected through questionnaire survey and the integrated scores were calculated. Multivariate logistic regression analysis was used to assess the association between integrated cognition-related lifestyle score and early cognitive decline.Results:In the 2 537 older adults surveyed, 28.7% had score of 5-6, while only 4.8% had high scores for all 6 healthy lifestyles. Significant differences in healthy lifestyle factor distributions were observed between men and women. Multivariate logistic regression model showed that the risks for early cognitive decline in the older adults who had lifestyle score of 4 and 5-6 were lower than that in those with lifestyle score of 0-3 ( OR=0.683, 95% CI: 0.457-1.019; OR=0.623, 95% CI: 0.398-0.976; trend P=0.030). In the women, the risks for early cognitive decline was lower in groups with score of 4 and 5-6 than in group with score of 0-3 ( OR=0.491, 95% CI: 0.297-0.812; OR=0.556, 95% CI: 0.332-0.929; trend P=0.024). Conclusion:Cognition-related healthy lifestyles are associated with significantly lower risk for early cognitive decline in the elderly, especially in women.

Objective To discuss the association of allele polymorphisms SNP-rs1799724(C>T)in the TNF-αand SNP-rs11559013(G>A)in the ALCAM with HCV chronic infection in Han population in Yunnan province. Methods 434 HCV chronic infectious patients and 444 healthy individuals of Han Chinese population in Yunnan province were recruited. Two single nucleotide polymorphisms(SNPs)in the SNP-rs1799724(C>T) of TNF-αgene and SNP-rs11559013(G>A)of ALCAM gene were determined by real-time TaqMan polymerase chain reaction. We evaluated the associations of the two SNPs with HCV chronic infection. Results The distributions of allele and genotype of SNP-rs1799724(C>T)in the TNF-αand SNP-rs11559013(G>A)in the ALCAM between hepatitis C virus(HCV)chronic infectious patients and the healthy controls were not statistically significant(P > 0.05). Conclusion SNP-rs1799724(C>T)in the TNF-αand SNP-rs11559013(G>A) in the ALCAM have no association with HCV chronic infection in the Han population in Yunnan province.

Objective:To establish a UVB damage cell model with HaCaT cells to investigate the protective effects of Zinc sulfate on the cell damage caused by UVB and its relevant mechanisms .Methods: The cells were divided into normal group , Zinc group,UVB group,Znic and UVB group.The addition of Zinc sulfate to the HaCaT cells was conducted 24h prior to the irradiation to the cells by UVB.Cell apoptosis was detected by Western blot and the expression of metallothionein and NF -κB/p65 were measured by im-munohistochemistry.Results:Compared with normal and Zn+UVB group, Bax/Bcl-2 rate in UVB group increased.Compared with normal group ,MT expression levels in UVB group ,Zn group increased ,and compared with UVB group ,MT expression level in Zn+UVB group increased .Compared with normal group and Zn+UVB group,NF-κB/p65 expression level in UVB group increased .Conclusion:Zinc sulfate alleviates the apoptosis of HaCaT cell induced by UVB because of the expression of MT .

The beta-secretase is one of prospective targets against Alzheimer's disease (AD). A three-dimensional quan titative structure-activity relationship (3D-QSAR) model of Hydroethylamines (HEAs) as beta-secretase inhibitors was established using Topomer CoMFA. The multiple correlation coefficient of fitting, cross validation and external validation were r2 = 0.928, q(loo)2 = 0.605 and r(pred)2 = 0.626, respectively. The 3D-QSAR model was used to search R groups from ZINC database as the source of structural fragments. As a result, a series of R groups with relatively high activity contribution was obtained to design a total of 15 new compounds, with higher activity than that of the template molecule. The molecular docking was employed to study the interaction mode between the new compounds as ligands and beta-secretase as receptors, displaying that hydrogen bond and hydrophobicity played important roles in the binding affinity between the new compounds and beta-secretase. The results showed that Topomer CoMFA and To pomer Search could be effectively used to screen and design new molecules of HEAs as beta-secretase inhibitors, and the designed compounds could provide new candidates for drug design targeting AD.
Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; Drug Design ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Molecular Docking Simulation ; Quantitative Structure-Activity Relationship