hsa_circ_0007460通过调节巨噬细胞的自噬和凋亡影响细胞内结核分枝杆菌的存活

环状RNA(circular RNA,circRNA)是一类缺乏5′-帽子和3′-poly(A)尾巴的非编码RNA,可以参与多种人类疾病的生物学过程。然而,对其在活动性肺结核(active pulmonary tuberculosis,ATB)中的诊断和功能价值却知之甚少。本研究旨在研究hsa_circ_0007460是否能作为ATB患者的潜在诊断生物标志物,并对其功能进行初探。通过实时荧光定量PCR(real-time quantitative fluorescent PCR,RT-qPCR)发现hsa_circ_0007460在32例ATB患者的外周血以及牛结核分枝杆菌的减毒株——BCG(bacillus Calmette-Guerin)感染的THP-1人源巨噬细胞中显著上调。受试者工作特征曲线(receiver operating curve,ROC)显示曲线下面积(the area under ROC curve,AUC)为0.7474,灵敏度76.67%,特异度78.13%。通过RNase R消化和放线菌素D抑制实验证实hsa_circ_0007460相较于其线性mRNA更加稳定,提示其有作为ATB的诊断生物标志物的潜力。通过蛋白质印迹(Western blot)、CCK-8(cell counting kit-8)、平板计数、免疫荧光等实验表明hsa_circ_0007460能调控巨噬细胞凋亡和自噬。最后,通过生物信息学分析预测下游的miRNA和mRNA,构建了hsa_circ_0007460/hsa-miR-3127-5p/PATZ1轴。上述研究结果表明,hsa_circ_0007460在ATB患者外周血中显著上调,可以作为潜在的诊断生物标志物,且hsa_circ_0007460能促进巨噬细胞凋亡、抑制巨噬细胞自噬从而促进胞内BCG的存活。

Novel Thrice-Weekly Isoniazid plus Rifapentine Short-Course Regimen for the Treatment of Latent Tuberculosis Infection in a Murine Model

1.Introduction Tuberculosis(TB),caused by Mycobacterium tuberculosis,remains a leading cause of death among infectious diseases worldwide.Latent tuberculosis infections(LTBI)contribute to the global burden of TB disease.TB preventive treatment(TPT)is a key intervention to achieve the End TB Strategy targets.The World Health Organization recommends LTBI treatment regimens,including 6 or 9 months of once-daily isoniazid(INH,H),4 months of once-daily rifampin(RIF,R),3 months of once-weekly rifapentine(RPT,P)plus INH(3HP),3 months of once-daily RIF plus INH,or 1 month of daily RPT plus INH(1HP).Clinicians and individuals with LTBI may be reluctant to implement TPT due in part to concerns regarding adherence to the long treatment duration and drug toxicity of the currently recommended LTBI treatment regimens.Shorter,better-tolerated,and cost-effective TPT regimens are highly desirable.Rifapentine is a long-acting rifamycin,and rifamycin-based regimens are now the preferred LTBI treatment because they have similar or better efficacy and higher completion rates due to their shorter duration.Based on our experiences with TPT practice among Chinese people with silicosis,we found that the 3HP regimen was not well tolerated due to an unexpectedly high frequency of adverse events(AEs)(70.4%)and grade 3 or 4 AEs(7.9%),especially the high incidence of flu-like systemic drug reactions(SDRs)(10.8%).