Drug-resistant tuberculosis (TB) outbreak has emerged as a global public health crisis. Therefore, new and innovative therapeutic options like host-directed therapies (HDTs) through novel modulators are urgently required to overcome the challenges associated with TB. In the present study, we have investigated the anti-mycobacterial effect of 4-(Benzyloxy)phenol. Cell-viability assay asserted that 50 μM of 4-(Benzyloxy)phenol was not cytotoxic to phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. It was observed that 4-(Benzyloxy)phenol activates p53 expression by hindering its association with KDM1A. Increased ROS, intracellular Ca and phagosome-lysosome fusion, were also observed upon 4-(Benzyloxy)phenol treatment. 4-(Benzyloxy)phenol mediated killing of intracellular mycobacteria was abrogated in the presence of specific inhibitors of ROS, Ca and phagosome-lysosome fusion like NAC, BAPTA-AM, and W7, respectively. We further demonstrate that 4-(Benzyloxy)phenol mediated enhanced ROS production is mediated by acetylation of p53. Blocking of p53 acetylation by Pifithrin-α (PFT- α) enhanced intracellular mycobacterial growth by blocking the mycobactericidal effect of 4-(Benzyloxy)phenol. Altogether, the results showed that 4-(Benzyloxy)phenol executed its anti-mycobacterial effect by modulating p53-mediated ROS production to regulate phagosome-lysosome fusion through Ca production.

中文翻译：

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4-(苄氧基)苯酚诱导的 p53 在 THP-1 细胞中表现出抗分枝杆菌反应，通过 ROS 依赖性细胞内 Ca2+ 途径触发吞噬体-溶酶体融合

耐药结核病（TB）爆发已成为全球公共卫生危机。因此，迫切需要新的创新治疗方案，例如通过新型调节剂进行宿主定向治疗（HDT），以克服与结核病相关的挑战。在本研究中，我们研究了 4-(苄氧基)苯酚的抗分枝杆菌作用。细胞活力测定表明，50 μM 4-(苄氧基)苯酚对佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 分化的 THP-1 (dTHP-1) 细胞没有细胞毒性。据观察，4-(苄氧基)苯酚通过阻碍 p53 与 KDM1A 的结合来激活 p53 表达。4-(苄氧基)苯酚处理后还观察到 ROS、细胞内 Ca 和吞噬体-溶酶体融合增加。在 ROS、Ca 和吞噬体-溶酶体融合的特异性抑制剂（如 NAC、BAPTA-AM 和 W7）分别存在的情况下，4-（苄氧基）苯酚介导的细胞内分枝杆菌杀伤作用被消除。我们进一步证明 4-(苄氧基)苯酚介导的 ROS 产生增强是由 p53 乙酰化介导的。Pifithrin-α (PFT-α) 阻断 p53 乙酰化可通过阻断 4-(苄氧基)苯酚的杀分枝杆菌作用来增强细胞内分枝杆菌的生长。总而言之，结果表明，4-(苄氧基)苯酚通过调节 p53 介导的 ROS 产生，通过 Ca 的产生来调节吞噬体-溶酶体融合，从而发挥其抗分枝杆菌作用。