Abstract
The redox-sensitive signaling system Keap1/Nrf2/ARE is a premier protective mechanism against oxidative stress that plays a key role in the pathogenesis and development of various diseases, including tuberculous granulomatous inflammation. We have previously reported that novel water-soluble phenolic antioxidant TS-13 (sodium 3-(4′-methoxyphenyl)propyl thiosulfonate) induces Keap1/Nrf2/ARE and attenuates inflammation. The aim of this study is the examination of the effect of TS-13 on tuberculous granulomatous inflammation. BALB/c mice were administered TS-13 (100 mg kg−1 day−1) through their drinking water starting immediately after Bacillus Calmette-Guérin (BCG) intravenous injection. Histological changes, production of reactive oxygen species (ROS) (activity of free-radical oxidation processes), and mRNA expression of Nrf2-driven, NF-κB-, AP-1-, and autophagy-dependent signal pathway genes in the liver and peritoneal exudate were evaluated 30 days later. After the 30th day of infection, the activity of the Keap1/Nrf2/ARE system was decreased and its effector genes entailed increasing ROS production in the liver. Therapeutic intervention with TS-13 is aimed at activating the Keap1/Nrf2/ARE system that leads to an increase in Nrf2 and Nrf2-mediated gene expression and a decrease in NF-κB expression. Changes in these pathways resulted in a decline of ROS production and a decrease in the number and the size of granulomas. In total, the results indicate that the Keap1/Nrf2/ARE system can be an effective pharmacological target in host-adjunctive treatment of tuberculosis.
Highlights
Before the advent of specific antituberculosis drugs in the middle of the last century, pathogenetic therapy was aimed at reestablishing an ablated immune system and correcting disturbed vital processes; this was the main treatment for patients with tuberculosis
Luminol was purchased from SERVA Electrophoresis GmbH; 2′,7′-dichlorodihydrofluorescein diacetate and TRIzol Reagent were obtained from Invitrogen; phorbol 12-myristate 13-acetate (PMA) and zymosan were obtained from Sigma-Aldrich; anti-Nrf2 antibodies were purchased from Abcam; RNAlater was purchased from Qiagen; iScript cDNA Synthesis Kit was obtained from Bio-Rad; BioMaster HS-qPCR mix was obtained from Biolabmix; culture media and fetal bovine serum were purchased from Biolot Medical; mounting media were obtained from BioVitrum; Bacillus Calmette-Guérin (BCG) vaccine was obtained from Microgen; and sodium 3-(4′ -methoxyphenyl)propyl thiosulfonate (TS-13, Figure 1) was synthesized based on 2,6-di-tert-butyl-phenоl as described previously [16]
One group of Bacillus CalmetteGuérin- (BCG-)infected animals was supplemented with a daily dose of 100 mg kg-1 day-1 TS-13 dissolved in drinking water for 30 days, while the other groups received water
Summary
Before the advent of specific antituberculosis drugs (streptomycin, isoniazid, ethambutol, rifampicin, and pyrazinamide) in the middle of the last century, pathogenetic therapy was aimed at reestablishing an ablated immune system and correcting disturbed vital processes; this was the main treatment for patients with tuberculosis. The additional use of pathogenetic therapy significantly influences tuberculosis treatment and results in better recovery of the functional state in vital systems of the body. It is the strategy affecting specific signaling systems and key transcription factors, especially redoxdependent (nuclear factor κB (NF-κB) [6,7,8], activating protein-1 (AP-1) [7], NFE2-related factor 2 (Nrf2)) [8,9,10] and other key cell processes, including autophagy [4, 6, 11] and lysosomal biogenesis [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
