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The Oral Delivery of Water-Soluble Phenol TS-13 Ameliorates Granuloma Formation in an In Vivo Model of Tuberculous Granulomatous Inflammation.

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.

SUBMITTER: Menshchikova EB

PROVIDER: S-EPMC8140857 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean area-under-the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.

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The Oral Delivery of Water-Soluble Phenol TS-13 Ameliorates Granuloma Formation in an In Vivo Model of Tuberculous Granulomatous Inflammation.

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