7. Exploring the mechanisms of combined administration for silicosis treatment from transcriptional and metabolic perspectives.
To elucidate the rationale behind the enhanced therapeutic efficacy of combined drug administration compared to monotherapy, we employed transcriptomic and metabolomic sequencing of lung tissues from silica-induced mice subjected to combined drug treatment. Transcriptomic analysis revealed a total of 849 DEGs between the combined drug and silica groups; among which, 393 were found to be upregulated, while 456 showed significant downregulation (Fig 9A, B), with particular emphasis on circadian rhythm, steroid biosynthesis, p53 signaling pathway, ribosome, et al (Fig 9C). Venn analysis further demonstrated that the combined drug therapy selectively targeted 10 pathways that exhibited alterations between silica and PBS groups. Among them, there are 6 unique target pathways specifically modulated by the combined drug therapy (Fig 9D). The potential mechanism underlying the synergistic enhancement observed in combined drug therapy may originate from these unique pathways. Meanwhile, there are 2 pathways, including p53 signaling pathway and steroid biosynthesis, that coincide with the modulatory effects of PFD. Additionally, 3 pathways, including steroid biosynthesis, endocytosis, and circadian rhythm, exhibit concurrence with the pharmacological actions of BIBF (Fig 9E-F). Collectively, these observations highlight the convergence of both combined drug therapy and monotherapy in their targeting of the steroid biosynthesis pathway. This intriguing outcome suggests the possible pivotal role of this pathway in the progression of silicosis.
Subsequent to the metabolic profiling, it becomes apparent that the majority of altered metabolites resulting from the comparison between combined drug therapy and the silica group are concentrated within the realm of D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, and steroid hormone biosynthesis, et al (Fig 9G, H). Venn analysis further revealed that there are 12 distinct pathways modulated by combined drug therapy relative to silicosis progression, with 3 pathways being exclusively regulated by the combined treatment, including aminoacyl-tRNA biosynthesis, alanine, aspartate and glutamate metabolism, as well as arginine and proline metabolism. Moreover, 4 pathways are shared with PFD and BIBF, including purine metabolism, pyrimidine metabolism, glycerophospholipid metabolism, and glutathione metabolism (Fig 9I, J).