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).