Systemic Pharmacology Reveals the Potential Targets and Signaling Mechanisms in the Adjuvant Treatment of Brucellosis with Traditional Chinese Medicine

Human brucellosis
is one of the world’s most common zoonoses,
caused by Brucella infection and characterized by
induced inflammation, which in severe cases can lead to abortion and
sterility in humans and animals. There is growing evidence that traditional
Chinese medicine (TCM) is beneficial as an adjunct to the treatment
of brucellosis. However, its specific targets of action and molecular
mechanisms remain unclear. In this study, a systematic pharmacological
approach was applied to demonstrate pharmacological targets, biological
functions, and signaling pathways of TCM as an adjunct to the treatment
of brucellosis (TCMTB). The results of network pharmacology were further
verified by in vitro experiments. Network analysis revealed that 133
active ingredients and 247 targets were screened in TCMTB. Further
data analysis identified 21 core targets and 5 core compounds in TCMTB,
including beta-sitosterol, quercetin, kaempferol, luteolin, and paeoniflorin.
Gene ontology and the Kyoto Encyclopedia of Gene and Genome analysis
showed that TCMTB might actively treat brucellosis by regulating inflammatory
response, enhancing immune function, and targeting signaling pathways
such as tuberculosis and TNF. Molecular docking results showed that
multiple compounds could bind to multiple targets. Further, in vitro
experiments confirmed that quercetin, among the active compounds screened,
induced the strongest immunomodulatory and pro-inflammatory cytokine
production during Brucella abortus infection.
Further, quercetin induced nitric oxide production, which attenuated
the ability of B. abortus to internalize
THP-1 cells as well as intracellular survival. This study reveals
the mechanism by which TCMTB aids in the treatment of brucellosis
through a synergistic multicomponent, multipathway, and multitarget
action. The contribution of quercetin treatment to B. abortus infection was demonstrated for the first
time, which may be related to the quercetin-induced production of
nitric oxide and immunomodulatory and inflammatory cytokines. These
predictions of the core compounds and targets may be used in the future
for the clinical treatment of brucellosis.