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Influenza is an acute respiratory infectious disease that threatens
human beings, which does great harm to high-risk groups in the epidemic
season, so it is of great significance to protect severe influenza
high-risk groups and actively treat critical influenza patients. In
addition to active immunity, the action mechanism of western medicine
has been relatively clear, such as oseltamivir, zanamivir and Arbidol.
Traditional Chinese medicine is a cultural treasure of Chinese medicine,
which has played an important role in the prevention and treatment of
influenza in recent years. However, due to the theory of syndrome
differentiation of TCM and human treatment, the treatment of TCM is
complicated. With the improvement of the separation and extraction
technology of monomer components of TCM, the effective components of TCM
are gradually defined, supplemented by the deepening of basic research
of TCM and the development of biological information. The application of
network pharmacology provides a new method for us to predict the
potential targets of the effective components of TCM.
Our study shows that the first five active ingredients of XBCQ are
quercetin, luteolin, kaempferol, wogonin and aloe emodin. Among the top
five active components of Jingyin granulep [13], four coincide with
them, and two overlap with the first five of compound Yizhihao [14],
which indirectly shows that the three groups have much in common in
antiviral active ingredients. The basic research of its monomer against
influenza virus has been verified at the different cell types and animal
model.
Quercetin is a kind of polyphenols derived from plants, which has
anti-inflammatory, anti-viral and anti-cancer activities [15-17].
Theremore, protein–chemical interactions suggest quercetin as promising
drug candidates against COVID-19 as well as other SARS-like viral
infections [18]. A strong relationship between quercetin and
influenza has been reported in the literature. Wu W found that quercetin
a broad-spectrum inhibitor of viral infection, including H1N1, H3N2,
H5N1.Quercetin interaction with the HA2 subunit and inhibit the entry of
the H5N1 virus, which indicates that quercetin acts as an inhibitory in
the early stage of infection [19]. These results corroborate the
findings of a great deal of the previous work in quercetin against
influenza.
Luteolin is a common flavonoid, ranging from scavenging free radicals,
anticancer activity to anti-influenza activity. there study show that
luteolin is most effective inhibitor to influenza via establishment and
verification of a screening method based on AlphaScreen
technique[20].Yan H found that luteolin inhibits the expression of
coat protein I complex, which is related to the entry and endocytosis
pathway of influenza virus. Its antiviral effect is consistent with
previous studies, indicating that the antiviral effect of the effective
ingredient of the prescription has a certain theoretical basis [21].
Luteolin inhibited the production of TNF-α and IL-6 in a dose-dependent
manner, and shortened the half-life of TNF-α and IL-6mRNA [22]. It
has also been reported that luteolin significantly reduced the
production of intracellular reactive oxygen species induced by TNF-α in
a dose-dependent manner [23]. Luteolin affects the MAPK pathway,
which can be demonstrated by the observation of IL-1 β-induced
inhibition of cJunN terminal kinase and p38 kinase activation in SW982
cells. Luteolin treatment also inhibited IL-1 β-induced AP-1 nuclear
translocation [24]. Luteolin also protects mice from
lipopolysaccharide-induced acute lung injury by inhibiting the
expression of TNF-α, IL-6, and COX-2. Luteolin down-regulates
LPS-induced leukocyte influx into alveolar space [25]. It was found
that luteolin attenuated LPS-induced acute lung injury by inhibiting
NF-KB and MAPK pathways [26].
In the protein interaction network, the key gene JUN is a transcription
factor which is essential for cellular growth and proliferation, across
the cell cycle, self-renewal, metabolism and survival processes. Here,
Studies have demonstrated that JUN contributes to fibrotic disease not
only by increasing activity through pro-fibrotic programs, but also by
influencing the host’s overall immune response [27, 28]. Promotes
activity of NR5A1 when phosphorylated by HIPK3 would increas
steroidogenic gene expression upon cAMP signaling pathway [29].
CASP8 is related to many human diseases. It produces a variety of
transcripts and has some non-apoptotic functions, such as regulating the
proliferation and differentiation of NK cells and B cells [30].
CASP8 is not only a necessary protease for the exogenous pathway of
apoptosis, but also a negative regulator of necrosis [31].
Interleukin-1β (IL-1β) is an important immune cytokine responsible for
inflammation, such as influenza or coinfection bacterica. It is related
to the severity of infection disease. All patients with H1N1 infection
significantly higher levels of IL-1β and IL-6 than lower respiratory
tract infections (LRTI), H1N1 virus infection induces significant
upregulation of both interleukins IL1β and IL-6 plasma
expressions.[32] IL-1β and interleukin-17A (IL-17A) are key
mediators of neutrophilic inflammation in influenza-induced chronic lung
inflammation. Blocking of IL-17A or IL-1 resulted to a virtual
abrogation of neutrophil recruitment in the initial phase of infection.
IL-17A and IL-1β are potential targets for treatment of viral
exacerbations [33]. Previous studies have demonstrated that NLRP3
inflammasome regulated IL-1β activation during coinfection, which
increases the amount of pro-IL-1β substrate for the inflammasome to
process [34]. There KEY Targets responses to lipapolysaccharide,
molecule of bacterial origin, tumor necrosis factor biological
processes. The small-molecule anti-influenza therapeutic durgs be
classified four-category currently: primary, neuraminidase inhibitors
oseltamivir and zanamivir, which prevent release of nascent virions.
Secondary, amantadine and rimantadine, which are M2 ion channel
inhibitors. Tertiary, avipirovir and baloxavir, which act on
transcription and replication of viral RNA. Quartic, Arbidol has been
shown to increase influenza virus HA stability and prevent the low
pH-induced HA transition to its fusogenic state. Our study shows that
component targets were mainly associated with cytokine receptor binding,
cytokine activity, receptor ligand activity, signaling receptor
activator in biological processes [35].
The IL-17 family is a subset of cytokines composed of IL-17A-F and plays
an important role in both acute and chronic inflammatory responses. Many
studies have revealed that delayed clearance of viral load and marked
cytokine activation in severe patients of H1N1 virus infection. The
IL-17 family signals through its corresponding receptors and activates
downstream pathways including NF- κ B, MAPK and C/EBP to induce the
expression of antimicrobial peptides, cytokines and chemokines. In the
study of H5N1-infected mice, it was found that IL-17 played a protective
role in the process of adaptive immunity of ”cytokine storm” and virus
clearance [36]. IL-17 has been shown to be protective in severe
pandemic influenza, indicating the existence of imbalanced pro-and
anti-Th17 responses during this disease [37]. IL-17 deficiency or
treatment with monoclonal antibodieswould alleviat acute lung injury
induced by the H1N1 virus in mice[38]. In contrast, other groups
have showed that IL-17 just played a pathogenic role by recruiting
neutrophils to the site of inflammation [39]. IL-17 may act as a
‘double-edged sword’ and contributes to pulmonary immunopathology
[40-42]. The TNF-α and NF-κB pathways are central regulators of
immune responses, cell survival, and apoptosis, and are modulated by
pathogens for their survival. Interference with TNF-α signaling
exclusively in distal airway epithelial cells resulted in abrogation of
CD8+ mediated lung injury and viral clearance [43, 44].
Molecular docking has been used in drug screening of influenza
Neuraminidase Inhibitors [45-48]. Our molecular docking studies
based on TCM compounds against known protein targets to treatment
influenza. Among the four targets chosen for molecular docking
experiments, JUN、CASP8、MAPK1 were reported as key gene in signaling
pathway mentioned above. Quercetin, luteolin and naringenin were
successful docked to JUN target proteins with a high binding energy. It
showed that Quercetin, luteolin and naringenin could bind to JUN, and
then inhibited influenza through multi-components, multi-targets and
multi-pathways. These findings validate the reliability of the active
ingredients screened by network pharmacology and their interaction with
influenza targets.