4.2 Possible mechanism
Inflammation, as a complex and comprehensive process, plays key role in
the emergence and development of variety diseases, such as
cancer(Diakos, Charles, McMillan, & Clarke, 2014), acute kidney
injury(Poston & Koyner, 2019), AS(Wolf & Ley, 2019),
stroke(Lambertsen, Finsen, & Clausen, 2019), etc. Multiple cells,
cytokines and pathways are involved in the process of inflammation. The
pivotal step in the inflammatory response is the infiltration of immune
cells, like macrophage, neutrophil. Activated immune cells secret
various cytokines such as IL-1 and TNF-α, and facilitate the activation,
proliferation and differentiation of T cells, B cells(Opal & DePalo,
2000). Simultaneously, the release of chemokines by macrophages also
directs the movement of monocytes and neutrophils towards the site of
inflammation, thereby amplifying the inflammatory response (Figure 11).
Research has indicated a strong correlation between inflammation and the
onset of AS. The formation of foam cells in the arterial wall is a
crucial aspect of AS, and it is closely linked to macrophages’
phagocytosis and accumulation of cholesterol(Ding et al., 2021; D. Wang
et al., 2019). SR-BI (Scavenger Receptor Class B Type I), a high-density
lipoprotein transport protein(Yesilaltay, Kocher, Rigotti, & Krieger,
2005), can facilitate the uptake of HDL and enhance the reverse
transport of cholesterol, thereby inhibiting foam cell
formation(Chistiakov, Melnichenko, Myasoedova, Grechko, & Orekhov,
2017; Y. Xu et al., 2021). Notably, icariin has been shown to increase
the expression of SR-BI protein, promoting HDL uptake and cholesterol
reverse transport, which in turn suppresses macrophage cholesterol
accumulation and foam cell formation, ultimately leading to therapeutic
benefits for AS(H. Yang et al., 2015). And Cluster of Differentiation 36
(CD36), as a membrane receptor, can also mediate the transport of
cholesterol and oxidize low-density lipoprotein, so it is involved in
the occurrence and development of AS(Maréchal et al., 2018; Tian, Xu,
Sahebkar, & Xu, 2020; R. Yang, Liu, & Zhang, 2022). At the same time,
P38 mitogen-activated protein kinase pathway (P38 MAPK) can promote the
activation of CD36(Maimaitiyiming, Zhou, & Wang, 2016). Icariin
derivatives can block P38 MAPK and then inhibit CD36 activity, thereby
inhibiting the process of AS Icariin machine derivatives can block P38
MAPK and then inhibit CD36 activity, thereby inhibiting the process of
AS Icariin machine derivatives can block P38 MAPK and then inhibit CD36
activity, thereby inhibiting the process of AS Icariin machine
derivatives can block P38 MAPK and then inhibit CD36 activity, thereby
inhibiting the process of AS Icariin machine derivatives can block P38
MAPK and then inhibit CD36 activity, thereby inhibiting the process of
AS Icariin machine derivatives can block P38 MAPK and then inhibit CD36
activity, thereby inhibiting the process of AS Icariin machine
derivatives can block P38 MAPK and then inhibit CD36 activity, thereby
inhibiting the process of AS machine derivatives can block P38 MAPK and
then inhibit CD36 activity, thereby inhibiting the process of AS
derivatives can block P38 MAPK and then inhibit CD36 activity, thereby
inhibiting the process of AS(H. Yang et al., 2015). As an inflammatory
disease, myocarditis is regulated by various pathway mechanisms, and
NF-κB is an important inflammatory signal transduction factor, which
plays an important role in the occurrence and development of
myocarditis(Yao et al., 2022). However, some studies have shown that
Sirtuin 6 (SIRT6) down-regulates the expression of NF-κB and reduce
myocardial inflammation by inhibiting the activation and nuclear
translocation of NF-κB(Z. Jin et al., 2023; Song et al., 2020). Icariin
up-regulate the level of SIRT6 to inhibit the activity of NF-κB and
down-regulate the levels of IL-2, IL-6, TNF-α, ICAM-1 and other
inflammatory factors to reduce myocardial inflammation(Y. Chen et al.,
2015). The JNK pathway plays an important role in many biological
processes including inflammation(H. Zhu et al., 2022). As the main
transcriptional component of JNK, c-Jun, plays a role in both apoptosis
and inflammation(H. Guo et al., 2020). However, it is worth noting that
NF-κB can enhance the activity of c-Jun, thereby promoting the
inflammatory process(Blonska & Lin, 2009). However, some studies have
found that icariin can inhibit the activity of c-Jun by inhibiting the
activation and release of NF-κB, thereby alleviating inflammation(H.
Zhou et al., 2015). The study suggests that TGF-β can promote the
transformation of cardiac fibroblasts into myofibroblasts and the
synthesis of collagen by activating Samd2 phosphorylation in the
heart.(Z.-G. Ma, Yuan, Wu, Zhang, & Tang, 2018). Icariin and its
derivatives can down-regulate the level of TGF-β factor and inhibit the
activity of Samd2, thereby inhibiting collagen synthesis and blocking
the nuclear translocation and expression of NF-κB. It is worth noting
that the nuclear translocation and expression of NF-κB can also be
achieved through the inhibition of IκB phosphorylation by ICS II(Fu et
al., 2018). Ultimately achieve the purpose of treating myocardial
inflammation.
Inflammatory processes are also present in many urological diseases.
Nucleotide-binding domain and Leucine-rich Repeat containing family,
Pyrin domain-containing 3 (NLRP3), as a component of inflammasome, can
regulate the level of downstream inflammatory factors, and NLRP3 is also
regulated by NF-κB(de Carvalho Ribeiro & Szabo, 2022; Sharma &
Kanneganti, 2021; Q. Wang et al., 2020). In lupus nephritis (LN) and IgA
nephropathy (IgAN), icariin can down-regulate the level of NLRP3 by
inhibiting the activation of NF-κB, thereby reducing the levels
inflammatory factors(Su et al., 2018; L. Zhang et al., 2017).
Apoptosis-associated speck-like protein containing a CARD (ASC) is also
an inflammasome that promotes the conversion of pro-caspase-1 to
caspase-1 in IgAN to increase the level of inflammatory factors such as
IL-1β(Hornung et al., 2009; Huang, Xu, & Zhou, 2021). Icariin and its
derivatives can inhibit the activity of ASC, and then block the
conversion process of pro-Caspase-1 to Caspase-1, then improve the level
of inflammatory factors and treat inflammation(L. Zhang et al., 2017).
As a protein kinase, IKKβ can phosphorylate IκBα to release NF-κB and
promote the production of inflammatory factors(Antonia, Hagan, &
Baldwin, 2021; X. Dong et al., 2022). However, it is worth noting that
icariin can delay this process by inhibiting the activity of IKKβ, so as
to reduce the damage of IgAN to the kidney. At the same time, icariin
can also treat IgAN by reducing the deposition of immunoglobulin A (IgA)
and the expansion of mesangial matrix(L. Zhang et al., 2017). In
nephrotoxicity and acute kidney injury, NF-κB is often inhibited by
icariin as a key node, thereby improving the levels of downstream
inflammatory factors such as TNF-α and inducible nitric oxide synthase
(iNOS)(P. Ma et al., 2015; Xie et al., 2018).
In neurological diseases, inflammatory mechanisms assume an important
role. In cerebral ischemia-reperfusion injury, studies have shown that
PPARα and PPARγ can down-regulate NF-κB inflammatory pathways by
inhibiting IκBα phosphorylation(Collino et al., 2006; Q. Li et al.,
2019), while icariin derivatives (IRS and ICS II) can increase High
PPARα and PPARγ levels further inhibit related inflammatory pathways to
achieve anti-inflammatory effects(Y. Deng et al., 2016; Xiong et al.,
2016). As a transcription factor, Nrf2 can increase the level of
superoxide dismutase (SOD) and reduce the generation of reactive oxygen
species (ROS) in neurodegenerative diseases (ND), thereby inhibiting
NF-κB and MAPK inflammatory pathways activation(Ge et al., 2021; Jia,
Zhang, Xu, Yao, & Wei, 2021; Kobayashi et al., 2016; L. Xu et al.,
2018). And icariin can up-regulate Nrf2 level and reduce inflammatory
response(L. Zhu et al., 2019). Experiments have shown that
Phosphatidylinositol 3-kinase/Protein kinase B pathway (PI3-K/Akt
pathway) can promote the release of inflammatory factors such as IL-1
and TNF-α in the process of nerve injury(C. Li, Zhao, Lin, Gong, & An,
2019). And existing studies have found that icariin can block the
inflammatory process by inhibiting the PI3-K/Akt pathway(G. Q. Wang et
al., 2017; H. Zhang et al., 2012).
In respiratory diseases, iNOS and Cyclooxygenase-2 (Cox-2), as two
enzymes related to inflammatory response, can respectively promote the
production of NO and Prostaglandin E2 (PGE2) when the body is stimulated
by stimuli such as bacteria and viruses, and then inflammation is
involved through a variety of inflammatory pathways(T. Li, Xu, Zhao,
Gao, & Xie, 2022; Stiller & Hjemdahl, 2022). Studies have shown that
icariin inhibits the activity of iNOS and Cox-2, thereby inhibiting the
synthesis of related inflammatory mediators(C. Q. Xu et al., 2010). As
for asthma, airway inflammation plays a pivotal role in its
pathophysiological symptoms, which is mainly manifested in the
infiltration of neutrophils and eosinophils(L. Dong et al., 2021). This
process is regulated by various inflammatory factors including
Interleukin-17 (IL-17)(Ritzmann, Lunding, Bals, Wegmann, & Beisswenger,
2022). And studies have shown that icariin significantly reduces airway
inflammation via reducing the level of IL-17(Wei et al., 2015).
Excessive secretion of mucus by mucous gland cells can also exacerbate
airway inflammation, and icariin can also reduce this process(Jaramillo,
Azzegagh, Tuvim, & Dickey, 2018). As an immune regulator, Forkhead box
P3 (Foxp3) plays a key role in regulating the generation and
differentiation of Regulatory T cells (Treg cells)(Y. Dong, Yang, &
Pan, 2021). Interestingly, Retinoic acid receptor-related orphan
receptor gamma t (RORγt) acts as a transcriptional Factors can bind to
Foxp3 and reduce its activity, thereby inhibiting the development and
function of Treg cells and relieving inflammation(W. Zhang et al.,
2021). And icariin can just up-regulate the level of RORγt to inhibit
the promoting effect of Foxp3 on the differentiation of Treg cells(Wei
et al., 2015).
In inflammatory diseases of the digestive system, icariin and its
derivatives exhibit multi-channel and multi-target characteristics in
fighting inflammation. In colitis, Signal Transducer and Activator of
Transcription 1 (STAT1) and Signal Transducer and Activator of
Transcription 3 (STAT3) are two transcription factors present in Cluster
of Differentiation 4 positive T lymphocytes (CD4+ T cells), which
phosphorylation can promote the differentiation of CD4+ T cells into Th1
and Th17 cells, and then secrete inflammatory factors such as IFN-γ and
IL-17 to promote inflammation(Celada et al., 2018; Kang, Biswas, Field,
& Snapper, 2019; Kappel et al., 2009; Luz-Crawford et al., 2013).
Icariin can inhibit the production of Th1 and Th17 cells by inhibiting
the phosphorylation of STAT1 and STAT3, thereby alleviating the
inflammatory effect(Tao et al., 2013). Furthermore, Cluster of
Differentiation 25 (CD25) and Cluster of Differentiation 69 (CD69) are
two molecules used to identify the state of T cell activation and
proliferation(Shevach, McHugh, Piccirillo, & Thornton, 2001; Wiggins et
al., 2022), among which CD25 can up-regulate the affinity of
Interleukin-2 (IL-2) receptor(Codarri Deak et al., 2022), thereby
guarantee the smooth flow of IL-2 pathway and promote the
differentiation of T cells, while CD69 can increase the activity of T
cells, prompt them to secrete inflammatory factors, and enhance cell
membrane adhesion and other functions. Icariin inhibits the activity of
CD25 and CD69 firstly, then inhibit the differentiation and function of
T cells(Tao et al., 2013).
In diseases of the motor system, the occurrence of inflammation is also
widely reflected. For osteolytic diseases, Receptor Activator of Nuclear
Factor Kappa-B Ligand (RANKL) can interact with Receptor Activator of
Nuclear Factor Kappa-B (RANK) to promote the activation of osteoclasts
and lead to osteolysis(Ikebuchi et al., 2018). Icariin can down-regulate
the level of RANKL and inhibit the combination with RANK, thereby
reducing the occurrence of osteolysis(Shao et al., 2015). As an enzyme,
Cox-2 can promote the transformation of arachidonic acid into PGE2, and
PGE2 can also promote the differentiation of osteoclasts(Zheng et al.,
2019). Therefore, icariin prevents this transformation by inhibiting the
activity of Cox-2 and reduces the differentiation of osteoclasts(Hsieh,
Sheu, Sun, & Chen, 2011). It is worth noting that NF-κB pathway, P38
MAPK pathway, and JNK pathway can all stimulate the formation of
osteoclasts and lead to osteolysis(An et al., 2019; Yin et al., 2019).
And icariin can inhibit this process(Hsieh et al., 2011; J. Liu et al.,
2016). In the related diseases of intervertebral disc degeneration, the
P13K/AKT pathway can promote the formation of bone matrix(D. Wang et
al., 2022). Icariin does exactly that to intensify this process(X. Deng
et al., 2017). Second, for osteitis and chondrocyte inflammation,
elevated TNF-α levels can upregulate Matrix Metalloproteinase-1(MMP1),
Matrix Metalloproteinase-1(MMP3), Matrix Metalloproteinase-1(MMP9),
Matrix Metalloproteinase-1(MMP13), ROS levels, while promoting the
degradation of IκBα and the nuclear translocation of NF-κB P65,
resulting in inflammation(X. Chen et al., 2021; Kong et al., 2019; L.
Liu & Kang, 2022). Icariin can inhibit the level of TNF-α to alleviate
this process(M. H. Liu, Sun, Tsai, Sheu, & Chen, 2010; Mi et al., 2018;
Pan, Zhang, Chen, & Yang, 2017).
According to research, tumor progression associated with chronic
inflammation closely(Manjili, Isbell, Ghochaghi, Perkinson, & Manjili,
2022). Myeloid-derived suppressor cells (MDSCs) can prevent the
activation of adaptive immunity to help tumor growth, and MDSCs are
affected by chronic inflammation, specifically by upregulating Toll-like
receptor 4 (TLR4) and MRP8/14 induced increased activity of MDSCs(H. Liu
et al., 2021; Y. Wang, Ding, Guo, & Wang, 2019). Interestingly, ICA and
ICT can downregulate the levels of TLR4 and MRP8/14 to inhibit the
activation of MDSCs, thereby delaying tumor progression(J. Zhou et al.,
2011).