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).