Jian-Yu Chen1†
Xiao-Yun Tian1†
Shan-Shan Wei2
Ying-Jie Yang1Shan Deng1Chun-Jie Jiao3Can-Jian Wang4Ke-Dan Chu1*
Xue-Qin Ma5*Wei Xu1*- 1Department of Pharmacology, School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- 2School of Pharmacy, Second Military Medical University, Shanghai, China
- 3Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, ZhengZhou, China
- 4Jiangxi University of Chinese Medicine, Nanchang, China
- 5Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Department of Pharmaceutical Analysis, School of Pharmacy, Ningxia Medical University, Yinchuan, China
JAK/STAT signaling pathways are closely associated with multiple biological processes involved in cell proliferation, apoptosis, inflammation, differentiation, immune response, and epigenetics. Abnormal activation of the STAT pathway can contribute to disease progressions under various conditions. Moreover, tofacitinib and baricitinib as the JAK/STAT inhibitors have been recently approved by the FDA for rheumatology disease treatment. Therefore, influences on the STAT signaling pathway have potential and perspective approaches for diverse diseases. Chinese herbs in traditional Chinese medicine (TCM), which are widespread throughout China, are the gold resources of China and have been extensively used for treating multiple diseases for thousands of years. However, Chinese herbs and herb formulas are characterized by complicated components, resulting in various targets and pathways in treating diseases, which limits their approval and applications. With the development of chemistry and pharmacology, active ingredients of TCM and herbs and underlying mechanisms have been further identified and confirmed by pharmacists and chemists, which improved, to some extent, awkward limitations, approval, and applications regarding TCM and herbs. In this review, we summarized various herbs, herb formulas, natural compounds, and phytochemicals isolated from herbs that have the potential for regulating multiple biological processes via modulation of the JAK/STAT signaling pathway based on the published work. Our study will provide support for revealing TCM, their active compounds that treat diseases, and the underlying mechanism, further improving the rapid spread of TCM to the world.
Introduction
Signal transducer and activator of transcriptions (STATs) family members play distinct roles in cell differentiation, tissue repair, and anti-tumor immunity. STAT activation is triggered by Janus kinases (JAKs), which are intracellular tyrosine kinases. Moreover, intracellular tyrosine kinases are activated by the abundance of membrane receptors binding to corresponding cytokines. In response to cytokines binding to specific JAKs, JAKs located in the cytoplasm undergo conformational changes, causing autophosphorylation or transphosphorylation. Subsequently, phospho-JAKs result in docking with different STATs, which causes dimerization of STATs, translocation into the nucleus, and initiate the transcription process (Stark et al., 2018). An overview of the JAK/STAT signaling pathway is presented in Figure 1. JAK/STAT is now recognized as one of the central mediators of widespread and varied human physiological processes. More specifically, its clinical applications have become increasingly important with the discovery of novel clinical syndromes caused by mutations in JAK and STAT genes (Luo et al., 2021a). JAK/STAT signaling regulates many cellular processes essential to maintaining cell homeostasis, whose dysregulation contributes to cancer progressions and inflammatory and autoimmune disorders and COVID-19 emergencies (Chen et al., 2021a; Solimani et al., 2021).
FIGURE 1. Activation of the JAK/STAT signaling pathway and involved diseases.
A wide spectrum of diseases has been alleviated by treating with JAK inhibitors. Evidence demonstrates that tofacitinib, a pan-Janus kinase (JAK) inhibitor, is the only FDA-approved drug for RA treatment that downregulated STAT3 signaling mainly by inhibiting JAK expression (Miklossy et al., 2013). Interestingly, even if tofacitinib is the only FDA-approved drug indirectly related to the STAT3 target, it is still more effective than most of these first-line drugs for RA patients, especially in patients with methotrexate-resistant active RA. Additionally, drugs targeting JAK/STAT signaling may effectively assist in the treatment of COVID-19 by restricting cytokine storm syndrome (Luo et al., 2020; Solimani et al., 2021), and three severe COVID-19 cases are reported to be observed to have sustained improvements in outcome with ruxolitinib, which targets the JAK/STAT pathway (Rojas and Sarmiento, 2021).
Chinese herbs, which have widespread distribution throughout China, are the gold resources in China. In the concepts of traditional Chinese medicine (TCM) theory, herbs and herb formulas have been extensively used for treating multiple diseases for thousands of years. Recently, TCM presented a remarkable effectiveness of high epidemic COVID-19 treatment through various approaches (Li et al., 2021a). Therefore, herbs and herb formulas are perspectives for promoting human health against diseases. Despite the wide variety of ingredients in TCM and their complex interactions with the human body, it is still quite difficult to disclose the molecular mechanisms, which severely hampers TCM modernization and internationalization. With the development of chemistry, active ingredients of TCMs and herbs have been further identified by chemists. Afterward, the pharmaceutical effect of active ingredients was subsequently confirmed by pharmacists. Meanwhile, the abundance of potential compounds had been reported to represent biological activities, suggesting that the herb kingdom may be regarded as a gold mine for drug discovery and development (Chen et al., 2022a; Chen et al., 2022b; Liu et al., 2022; Zheng et al., 2022).
Based on the important roles of JAK/STAT signaling in various diseases, in this review, we summarized various TCM formulas, herbs, natural compounds, and phytochemicals which have potential for regulating multiple biological processes via modulation of the JAK/STAT signaling pathway based on the published work. Our study will provide support for revealing TCMs, herbs, and their active compounds to treat diseases and the underlying mechanisms.
Activation of the JAK/STAT signaling pathway and involved diseases
The Janus kinase family consists of four members: JAK1, JAK2, JAK3, and TYK2. All, but JAK3, are ubiquitously expressed, except for JAK3, which is confined to hematopoietic cells. In response to cytokine binding, the receptor of JAKs on the juxta membrane becomes active. Once the receptor is bound, it undergoes intracellular conformation. The STAT family of transcription factors, which includes STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, plays distinct roles in cell differentiation, tissue repair, and anti-tumor response. Activation of the JAK/STAT signaling pathways is involved in five processes. First, the cytokines and growth factors engage their corresponding receptors, causing their dimerization and recruitment of related JAKs. Second, the activation of JAK causes tyrosine phosphorylation of the receptors and formation of STAT docking sites. Third, the STAT proteins are phosphorylated by tyrosine. Fourth, the STAT protein dissociates from the receptor to form homodimers or heterodimers. Fifth, in the nucleus, STAT dimers bind DNA and regulate transcription. JAK activation of STAT is the best-characterized pathway, but STATs can also be activated by receptors with intrinsic RTK activity, such as EGFR and PDGFR, and by nonreceptor tyrosine kinases (NRTKs) other than JAKs, such as Src kinase and ABL (Butturini et al., 2020). STATs mediated their biological effects by transactivating a unique profile of target genes dependent on their interactions with STAT-associated regulatory factors. Abnormal activation of JAK/STAT signaling can contribute to disease progressions under various conditions, for example, JAK/STAT signaling regulates inflammation and immunity, cell apoptosis, cell proliferation and differentiation, as well as metabolism, which subsequently cause autoimmune disease, cancer, infectious diseases, and metabolism-related diseases.
Traditional Chinese medicines or herbs or natural compounds in treating various diseases present good performance both in clinical and pre-clinical conditions
Chinese herbs, which have widespread distribution throughout China, are the gold resources of China. Herbs and herb formulas have been extensively utilized for treating multiple diseases based on traditional Chinese medicine (TCM). It has been reported that TCM presents significant management in treating influenza (Xiong et al., 2020), cardiovascular diseases (Layne and Ferro, 2017), acute pancreatitis (Li et al., 2017), depression (Zhang and Cheng, 2019), and so on. Particularly, in recent years of the COVID-19 outbreak, TCM presents remarkable effectiveness of high epidemic 2019-new coronavirus (SARS-CoV-2) treatment through various approaches (Yang et al., 2020a; Li et al., 2021a). Herbs and herb formulas can be beneficial in promoting human health against diseases. Despite the variety of ingredients in TCM and herbs and their complex interactions with the human body, the molecular mechanisms remain elusive, severely hampering TCM modernization and internationalization. As the development of chemistry has progressed, active ingredients from TCMs and herbs have further been identified by chemists. The pharmaceutical effect of active ingredients was then confirmed by pharmacists. Meanwhile, a vast array of compounds that represent biological activity had been reported, suggesting that the herb kingdom might be considered a gold mine for discovering new drugs, considering the importance of JAK/STAT signaling to various diseases. Hence, we summarized here different TCM formulas, herbs, natural compounds, and phytochemicals with the potential to regulate multiple biological processes via modulation of JAK/STAT signaling. We aimed to identify effective therapies or potential health benefits through regulating STAT agents.
Chinese herbs and herb formulas, natural compounds, and phytochemicals through regulating the STAT1 signaling pathway
STAT1 signaling is activated by interferon (IFN), interleukin (IL-6), transforming growth factor-1 (TGF-1), tumor necrosis factor (TNF), and angiotensin II (Yu et al., 2009). STAT1 has been predicted as a prognostic biomarker in patients with solid cancer (Zhang et al., 2020), and targeting the IFN/STAT1 pathway could be a promising strategy to protect radioresistance (Liu et al., 2020a). Gemcitabine was identified as an antiviral that induces an IFN response by phosphorylating STAT1 (Li et al., 2020a). Activation of STAT1 signaling is indispensable to various diseases. STAT1, as a mediator of IFN-γ and TLR signaling, participates in endothelial cell dysfunction and cardiovascular diseases (Sikorski et al., 2011). Additionally, IFN-γ-initiated STAT1 promotes Th1 cell differentiation, which was subsets of CD4 effector T cells, and produces IFN-γ, TNF-α, and IL-1β to facilitate β cell apoptosis, finally resulting in progression of type 1 diabetes (Yue et al., 2022). Moreover, Th1 cells and the other subset of CD4 effector T cells, Th17 cells, have been reported to be associated with autoimmune diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, and (multiple sclerosis) MS (Delgado-Ramirez et al., 2021). The transcription factor STAT1 binds to and sequences FAS, promoting Th17 cell differentiation and inhibiting Th1 cell development (Meyer Zu Horste et al., 2018). Clonal expansion of antiviral NK cells is regulated by STAT1-mediated epigenetic control of Rsad2 (Wiedemann et al., 2020a). Hence, Chinese herbs and herbal formulas, natural compounds, and phytochemicals for treating diseases and their involved molecular mechanisms regarding STAT1 signaling are summarized to support evidence for their potential health benefits, which is shown in Table 1.
TABLE 1. Chinese herbs and herb formulas, natural compounds, and phytochemicals in the treatment of diseases through regulating STAT1.
Regarding the aspects of Chinese herbal formulas, approximately five herbal formulas regulating STAT1 cascade were collected in preclinical investigational studies, and these were Yu-Ping-Feng decoction (Zhou et al., 2021), Yiguanjian decoction (Boriero et al., 2021), Sijunzi decoction (Xiong and Qian, 2013), Yu-Ping-Feng powder (Xiong and Qian, 2013), Ganghuo Kanggan decoction (Lai et al., 2020), and Xin-Jia-Xiang-Ru-Yin (Li et al., 2018). These formulas, Yiguanjian decoction (Boriero et al., 2021), Sijunzi decoction (Xiong and Qian, 2013), Yupingfeng powder (Lai et al., 2020), Ganghuo Kanggan decoction (Lai et al., 2020), and Xin-Jia-Xiang-Ru-Yin (Li et al., 2018), were crucial for treating hepatic fibrosis, spleen deficiency, and influenza through inhibiting STAT1 signaling, whereas the other formula, Yu-Ping-Feng decoction, induces opposite effects on STAT1 activation to anti-cancer (Zhou et al., 2021). Extracts from two herbs, including a natural extract from Gardenia jasminoides J. Ellis (GJ-4) (Liu et al., 2021) and bisabolane-type sesquiterpenoids isolated from turmeric (Ti et al., 2021), were mentioned here to antagonize Alzheimer’s disease (AD) and infection through inactivating STAT1. Correspondingly, about nine natural compounds and phytochemicals isolated from herbs and plants exhibited good performance in anti-cancer (Liang et al., 2021a; Jiang et al., 2022), treating allergic rhinitis (Zhou et al., 2021), MS (Du et al., 2021a), nonalcoholic steatohepatitis (Luo et al., 2021b), anti-depression (Zheng et al., 2021) and promoting skin-moisturizing activities (Chen et al., 2021b), acute lower respiratory tract infection (Wang et al., 2020a), renal inflammatory injury (Hu et al., 2020), and ischemic cerebrovascular diseases (Boriero et al., 2021) through influencing STAT1 signaling. Natural compounds’ combined utilization has been increasingly popular in recent years for their decrease of deficiencies and complementary advantages. TS IIA and AS IV and TS IIA and Puerarin were presented here for their excellent performance in protecting against lumbar intervertebral disc degeneration (Du et al., 2021b) and idiopathic pulmonary fibrosis (IPF) (Xue et al., 2021) through restricting STAT1 cascade via combined utilization. As mentioned above, potential candidates, including baicalin (Jiang et al., 2022), dihydroartemisinin (Du et al., 2021a), kahweol (Chen et al., 2021b), and Yu-Ping-Feng decoction (Zhou et al., 2021), exerted their anti-cancer and anti-infection properties through upregulating cell apoptosis and reinforcing immune system via activating STAT1 signaling, which caused high levels of apoptotic proteins, that is, caspases and enhanced the expression of immune cells, such as T cells and B cells. Conversely, compounds effectively treated allergic rhinitis (Zhou et al., 2021) and influenza (Ti et al., 2021) through inhibiting STAT1 signaling, reducing the expression of inflammatory mediators, and regulating cell differentiation.
Chinese herbs and herb formulas, natural compounds, and phytochemicals through regulating the STAT2 signaling pathway
STAT2 is another member of the STAT family, which is frequently activated in response to type I interferon (IFN α and IFN β) and subsequent JAK1 and TYK2 in the canonical STAT2 cascade (Duncan and Hambleton, 2021). The principal transducer signals of STAT2 is its downstream of the IFN-I and IFN-III receptors by forming a heterotrimeric transcription factor complex containing STAT1 and interferon regulatory factors (IRF9), and the complex is called interferon-stimulated gene factor 3 (ISGF3), which is an interferon-stimulated response element (ISRE) in DNA (Levy et al., 1988). Therefore, deficiency of STAT2 results in impaired STAT1, heterotrimeric formation, prevents the activation of ISGF3, and causes tissue-specific immune defects in response to IFN stimulation (Au-Yeung et al., 2013). Additionally, mutations in STAT2 cause virulent susceptibility and type I interferonopathy in humans (Duncan and Hambleton, 2021). Here, literature regarding the influences of Chinese herbs and herb formulas, natural compounds, and phytochemicals on STAT2 signaling has been collected, which is shown in Table 2.
TABLE 2. Chinese herbal formulas or active ingredients in the treatment of infected or inflammatory diseases through influencing STAT2.
As a result of the investigational preclinical studies on Chinese herbal formulas, approximately three herbal formulas regulating STAT2 cascades have been identified, including Mahuang tang and Yinqiao powder (Xue-mei, 2020), Si-Ni-San (Cai et al., 2021). In particular, Mahuang tang and Yinqiao powder (Xue-mei, 2020) antagonized acute upper respiratory tract infection by activating STAT2, resulting in improving the immune barrier function of mouse nasal mucosa, whereas, Si-Ni-San inhibited STAT2 activation for alleviating ulcerative colitis (UC) (Cai et al., 2021). Additionally, 5-hydroxymethylfurfural (5-HMF) (Zou et al., 2021) and Euphorbia angustifolia polysaccharide (Mingyu et al., 2019) has antiviral potential, including vesicular stomatitis virus (VSV) and hepatitis B virus (HBV), through promoting lymphocyte proliferation and survival (Yuan et al., 2020), whereas Atractylodis macrocephalus polysaccharides (RAMPtp), which were extracted from Atractylodis Macrocephale Rhizoma, effectively increased the proliferation and survival of intestinal epithelial cells and maintained the intestinal barrier function, as well as decreased inflammatory cytokines, and finally relieved IBD (Zong et al., 2021). Chinese herbs and herb formulas, natural compounds, and phytochemicals that regulate the STAT2 signaling pathway are shown in Table 2.
Chinese herbs and herb formulas, natural compounds, and phytochemicals through regulating the STAT3 signaling pathway
Abundant studies have provided substantial insight into the role of T helper 17 (Th17) and regulatory T cells (Tregs) in autoimmune diseases (Dolff et al., 2019; Ding et al., 2021). Th17 cells trigger inflammation by secreting diverse cytokines, which induce other neighboring cells to become activated and, in turn, produce more proinflammatory cytokines and chemokines (Bunte and Beikler, 2019; Kamali et al., 2019; Wu and Wan, 2020). Treg cells, a subgroup of CD4+ T cells, are characterized by expressing transcription factor Foxp3 and secreting either TGF-β or IL-10 to counter the Th17-induced inflammation response. STAT3 is another transcription factor in STAT family members that facilitates differentiation of Th17 cells by activating its downstream target genes, retinoic acid receptor-related orphan nuclear receptor (RORγt), and expression of IL-17 (Macaubas et al., 2022). RORγt and IL-17 are unique transcription factors and cytokines of Th17 cells (Chen et al., 2011), which indicated that STAT3 facilitated Th17 cell differentiation and IL-17 expression. Meanwhile, STAT3 restricted Tregs by inhibiting its unique transcription factor Foxp3 (Aqel et al., 2021). Inhibiting STAT3 recalibrates CD4+ T responses by interference on both effector and regulatory cells, which provides potential clinically applicable treatment options (Aqel et al., 2021). Additionally, activating STAT3 signals promotes cell proliferation by promoting the progression of the cell cycle and inhibiting apoptosis in cancer (Ashrafizadeh et al., 2021). Blocking STAT3 signaling is considered one of the effective therapeutic options for reversing high self-immune responses via antagonizing IL-17A expression, Th17 differentiation, and T lymphocyte proliferation.
Four herbal formulas are summarized here, and they are Buyang Huanwu Decoction (BYHWD), Yanghe decoction (YHD), Maxing Shigan decoction (MXSGD), and Fufang Fanshiliu decoction (FFSLD). Moreover, their distinct effects on STAT3 signaling are shown in Table 3, BYHWD protected against transient ischemic stroke through upregulating p-STAT3. However, the others exhibited good performances for anti-COVID-19, T2DM, and anti-breast cancer by blocking STAT3 signaling. Correspondingly, about nine natural compounds and phytochemicals influence STAT3 signaling for hypertensive heart disease (Ye et al., 2020) and IBD (Zhao et al., 2016). Among all mentioned above, these natural compounds belong to flavonoids (baicalin and quercetin), polyphenols (curcumin, gallic acid, and rosmarinic acid), terpenoids (celastrol and bilobalide), phenylpropanoids (imperatorin), and 3-deoxy-2β,16-dihydroxynagilactone E. Those natural compounds accomplished treatment for myocardial ischemia/reperfusion injury (Xu et al., 2020), diabetic cardiomyopathy (Abdelsamia et al., 2019), IBD (Zhao et al., 2016), alcoholic liver disease (ALD) (Zhu et al., 2017), neuropathic pain (Yang et al., 2021), psoriasis (Zhang et al., 2021a), hypertensive heart disease (Ye et al., 2020), AD (Xiang et al., 2021), cancer cachexia (Chen et al., 2020a), and cancer (Shan et al., 2019). The underlying mechanisms for these compounds treating diseases preferred restraining STAT3 signaling activation. As for synergy utilization of compounds, frankincense and myrrh (Gao et al., 2020), curcumin, and BioPerine (Pillai et al., 2021) were combined applications for multiple myeloma and atherosclerosis through inhibiting STAT3 signaling. The extract of Sophorae Flos (SLE) (Liu et al., 2019), Rosae Multiflorae Fructus, and Lonicerae Japonicae Flos (RLE) decreased STAT3 signaling activation by antagonizing p-STAT3 and resulted in an inhibitory effect on inflammatory cytokines, which finally exerted their effects on RA and melanoma (Liu et al., 2019). Chinese herbal formulas or active ingredients in the treatment of infected or inflammatory diseases through influencing STAT3 are shown in Table 3.
TABLE 3. Chinese herbal formulas or active ingredients in the treatment of infected or inflammatory diseases through affecting STAT3.
Chinese herbs and herb formulas, natural compounds, and phytochemicals through regulating the STAT4 signaling pathway
As one member of the STAT family involved in transducing signals in response to IL-12, STAT4 plays an integral role in the generation of inflammation during immune responses and immune-mediated diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and psoriasis (Yang et al., 2020b). Activation of the IL-12/JAK/STAT4 cascade produces an abundance of IFN-γ and promotes Th1 cell differentiation by inducing an ETS transcription factor, EMR (Ouyang et al., 1999). IL-12 facilitated interferon regulatory factor-1 (IRF1) in natural killer (NK) and T cells (Galon et al., 1999), and it also increased the expression of IRF4 and IRF8 genes, resulting in intensive innate immune responses (Lehtonen et al., 2003). Additionally, STAT4 gene polymorphisms are at a higher risk of type 2 diabetes and systemic sclerosis (Xu et al., 2016), and STAT4 was regarded as diagnostic biomarker candidates and therapeutic targets for heart failure combined with depression (Huang et al., 2022). Based on its essential role in inflammation and autoimmunity, it is a promising therapeutic target for autoimmune diseases.
As a result of the investigational preclinical studies on Chinese herbal formulas, approximately two herbal formulas regulating STAT4 cascades have been identified, namely, Liuweibuqi capsules and Hei-Gu-Teng-Zhui-Feng-Huo-Luo granule. Liuweibuqi capsules were reported to be effective in treating chronic obstructive pulmonary disease (COPD) through antagonizing STAT4, but activating STAT6 (Shen et al., 2019). The Hei-Gu-Teng-Zhui-Feng-Huo-Luo granule downregulated IL-12-stimulated STAT4 signaling and caused low levels of TNF-α, IL-1β, and IL-6 in collagen-induced arthritis (Zheng et al., 2018). Three kinds of extracts from herbs, namely, Pinellia pedatisecta Schott extract (PE) (Wang et al., 2021a), aqueous extract of Fritillariae cirrhosae (FC-AE) (Li et al., 2020b), and Euphorbia helioscopia L. aqueous extract (EAE) exhibited their excellent performance in alleviation of COPD and anti-cancer through inhibiting STAT4 signaling. Meanwhile, Euphorbia helioscopia L. aqueous extract (EAE) (Ling-ling et al., 2021) represented its therapeutical effect on COPD through activating STAT6 cascades (Ling-ling et al., 2021). Four compounds isolated from herbs, saikosaponin A, cynaropicrin, xanthatin, and baicalin, were reported here for breast cancer (Zhao et al., 2019), colorectal cancer (CRC) (Zheng et al., 2020), Non-small-cell lung cancer (NSCLC) (Zheng et al., 2020), and sepsis (Liu et al., 2020b). To be specific, saikosaponin A inhibited breast cancer growth and promoted a shift of Th1/Th2 balance toward Th1 through activating STAT4 signaling (Zhao et al., 2019), which presented anti-cancer performance. Xanthatin antagonized NSCLC through inhibiting STAT4 signaling and suppressing cell proliferation, migration, and invasion (Zhang et al., 2021b). Cynaropicrin and baicalin inhibited both STAT3 and STAT4 signaling, resulting in frequent apoptosis and Treg differentiation (Liu et al., 2020b; Zheng et al., 2020). Chinese herbal formula or active ingredients in the treatment of infected or inflammatory diseases through influencing STAT3 are shown in Table 4.
TABLE 4. Chinese herbs and herb formulas, natural compounds, and phytochemicals in the treatment of diseases through mediating STAT4.
Chinese herbs and herb formulas, natural compounds, and phytochemicals through regulating the STAT5 signaling pathway
Two adjacent genes encoded STAT5 in mammals, namely, Stat5a and Stat5b, which drive tumor development, metastasis, survival and drug resistance to treatment (Verhoeven et al., 2020), NK cell development, maturation, survival, and cytotoxicity (Wiedemann et al., 2020b). JAK/STAT5 is frequently activated by IL-2, IL-15, EPO, GM-CSF, TPO, and other factors (Rani and Murphy, 2016; Orlova et al., 2019). Different activation procedures of JAK/STAT5 induced by different cytokines cause distinct actions. IL-2 and IL-15 at upstream of STAT5 promote the early and late stages of the adaptive NK cell response to different mouse cytomegalovirus (MCMV) infections (Wiedemann et al., 2020b). GM-CSF effectively drives the expression of inflammatory factors in macrophages through activating the STAT5 cascade, which upregulated the immune stimulatory gene levels, and in contrast to tissue remodeling factors increased caused by loss of STAT5 (Jesser et al., 2021). Moreover, lessened pathogenic Th17 cells and monocyte-derived cells (MDCs) in the meninges were observed in the STAT5 tetramer-deficient Stat5a–Stat5b N-domain double knock-in mouse strain, suggesting that the GM-CSF-STAT5 tetramer-CCL17 cascade in MDCs promotes autoimmune neuroinflammation (Monaghan et al., 2021). IL-2/STAT5 signaling contributed to monitoring the ratio of Th9/Th17-like in vitro and allergic disease. To be specific, STAT5 restricted a Th17-like program in the process of Th9 cell differentiation (Canaria et al., 2021). As shown above, STAT5 regulates the development of inflammation and tumor-related diseases (Surbek et al., 2021).
In total, eight compounds were collected for their biological potential for treating diverse diseases. Dihydromyricetin blocked STAT5 signaling and reduced oxidative stress, mitigating mast cell activity, which effectively alleviated allergic diseases (Chang et al., 2021). Upregulation of cryptotanshinone on the expression of p-STAT5 supported protection against ischemic stroke (Zhu et al., 2021), whereas the inhibitory effect of cryptotanshinone effectively antagonized chronic myelocytic leukemia (CML) (Dong et al., 2018). Additionally, tetrahydroquinoline derivatives (Polomski et al., 2021) and taxodione (Uchihara et al., 2018) antagonized chronic myelocytic leukemia by inhibiting activation of STAT5 signaling. Moreover, silibinin (Rugamba et al., 2021), naringenin (Niu et al., 2018), xanthoplanine (Shi et al., 2020), and menthol (Suzuki et al., 2020) exhibited the biological potential of NSCLC, autoimmune inflammatory disorders, and arterial inflammation through inhibiting STAT5 signaling. Extracts of two herbs are mentioned here to antagonize diverse diseases through regulating STAT5. Ginseng powder possesses the potential for immunity upregulation through increasing activation of B-cell, Th1 cell, and NK-cell via both activating STAT5 signaling and blocking STAT3 signaling (Park et al., 2022). Trifolium repens Linn (Sarno et al., 2020) was reported to be effective in treatment of chronic myelogenous leukemia through inhibiting p-STAT5. Bu-Shen-Zhu-Yun decoction (Feng et al., 2021) and Bufei Yishen formula (Zhao et al., 2018) are crucial for treating hyperprolactinemia infertility and COPD through activating STAT5 signaling. You-Gui-Yin (Li et al., 2020c) and Guizhi-Shaoyao-Zhimu decoction (Zhang et al., 2019) were effective in the treatment of chronic kidney disease and rheumatoid arthritis through inhibiting STAT5 signaling, which shown in Table 5.
TABLE 5. Chinese herbs and herb formulas, natural compounds, and phytochemicals in the treatment of diseases through regulating STAT5.
Chinese herbs and herb formulas, natural compounds, and phytochemicals through regulating the STAT6 signaling pathway
The STAT6, another important member of the STAT family, is activated primarily by IL-4 and IL-13 (Czimmerer et al., 2018). STAT6 has been reported to be crucial in Th2 cell differentiation (Forbes et al., 2010). Additionally, variants of STAT6 were closely associated with asthma risk (Qian et al., 2014), and deficiency of STAT6 affects immune function, glycolysis, and B cell morphology, which contributes to various diseases. Therefore, regulation of B cells by STAT6 can perhaps be a prospective therapeutic approach for human diseases (Wang et al., 2021b). As shown in Table 6, two Chinese herbal formulas regulating STAT6 cascades have been identified, namely, Srolo Bzhtang (Jing et al., 2019) and Banhahubak-tang tablet (Nam et al., 2020), which both antagonized airway inflammation (Jing et al., 2019) and allergic asthma (Nam et al., 2020) through blocked STAT6 signaling. Total glucosides of paeony blocked STAT6 signaling and promoted M2 macrophage polarization for treating lupus nephritis (Forbes et al., 2010). Sixteen compounds isolated from herbs or plants presented their biological activities for treating diseases. Three compounds, namely, ginsenoside Rb1 (Zhang et al., 2018), luteolin (Wang et al., 2020b), and physalin D (Ding et al., 2019) exhibited potential therapeutic effects on coronary artery disease, inflammation, and imbalance of macrophage polarization-related diseases. The others preferentially executed their primary role for downregulation of STAT6 signaling in the treatment of various diseases, for instance, atopic dermatitis symptoms (Sung and Kim, 2018), cancer metastasis (Yang et al., 2018), allergic airway inflammation (Chen et al., 2018; Li et al., 2020d), asthma (Ma et al., 2020), allergic asthma (Chen et al., 2017; Ma et al., 2019), diabetes-associated inflammation (Oh et al., 2020), chronic kidney disease (Li et al., 2020e), cervical cancer (Duan et al., 2021), inflammation (Liu et al., 2018), insulin resistance (Subash-Babu and Alshatwi, 2018), and AD (Choi et al., 2020).
TABLE 6. Chinese herbs and herb formulas, natural compounds, and phytochemicals in the treatment of diseases through regulating STAT6.
Summary and prospect
JAK/STAT signaling pathways are closely implicated in multiple biological processes involved in cell proliferation, apoptosis, inflammation, differentiation, immune response, and epigenetics (Chen et al., 2021c). In response to extracellular signaling proteins, such as IL-6, TNF-α, and IFNs, which are widespread in an inflammatory microenvironment, JAK/STAT pathways are then activated. Activation of JAK/STAT signaling either contributes to direct expression of the proinflammatory cytokine or induces inflammatory cell proliferation, promoting secretion of cytokines, where both assist in forming a positive feedback loop with JAK/STAT and result in more disease severity. Moreover, multitudinous cascades have been reported to represent complicated crosstalk with JAK/STAT pathways through diverse cytokine pathways. For example, activation of NF-κB leads to increase of inflammatory cytokines, such as IL-6, which result in STAT3 activation and transcription; produces various cytokines; and in turn, promotes NF-κB and STAT3 activation (Grivennikov et al., 2010). Notch-driven differentiation of astrocytes induced by STAT3 is essential in the development of the central nervous system (Kamakura et al., 2004).
Chinese herbs in traditional Chinese medicine (TCM), which have widespread distribution throughout China, are the gold resources of China and have been extensively used for treating multiple diseases for thousands of years. However, Chinese herbs and herb formulas exert their effect on treating diverse diseases through JAK/STAT pathways that have not been elaborated, which limits their approval and applications. In this review, we summarized various herbs, herb formulas, natural compounds, and phytochemicals isolated from herbs that have the potential for regulating multiple biological processes via modulation of the JAK/STAT signaling pathway based on the published work. Regarding natural compounds, for instance, celastrol alleviated hypertensive heart disease and cancer metastasis through inhibiting STAT3 (Ye et al., 2020) and STAT6 (Yang et al., 2018) signaling, respectively. Luteolin helped treat acute lower respiratory tract infection by activating STAT1 (Wang et al., 2020a) and alleviating inflammation through both inhibiting STAT3 and activating STAT6 (Wang et al., 2020b). Cryptotanshinone was regarded as the STAT3 and STAT5 regulator for ischemic stroke (Zhu et al., 2021) and chronic myelocytic leukemia (Dong et al., 2018). Baicalin regulated multiple members of the STAT family, including STAT1, STAT3, STAT4, and STAT5, for treating T2D-induced liver tumor, sepsis, and myocardial ischemia reperfusion injury (Jiang et al., 2022). In addition, dihydroartemisinin ameliorated multiple sclerosis (Du et al., 2021a) and gastric cancer (Liang et al., 2021a) through regulating STAT1 signaling. Moreover, Yu-Ping-Feng decoction (Boriero et al., 2021; Zhou et al., 2021), Sijunzi decoction (Xiong and Qian, 2013), and Yu-Ping-Feng powder (Xiong and Qian, 2013) exerted their effects on anti-NSCLC and spleen deficiency through influencing STAT1 signaling. Meanwhile, we also summarized the candidates for treating diverse diseases involved in JAK/STAT signaling, such as anti-cancer, ameliorating inflammation, allergic asthma, chronic kidney disease, rheumatoid arthritis, and fibrosis. Regarding the aspects of antineoplastics, eight compounds from natural plants or herbs were collected, namely, lanatoside C, saikosaponin A, celastrol, cynaropicrin, dihydroartemisinin, imperatorin, baicalin, and silibinin, which exhibited their potential for anti-tumor or anti-cancer effects. Moreover, inhibitory effects of STAT1, STAT3, and STAT4 activation by these compounds still come to predominate, which was the same as that regulated by two formulas and two extracts. In this respect of anti-inflammation, including airway inflammation, RA, and arterial inflammation, these TCM and their corresponding extracts or active compounds are preferred to influence STAT1 and STAT6 signaling, which are shown in Figure 2. These extracts or active compounds belong to heat-clearing (Qingre) and dewetting (Zaoshi), heat-killed (Xiehuo), and detoxifying (Jiedu) traditional Chinese medicines and are used for treating inflammation and cancer in clinical formulas by regulating JAK/STAT alone, or its crosstalk with NF-κB, and Notch signaling.
FIGURE 2. TCM formulas and their corresponding extracts or active compounds in the treatment of diseases through regulating the JAK/STAT signaling pathway.
Overall, our study will provide support for revealing TCM formulas and their corresponding extracts or active compounds in the treatment of diseases and the underlying mechanisms, which further improve rapid TCM spread to the world and drug discovery regarding regulating STAT signaling.
Author contributions
WX, K-DC, and X-QM contributed to revising the manuscript and provided financial support. J-YC and X-YT wrote the manuscript. Other authors, including S-SW, Y-JY, SD, C-JJ, and C-JW, contributed the table material.
Funding
This work was supported by the National Natural Science Foundation of China (No. 81903629), the Foundation of Fujian University of Traditional Chinese Medicine (No. X2019004), and the Natural Science Foundation of Fujian Province (No. 2022J01868).
Conflicts of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: natural compounds, herbs, herb formulas, traditional Chinese medicines (TCMs), JAK/STATs
Citation: Chen J-Y, Xiao-Yun Tian , Wei S-S, Yang Y-J, Deng S, Jiao C-J, Wang C-J, Chu K-D, Ma X-Q and Xu W (2022) Perspectives of herbs and their natural compounds, and herb formulas on treating diverse diseases through regulating complicated JAK/STAT signaling. Front. Pharmacol. 13:993862. doi: 10.3389/fphar.2022.993862
Received: 14 July 2022; Accepted: 29 August 2022;
Published: 17 October 2022.
Edited by:
Qianqian Wang, Dalian University, ChinaReviewed by:
Yunyao Jiang, Tsinghua University, ChinaCopyright © 2022 Chen, Xiao-Yun Tian, Wei, Yang, Deng, Jiao, Wang, Chu, Ma and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ke-Dan Chu, Y2h1a2Q1OTE3QDE2My5jb20=; Xue-Qin Ma, bWF4dWVxaW4yMTdAMTI2LmNvbQ==; Wei Xu, MjAwMDAxN0BmanRjbS5lZHUuY24=
†These authors have contributed equally to this work and share first authorship