Abstract
Inflammatory disorders underlie varieties of human diseases. San-Huang-Xie-xin-Tang (SHXXT), composed with Rhizoma Rhei (Rheum palmatum L.), Rhizoma Coptidis (Coptis chinensis Franch), and Radix Scutellaria (Scutellaria baicalensis Georgi), is a famous formula which has been widely used in the fight against inflammatory abnormalities. Mutual reinforcement is one of the basic theories of traditional Chinese medicine. Here this article reviewed and analyzed the recent research on (1) How the main constituents of SHXXT impact on inflammation-associated signaling pathway molecules. (2) The interaction between the main constituents and efflux pumps or intestinal transporters. The goal of this work was to, (1) Provide evidence to support the theory of mutual reinforcement. (2) Clarify the key targets of SHXXT and suggest which targets need further investigation. (3) Give advice for the clinical use of SHXXT to elevated the absorption of main constituents and eventually promote oral bioavailability. We search literatures in scientific databases with key words of “each main SHXXT constituent,” in combination with “each main inflammatory pathway target molecule” or each main intestinal transporter, respectively. We report the effect of five main constituents on target molecules which lies in three main inflammatory signaling pathways, we as well investigate the interaction between constituents and intestinal transporter. We conclude, (1) The synergistic effect of constituents at both levels confirm the mutual reinforcement theory of TCM as it is proven in this work. (2) The effect of main constituents on downstream targets in nuclear need more further investigation. (3) Drug elevating the absorption of rhein, berberine and baicalein can be employed to promote oral bioavailability of SHXXT.
Introduction
Inflammation, a complex response triggered by pernicious stimuli like pathogens or irritants, verified to be involved in process of many diseases such as Alzheimer Disease, type 2 diabetes, rheumatoid arthritis, etc., (Chiapinotto Spiazzi et al., 2015; Garimella et al., 2015; Saito et al., 2015). Generally, inflammation is classified as acute and chronic type. Acute type only last a few days with neutrophil infiltration, while chronic type can last up to years with infiltrations of lymphocytes and macrophages (Ambrozova et al., 2016). Inflammatory pathways perform a crucial part for signal transduction and recent research provide genuine evidence showing NF-κB, MAPK and JAK/STAT are the three main pathways (Bertolini, 2012; Ottani et al., 2015).
As a famous traditional Chinese medicine (TCM) formula which has been used for centuries, San-Huang-Xie-Xin-Tang (SHXXT) displays good curative activation in the treatment of inflammatory disorders such as atherosclerosis (Wang Y. S. et al., 2011), upper respiratory tract infection (Ma et al., 2009; Kim et al., 2014), diabetic nephropathy (Wu et al., 2015), gastritis, gastric bleeding and peptic ulcers (Lo et al., 2005), and these protective effects are correlated with reactions of weakening inflammatory by suppressing cytokine/chemokine production. SHXXT has a quite simple composition with only three herbals, namely Radix et Rhizoma Rhei (Rheum palmatum L.) [RR, yields anthraquinones like emodin(Emo), rhein(Rhe) and aloe-emodin (Aem)], Rhizoma Coptidis (Coptis chinensis Franch) [RC, yields alkaloids like berberine(Ber) and coptisine(COP)], and Radix Scutellaria (Scutellaria baicalensis Georgi) [RS, yields flavonoids like baicalin(Bai) and baicalein (Bae)]. Previous studies show the basic effective constituents of SHXXT responsible for the anti-inflammatory effect may be Ber, Bai, Emo, Rhe, and Aem (Ma et al., 2009), plus, Bae is considered as a quality control indicator of RS (Zhang et al., 2013b). In regard of the bioavailability of SHXXT, A rapid and sensitive UPLC-ESI/MS method determined 17 active SHXXT constituents with good linearity in a relatively wide concentration ranges, among which, Bai is the most abundant. In bloodstream, the major forms of SHXXT include Bae, Emo, Aem and Rhe, while only the parent form of Rhe can be detected, and the conjugated effect may be accounted for their physicochemical property differences (Li et al., 2010; Shia et al., 2011).
Intestinal transporters (IT), such as P-gp, MRP, BCRP (Sampson et al., 2015), SGLT1 (Asano et al., 2004) and OCT (Bader et al., 2014), play a critical role in the process of intracellular and efflux transport. Numerous evidence illustrate the main constituents in SHXXT are the substrates of efflux transporters which leads to a very low oral bioavailability (Huang S. et al., 2011; He et al., 2014; Wei et al., 2014; Di et al., 2015). However, most studies only concentrate on solitary constituent, whether they have mutual effect on respective absorption remains to be elucidated.
There's growing evidence indicating that all those constituents above, while exclusively dosed, possess anti-inflammation effect by affecting a variety of target molecules in signaling pathways (Shih et al., 2007; Hamsa and Kuttan, 2012; Zhang et al., 2013a; Hu et al., 2014). We are all clear that, Chinese herbal combination should not only improve curative effects and reduce side effects, but also promote the mutual absorption of effective constituents. In this study, we review the recent studies and discuss how the three classic herbals of SHXXT, RS, RR, and RC, reach the goal of synergistic interaction at both pharmacodynamics and pharmacokinetic level.
Pharmacodynamic level
Effect of the active constituents on molecules in NF-κB pathway
TLR-4 is the first described TLRs in mammals, it responds to LPS which can trigger NF-κB activation and pro-inflammatory cytokines secretion (Lee et al., 2010), constituents that can block the binding between TLR-4 and LPS are supposed to be valued in inflammation treatment (Wu et al., 2016). As summarized in Table 1, It is reported that Ber, Bai and Rhe exert inhibitory effect on TLR-4 expression in varies of models (Lee et al., 2010; Li et al., 2011; Cabrera-Benitez et al., 2012; Hou et al., 2012; Chen C. C. et al., 2014; Chen et al., 2015), and the combination of TLR-4 and LPS is observed to be blocked by Ber (Jeong et al., 2014). So, it seems that the anti-inflammatory mechanism of SHXXT begins at a really early stage, ever since LPS are interacting with upstream membrane protein.
Table 1
| Target | Animal or cell culture | Model building | Control (P or N) | Drug | Dose | Treat time | Result |
|---|---|---|---|---|---|---|---|
| TLR-4 | Microglial cells | IL-1β | Vehicle | Ber | 50 μM | 24 h | TLR-4 expression↓ Chen C. C. et al., 2014 |
| BALB/c mice | LPS | Yohimbine | Ber | 50 mg/kg | 3 d | TLR-4 mRNA expression in ileum tissue↓ Li et al., 2011 | |
| C3H/HeN,C3H/HeJ mice | TNBS | Vehicle | Ber | 10–20 mg/kg | 3 d | TLR-4 expression in colonic epithelial cell↓ Lee et al., 2010 | |
| PM cell | LPS | Mangiferin | Ber | 10,20 μM | 1 h | TLR-4 & LPS banding↓ Jeong et al., 2014 | |
| Microglial cells | OGD | Vehicle | Bai | 40,20.10 ug/ml | 24 h | TLR-4 mRNA expression↓ Hou et al., 2012 | |
| IgAN SD rats | BSA, LPS, and CCl4 | Vehicle | Rhe | 400 mg/kg/d | 6 w | TLR-4 expression in renal↓ Chen et al., 2015 | |
| BEAS-2B cell | LPS | CKT0103 | Rhe | 10 μM | 18 h | TLR-4 level↓ Cabrera-Benitez et al., 2012 | |
| BALB/c mice | LPS | TAK-242 | Rhe | 100 mg/kg | TLR-4 expression↓ Zhang et al., 2015 | ||
| Wistar rats | LPS | Vehicle | Emo | 10mg/kg/hr | 1,2 h | TLR-4 expression↓ Li A. et al., 2013 | |
| MyD88 | Microglial cells | IL-1β | Vehicle | Ber | 50 μM | 24 h | MyD88 expression↓ Chen C. C. et al., 2014 |
| Microglial cells | OGD | Vehicle | Bai | 20 ug/ml | 2 h | MyD88 activation↓ Hou et al., 2012 | |
| C57BL/6 mice | DSS | Mesalazine | Bai | 100 mg/kg/12 h | 7 d | colon MyD88 expression↓ Feng et al., 2014 | |
| ICR mice | Placebo | Ribavirin | Bai | 375 mg/kg/d | 7 d | MyD88 mRNA expression↓ Wan et al., 2014 | |
| TNFR1 | HEK293 cell | TNF-α | None | Ber | 25 μmol/L | 24 h | TNFR1gene expression↓ Pandey et al., 2008 |
| TRADD | HEK293 cell | TNF-α | None | Ber | 25 μmol/L | 24 h | TRADD gene expression↓ Pandey et al., 2008 |
| TRAF2 | HEK293 cell | TNF-α | None | Ber | 25 μmol/L | 24 h | TRAF2 gene expression↓ Pandey et al., 2008 |
| SAP SD rats | ST | SO | Emo | 30 mg/kg | 6 h | TRAF2 protein expression↓ Wu et al., 2013 | |
| TRAF6 | Microglial cells | OGD | Vehicle | Bai | 40 ug/ml | 4 h | TRAF6 protein level↓ Hou et al., 2012 |
| NIK | HEK293 cell | TNF-α | None | Ber | 25 μmol/L | 24 h | NIK gene expression↓ Pandey et al., 2008 |
| Fischer 344 rats | “Age” diet | Young rats | Bai | 10,20 mg/kg/d | 10 d | NIK phosphorylation↓ Kim et al., 2006 | |
| Raf | Fischer 344 rats | “Age” diet | Young rats | Bai | 10,20 mg/kg/d | 10d | Raf phosphorylation↓ Kim et al., 2006 |
| U251/U87 cell | None | Vehicle | Ber | 15 μM | 1-7 d | p-Raf phosphorylation↓ Liu et al., 2015 | |
| IRAK1 | PM cell | LPS | Mangiferin | Ber | 10,20 μM | 90 min | phosphorylation of IRAK1↓ Jeong et al., 2014 |
| IKK | PM cell | LPS | Mangiferin | Ber | 10,20 μM | 90 min | phosphorylation of IKK-β↓ Jeong et al., 2014 |
| HEK293 cell | TNF-α | None | Ber | 25 μmol/L | 24 h | IKK-β gene expression↓ Pandey et al., 2008 | |
| KM mice | HCM diet | Vehicle | Ber | 50 mg/kg | 2 w | IKKβ phosphorylation in liver and adipose tissue↓ Shang et al., 2010 | |
| ARD Wistar rats | HCM diet | Normal diet | Ber | 150 mg/kg/d | 12 w | renal IKKβ protein level↓ Wan et al., 2013 | |
| Fischer 344 rats | “Age”diet | Young rats | Bai | 10,20 mg/kg/d | 10 d | p-IKK expression↓ Kim et al., 2006 | |
| HBE16 cells | LPS | Vehicle | Bai | 10–100μM | 24 h | p-IKK expression↓ Dong et al., 2015 | |
| BALB/c mice | cisplatin | Vehicle | Bae | 50 mg/kg/d | 15 d | p-IKK protein expression↓ Sahu et al., 2015 | |
| Raw264.7 cell | LPS | Vehicle | Rhe | 17.5,35 μM | 2 h | IKKβ activity↓ Gao et al., 2014 | |
| BALB/c mice | LPS | CMCS | Rhe | 20–80 mg/kg/d | 7 d | p-IKKβ protein expression↓ Yu et al., 2015 | |
| IκBα | PM cell | LPS | Yohimbine | Ber | 2 μM | 90 min | phosphorylation of IκBα↓ Li et al., 2012 |
| Jurkat cell | TNF-α | None | Ber | 50 μmol/L | 18 h | IκB-α degradation↓ Pandey et al., 2008 | |
| Mesangial cell | LPS | PDTC | Ber | 30,90 μM | 12 h | IκBα protein expression↑ Jiang et al., 2011 | |
| BALB/c mice | DSS | CK | Ber | 100 mg/kg | 3 d | colon IκBα protein expression↑ Li et al., 2014 | |
| C57BL/6 mice | LPS | Yohimbine | Ber | 50 mg/mg | 3 d | spleen IκBα phosphorylation↓ Li et al., 2012 | |
| BALB/c mice | DSS | CK | Ber | 100 mg/kg | 3 d | p-IκBα protein expression of in cytoplasm of colon cell↓ Li et al., 2014 | |
| Raw264.7 cell | LPS | BAY11-7082 | Bae | 10 μM | 2 h | IκBα phosphorylation↓ Fan et al., 2013 | |
| BALB/c mice | Cisplatin | Vehicle | Bae | 50 mg/kg/d | 15 d | p-IκBα protein expression↓ Sahu et al., 2015 | |
| C57BL/6 mice | Surgery | SO | Bae | 100 mg/kg/d | 7 d | IκBα degradation↓ Wang W. et al., 2015 | |
| WKY rats | LPS | SO | Bae | 10 mg/kg | 6 h | p- IκBα expression↓ Lee et al., 2011 | |
| Microglial cells | OGD | Vehicle | Bai | 40,20 ug/ml | 4 h | p-IκBα protein level↓ Hou et al., 2012 | |
| DBA/1 mice | CII | PBS | Emo | 10 mg/kg | 10 d | IκBα degradation↓ Hwang et al., 2013 | |
| HUVECs | LPS | DMSO | Emo | 10–50 μg/ml | 30 min | IκBα degradation↓ Meng et al., 2010 | |
| MEC | LPS | Vehicle | Emo | 10,20,40 μg/ml | 1 h | IκBα degradation↓ Yang Z. et al., 2014 | |
| BMMCs | PMA+ A23187 | PDTC | Emo | 1–20 μM | 1 h | p-IκBα / IκBα↓ Lu et al., 2013 | |
| Raw264.7 cell | LPS | Vehicle | Rhe | 17.5,35 μM | 30 min | IκBα phosphorylation↓ Gao et al., 2014 | |
| Chondrocytes | IL-1β | Vehicle | Rhe | 10 μM | 18 h | IκBα degradation↓ Domagala et al., 2006 | |
| Raw264.7 cell | LPS | BAY11-7082 | Aem | 10,20 μM | 12 h | IκBα degradation↓ Hu et al., 2014 | |
| BALB/c mice | LPS | CMCS | Rhe | 20–80 mg/kg/d | 7 d | p-IκBα protein expression↓ Yu et al., 2015 | |
| NF-κB | PM | LPS | Yohimbine | Ber | 2 μM | 90 min | NF-κB translocation and phosphorylation↓ Li et al., 2012 |
| SD rats | Surgery | Interceed | Ber | 0.75,1.5 mg/ml | 14 d | NF-κB phosphorylation↓ Zhang et al., 2014 | |
| SD diabets rats | STZ | Vehicle | Ber | 200 mg/kg | 12 w | renal NF-κB expression↓ Xie et al., 2013 | |
| Jurkat cell | TNF-α | None | Ber | 50 μmol/L | 18 h | NF-κB activation↓ Pandey et al., 2008 | |
| ARD wistar rats | HCM diet | Normal diet | Ber | 150 mg/kg/d | 12 w | Renal NF-κB DNA banding↓ Wan et al., 2013 | |
| BALB/cN mice | Cisplatin | Vehicle | Ber | 3 mg/kg | 2 d | NF-κB expression↓ Domitrović et al., 2013 | |
| C57BL/6 rats | Cigarettes | Vehicle | Ber | 50 mg/kg | 4d | lung NF-κB DNA banding↓ Lin K. et al., 2013 | |
| BALB/c mice | LPS | Yohimbine | Ber | 50 mg/Kg | 3 d | ileum NF-κB activation↓ Li et al., 2011 | |
| C3H/HeN, C3H/HeJ rats(colitis) | TNBS | Vehicle | Ber | 10,20 mg/kg | 3 d | colon NF-κB activation↓ Lee et al., 2010 | |
| Raw264.7 cell | LPS | BAY11-7082 | Bae | 10 μM | 2 h | NF-κB activation↓ Fan et al., 2013 | |
| DBA/1 mice | CII | PBS | Emo | 10 mg/kg | 10 d | NF-κB binding activity↓ Hwang et al., 2013 | |
| MEC | LPS | Vehicle | Emo | 10,20,40 μg/m | 1 h | NF-κB activation↓ Yang Z. et al., 2014 | |
| SD rats | ADM | Benazepril | Rhe | 100 mg/kg/d | 6–12 w | Renal NF-κB activation↓ Ji et al., 2005 | |
| p65 | PM cell | LPS | Mesalazine | Ber | 10,20 μM | 1 h | p65 phosphorylation↓ Jeong et al., 2014 |
| Jurkat cell | TNF-α | None | Ber | 50 μmol/L | 18 h | p65 phosphorylation and translocation↓ Pandey et al., 2008 | |
| NIT-1 cell | LPS | Vehicle | Ber | 2.5,5.0 μM | 24 h | p65 phosphorylation↓ Hamsa and Kuttan, 2012 | |
| Mesangial cell | LPS | PDTC | Ber | 30,90 μM | 12 h | p65 translocation↓ Jiang et al., 2011 | |
| B16F-10 cell | LPS | Vehicle | LPS | 2 μg/mL | 2 h | p65 DNA-bound↓ Hamsa and Kuttan, 2012 | |
| ARD Wistar rats | HCM diet | Normal diet | Ber | 150 mg/kg/d | 12 w | Renal p65 protein level↓ Wan et al., 2013 | |
| C57BL/6 rats | Cigarettes | Vehicle | Ber | 50 mg/kg | 4 d | p65 translocation↓ Lin K. et al., 2013 | |
| BALB/c mice | DSS | CK | Ber | 100 mg/kg | 3 d | p65 translocation↓ Li et al., 2014 | |
| BALB/c mice | Cisplatin | Vehicle | Bae | 50 mg/kg/d | 15 d | p65 translocation↓ Sahu et al., 2015 | |
| C57BL/6 mice | Surgery | SO | Bae | 100 mg/kg/d | 7 d | p65 expression↓ Wang W. et al., 2015 | |
| C57BL/6 mice | Ang II | Vehicle | Bae | 25 mg/kg | 14 d | p65 expression↓ Wang A. W. et al., 2014 | |
| Raw264.7 cell | LPS | BAY11-7082 | Bae | 10 μM | 2 h | p65 translocation↓ Fan et al., 2013 | |
| Cardiomyocytes | I/R | Vehicle | Bae | 25 μM | 30 min | p65 phosphorylation↓ Song et al., 2014 | |
| ICR mice | Placebo | Ribavirin | Bai | 375 mg/kg/d | 7 d | p65 protein level↓ Wan et al., 2014 | |
| WKY rats | LPS | SO | Bae | 10 mg/kg | 6 h | p-p65 expression↓ Lee et al., 2011 | |
| DBA/1 mice | CII | PBS | Emo | 10 mg/kg | 10 d | p65 translocation↓ Hwang et al., 2013 | |
| BALB/c mice | LPS | Saline | Emo | 100 mg/kg/12h | 3.5 d | p65 phosphorylation↓ Xiao et al., 2014 | |
| Wistar rats | LPS | Vehicle | Emo | 10 mg/kg/hr | 1,2 h | p65 expression↓ Li A. et al., 2013 | |
| HUVECs | LPS | IL-1β | Emo | 10–50μg/ml | 30 min | p65 translocation↓ Meng et al., 2010 | |
| MEC | LPS | GW9662 | Emo | 10,20,40 μg/ml | 1 h | p-p65 expression↓ Yang Z. et al., 2014 | |
| MDA-MB-435s | TNF-α | Vehicle | Rhe | 50–200 μM | 48 h | p65 nuclear translocation↓ Fernand et al., 2011 | |
| Raw264.7 cell | LPS | Vehicle | Rhe | 17.5,35 μM | 1 h | p65 level in nuclear↓ Gao et al., 2014 | |
| BALB/c mice | LPS | CMCS | Rhe | 20–80 mg/kg/d | 7 d | p-p65 protein expression↓ Yu et al., 2015 | |
| p50 | B16F-10 cell | LPS | Vehicle | Ber | 2 μg/mL | 2 h | p50 DNA-bound↓ Hamsa and Kuttan, 2012 |
| ARD Wistar rats | HCM diet | Normal diet | Ber | 150 mg/kg/d | 12 w | renal p50 protein level↓ Wan et al., 2013 | |
| DBA/1 mice | CII | PBS | Emo | 10 mg/kg | 10 d | p50 translocation↓ Hwang et al., 2013 | |
| MDA-MB-435s | TNF-α | Vehicle | Rhe | 50–200 μM | 48 h | p50 nuclear translocation↓ Fernand et al., 2011 | |
| GSK3β | HT-29/B6 cell | TNF-α | BAY11-7082, Genistein | Ber | 50 μM | 26,2 h | GSK3β phosphorylation↓ Amasheh et al., 2010 |
| IRF3 | PM | LPS | Yohimbine | Ber | 2 μM | 2 h | IRF3 phosphorylation↓ Li et al., 2012 |
| BALB/c mice | LPS | Yohimbine | Ber | 50 mg/kg | 3 d | spleen IRF3 phosphorylation↓ Li et al., 2012 | |
| DC1.2 cell | Poly(I:C) | Vehicle | Rhe | 1–10 μM | 5 h | p-IRF3 expression↓ Yuan et al., 2015 |
Effect of the active constituents on molecules in NF-κB pathway.
It has been identified that, MyD88 is recruited by TLR4 at plasma membrane to stimulate the initial activation of IKK, and it may be responsible for the early peak in NF-κB activity (Cheng Z. et al., 2015). Apart from MyD88, there are many other adapter molecules (such as TRAF3, TRAM and TRADD) sharing similar activity. NIK will promote NF-κB activation once combined with TRAF2 (Lee et al., 2014). Among them, MyD88 has been most systemically studied both in vivo and in vitro. In respect of these adaptor molecules, Ber and Bai negatively regulate their protein expressions (Pandey et al., 2008; Hou et al., 2012; Lim et al., 2012; Chen C. C. et al., 2014; Feng et al., 2014; Wan et al., 2014), however the main constituents from RR are rarely mentioned.
Enzyme complex IKK (α-γ) have a crucial role in regulating NF-κB signaling pathway (Bagnéris et al., 2015). In general, IκBα forms a heterodimer with p65 (RELA) and p50 (NF-κb1), making NF-κB sequestered in cytoplasm. Once activated, IκBα goes phosphorylated meanwhile p65 is liberated and translocate into nuclear, which leads to gene transcription (Pandey et al., 2008). Depicted in Figure 1, the majority of current studies focus on upstream molecules from IKK to p65. Data in Table 1 show the main constituents of SHXXT can inhibit (1) the expression and phosphorylation of IKK, (2) the expression, phosphorylation and degradation of IκBα, (3) the expression, phosphorylation and translocation of p65 and (4) the expression, phosphorylation, DNA banding and activation of NF-κB in multiple in-vivo and in-vitro models, such as mesangial (Jiang et al., 2011), RAW264.7 (Fan et al., 2013), MEC (Yang Z. et al., 2014) etc., and ARD rats (Wan et al., 2013), C57BL/6 mice (Wang W. et al., 2015), DBA/1 mice (Hwang et al., 2013), etc.
Figure 1
We know that, GSK3β is not active until dephosphorylated, and the activation will promote inflammation process undergoes Alzheimer Disease and diabetes (Venna et al., 2015). IRF3 is a target of TLR-4 signaling pathway, acting as regulating and activating the transcription of interferon which results inflammatory responses (Cheng B. C. Y. et al., 2015). Briefly, phosphorylation of these two downstream molecules are both identified to be reversed by Ber or Rhe treatment in either animal or cell inflammatory model (Amasheh et al., 2010; Li et al., 2012; Yuan et al., 2015), which cover the effect shortage of RS constituents at this part.
Effect of the active constituents on molecules in MAPK pathway
MAPK can be divided into several subfamilies including p38, ERK and JNK (Lou et al., 2011). Upstream TAK1 forms a complex consist of TAB1, TAB2, and TRAF6 and then sequentially activate MKK and JNK. The presence of Ras will activate c-raf, MEK and ERK, followed by c-fos regulation once transported into nucleus. Subsequently, the regulated c-fos recruits c-jun to form AP-1 complex (Figure 1).
Accumulative data shown in Table 2 leads to a conclusion that p38, ERK, and JNK attract the most focus of study in MAPK pathway. In-vitro study results reveal that the increased level of p38, ERK or JNK phosphorylation stimulated by cytokines/chemokines like LPS (Lin Y. et al., 2013), IL-1β (Legendre et al., 2007), oxLDL (Chen J. et al., 2014), PMA (Huang Z. et al., 2011), ischemia (Song et al., 2014), OGD (Hou et al., 2012), HG (Li et al., 2009) and CoCl2 (Fernand et al., 2011), or in-vivo elevated level induced by insulin (Lu et al., 2010), collagen (Wang Z. et al., 2014) and cisplatin (Sahu et al., 2015) can be significantly attenuated by either RR, RC, or RS constituent intervention. To further investigate whether p38, ERK and JNK are the only targets, molecules lied on the upstream and downstream are taken into consideration. Turns out, Ber, Bai as well as Rhe treatments all show inhibitory effect on MEK phosphorylation (Shen et al., 2011; Lim et al., 2012; Liu et al., 2015). Nevertheless, for the enhanced phosphorylation of TAK1, Ber is the only reported SHXXT constituent (Zhang et al., 2014). In addition, Ber, Bai, or Rhe also display markedly suppressing effect on endonuclear translocation factors like c-fos and CREB (Hamsa and Kuttan, 2012), c-jun (Hou et al., 2012), ATF-2(Legendre et al., 2007), CHOP (Zha et al., 2010), or AP-1 complex (Domagala et al., 2006).
Table 2
| Target | Animal or cell culture | Model building | Control (P or N) | Drug | Dose | Treat time | Result |
|---|---|---|---|---|---|---|---|
| MEK | Fischer 344 rats | “Age” diet | Young rats | Bai | 10,20 mg/kg/d | 10 d | MEK phosphorylation↓ Kim et al., 2006 |
| VSMC | PDGF | Vehicle | Bai | 5–40 μM | 48 h | p-MEK phosphorylation↓ Hu et al., 2010 | |
| U251/U87 cell | None | Vehicle | Ber | 15 μM | 1–7 d | p-MEK phosphorylation↓ Liu et al., 2015 | |
| Jurkat cell | SDF-1β | Pyscion | Emo | 1 μg/ml | 1 h | p-MEK phosphorylation↓ Shen et al., 2011 | |
| TAK1 | SD rats | Surgery | Interceed | Ber | 0.75,1.5 mg/ml | 14 d | TAK phosphorylation Zhang et al., 2014 |
| JNK | THP-1 cell | oxLDL | Vehicle | Ber | 25 μM | 1 h | JNK phosphorylation↓ Chen J. et al., 2014 |
| RAW264.7 cell, PM | LPS | Vehicle | Ber | 5 μM | 2 h | JNK phosphorylation↓ Jeong et al., 2009 | |
| PM | LPS | Yohimbine | Ber | 2 μM | 90 min | JNK activation↓ Li et al., 2012 | |
| CIA SD rats | Collagen | PBS | Ber | 200 mg/kg | 28 d | JNK expression↓ Wang Z. et al., 2014 | |
| SD rats | Surgery | Interceed | Ber | 0.75,1.5 mg/ml | 14 d | JNK phosphorylation↓ Zhang et al., 2014 | |
| BALB/c mice | LPS | Yohimbine | Ber | 50 mg/kg | 3 d | Spleen JNK phosphorylation↓ Li et al., 2012 | |
| CIA SD rats | Collagen | PBS | Ber | 200 mg/kg | 28 d | p-JNK expression↓ Wang Z. et al., 2014 | |
| NIT-1 cell | LPS | Vehicle | Ber | 2.5,5.0 μM | 24 h | p-JNK expression↓ Hamsa and Kuttan, 2012 | |
| Cardiomyocytes | I/R | Vehicle | Bae | 25 μM | 30 min | JNK1/2 phosphorylation↓ Song et al., 2014 | |
| Microglial cells | OGD | Vehicle | Bai | 40,20 ug/ml | 4 h | p-JNK protein level↓ Hou et al., 2012 | |
| BALB/c mice | Cisplatin | Vehicle | Bae | 50 mg/kg/d | 15 d | p-JNK expression↓ Sahu et al., 2015 | |
| C57BL/6 mice | Surgery | SO | Bae | 100 mg/kg/d | 7 d | p-JNK expression↓ Wang W. et al., 2015 | |
| TRMs rats | None | WT | Bae | 10–40 mg/kg | 14 d | p-JNK expression↓ Mao et al., 2014 | |
| SAP SD rats | ST | SO | Emo | 30 mg/kg | 6 h | p-JNK protein expression↓ Wu et al., 2013 | |
| BMMCs | PMA+ A23187 | SP600125 | Emo | 1–20 μM | 1 h | p-JNK/JNK↓ Lu et al., 2013 | |
| MEC | LPS | Vehicle | Emo | 10,20,40 μg/ml | 1 h | p-JNK expression↓ Yang Z. et al., 2014 | |
| Chondrocytes | IL-1β | DMSO | Rhe | 100 μM | 18 h | JNK activation↓ Legendre et al., 2007 | |
| Raw264.7 cell | LPS | SP600125 | Aem | 5,10,20 μM | 4 h | JNK phosphorylation↓ Hu et al., 2014 | |
| ERK | PM | LPS | Yohimbine | Ber | 2 μM | 90 min | ERK activation↓ Li et al., 2012 |
| HepG2 cell | Palmitate | PD98059 | Ber | 10 μM | 30 min | ERK phosphorylation↓ Lu et al., 2010 | |
| BV2 microglial | IFN-γ | Vehicle | Ber | 10 μM | 30 min | ERK phosphorylation↓ Lu et al., 2010 | |
| RAW264.7 cell, PM | LPS | Vehicle | Ber | 5 μM | 2 h | ERK phosphorylation↓ Jeong et al., 2009 | |
| BALB/c mice | LPS | Yohimbine | Ber | 50 mg/kg | 3 d | Spleen ERK phosphorylation↓ Li et al., 2012 | |
| CIA SD rats | Collagen | PBS | Ber | 200 mg/kg | 28 d | p-ERK expression↓ Wang Z. et al., 2014 | |
| U266 cells | IL-6 | PD98059 | Bae | 50 μM | 1 h | ERK1/2 phosphorylation↓ Liu et al., 2010 | |
| Fischer 344 rats | “Age” diet | Young rats | Bai | 10,20 mg/kg/d | 10 d | p-ERK1/2 expression↓ Kim et al., 2006 | |
| BALB/c mice | Cisplatin | Vehicle | Bae | 50 mg/kg/d | 15 d | p-ERK expression↓ Sahu et al., 2015 | |
| C57BL/6 mice | Surgery | SO | Bae | 100 mg/kg/d | 7 d | p-ERK expression↓ Wang W. et al., 2015 | |
| C57BL/6 mice | Ang II | Vehicle | Bae | 25 mg/kg | 14 d | p-ERK1/2 expression↓ Wang A. W. et al., 2014 | |
| Chondrocytes | IL-1β | Vehicle | Rhe | 10 μM | 18 h | ERK1/2 phosphorylation↓ Domagala et al., 2006 | |
| Chondrocytes | IL-1β | DMSO | Rhe | 100 μM | 18 h | ERK activation↓ Legendre et al., 2007 | |
| BALB/c mice | LPS | Vehicle | Emo | 1–4 mg/kg | 12 h | ERK phosphorylation↓ Li D. et al., 2013 | |
| MEC | LPS | Vehicle | Emo | 10,20,40 μg/ml | 1 h | p- ERK expression↓ Yang Z. et al., 2014 | |
| BMMCs | PMA+ A23187 | U0126 | Emo | 1–20 μM | 1 h | p- ERK / ERK ↓ Lu et al., 2013 | |
| Raw264.7 cell | LPS | PD98059 | Aem | 5,10,20 μM | 12 h | ERK1/2 phosphorylation↓ Hu et al., 2014 | |
| P38 | THP-1 | oxLDL | Vehicle | Ber | 25 μM | 1 h | p38 phosphorylation↓ Chen J. et al., 2014 |
| THP-1 | PMA | Vehicle | Ber | 5–50 μM | 1 h | Block p38 pathway Huang Z. et al., 2011 | |
| RAW264.7 cell, PM | LPS | Vehicle | Ber | 5 μM | 2 h | p38 phosphorylation↓ Jeong et al., 2009 | |
| CIA SD rats | Collagen | PBS | Ber | 200 mg/kg | 28 d | p-p38 expression↓ Wang Z. et al., 2014 | |
| SD rats | LPS | Vehicle | Ber | 100 mg/kg | 24 h | p38 expression↓ Godugu et al., 2014 | |
| BALB/cN mice | Cisplatin | Vehicle | Ber | 3 mg/kg | 2 d | Renal p38 expression↓ Domitrović et al., 2013 | |
| Cardiomyocytes | I/R | Vehicle | Bae | 25 μM | 30 min | p38 phosphorylation↓ Song et al., 2014 | |
| Microglial cells | OGD | Vehicle | Bai | 40, 20 ug/ml | 4 h | p-p38 protein level↓ Hou et al., 2012 | |
| BALB/c mice | Cisplatin | Vehicle | Bae | 50 mg/kg/d | 15 d | p-p38 expression↓ Sahu et al., 2015 | |
| C57BL/6 mice | Surgery | SO | Bae | 100 mg/kg/d | 7 d | p-p38 expression↓ Wang W. et al., 2015 | |
| TRMs rats | None | WT | Bae | 10–40 mg/kg | 14 d | p-p38 expression↓ Mao et al., 2014 | |
| HUVECs | LPS | Vehicle | Rhe | 0,5,10,20 μM | 24 h | p38 phosphorylation↓ Hu et al., 2013 | |
| HUVECs | LPS | ip38 | Rhe | 20 μM | 24 h | p38 phosphorylation↓ Lin Y. et al., 2013 | |
| SAP SD rats | ST | SO | Emo | 30 mg/kg | 6 h | p-p38 protein expression↓ Wu et al., 2013 | |
| HBZY-1 | HG | SB203580 | Emo | 30–60 μM | 24 h | p-p38 protein expression↓ Li et al., 2009 | |
| MEC | LPS | Vehicle | Emo | 10,20,40 μg/ml | 1 h | p-p38 protein expression↓ Yang Z. et al., 2014 | |
| BMMCs | PMA+ A23187 | SB203580 | Emo | 1–20 μM | 1 h | p-p38 /p38↓ Lu et al., 2013 | |
| HUVECs | CoCl2 | Vehicle | Rhe | 50 μM | 6 h | p-ERK acivation↓ Fernand et al., 2011 | |
| Raw264.7 cell | LPS | SB203580 | Aem | 10,20 μM | 4 h | p38 phosphorylation↓ Hu et al., 2014 | |
| IRS-1 | 3T3-L1 cell | TNF-α | Pioglitazone | WE | 30–100 mg/L | 24 h | IRS-1 phosphorylation↓ Yuan et al., 2014 |
| HepG2 cell | Palmitate | SS | Ber | 0.1–10 μM | 30 min | IRS-1 phosphorylation↓ Lou et al., 2011 | |
| MAPK APK2 | HUVECs | LPS | ip38 | Rhe | 20 μM | 24 h | MAPKAPK2 phosphorylation↓ Lin Y. et al., 2013 |
| CREB | B16F-10 cell | LPS | Vehicle | Ber | 2 μg/ml | 2 h | CREB DNA-bound↓ Hamsa and Kuttan, 2012 |
| c-Rel | B16F-10 cell | LPS | Vehicle | Ber | 2 μg/ml | 2 h | c-Rel DNA-bound↓ Hamsa and Kuttan, 2012 |
| c-fos | B16F-10 cell | LPS | Vehicle | Ber | 2 μg/ml | 2 h | c-Fos DNA-bound↓ Hamsa and Kuttan, 2012 |
| c-jun | Microglial cells | OGD | Vehicle | Bai | 40 ug/ml | 4 h | p-c-jun protein level↓ Hou et al., 2012 |
| AP-1 | Chondrocytes | IL-1β | DMSO | Rhe | 100 μM | 18 h | AP-1 DNA binding↓ Legendre et al., 2007 |
| Chondrocytes | IL-1β | Vehicle | Rhe | 10 μM | 18 h | AP-1 DNA binding↓ Domagala et al., 2006 | |
| ICR mice | Placebo | Ribavirin | Bai | 375 mg/kg/d | 7 d | c-jun/AP-1 expression↓ Wan et al., 2014 | |
| ATF2 | B16F-10 cell | LPS | Vehicle | Ber | 2 μg/ml | 2 h | ATF-2 DNA-bound↓ Hamsa and Kuttan, 2012 |
| CHOP | J744A.1 macrophages | Protease inhibitor | Vehicle | Ber | 0–2.0 mg/ml | 2 h | nuclear CHOP expression↓ Zha et al., 2010 |
Effect of the active constituents on molecules in MAPK pathway.
Effect of the active constituents on molecules in AMPK pathway
AMPK serves as a cellular energy sensor to modulate lipid metabolism, and it can be activated by upstream kinases like LKB1 and CaMKK (Yang Y. et al., 2014; Li N. S. et al., 2016). There is a mechanism underlined the relationship, thus once AMPK activated, the nuclear translocation of Nrf2 is promoted, which contribute to the diminution of pro-inflammatory cytokines production. Nrf2 can also drive downstream HO-1 expression in with the considerable beneficial protect effect against cell injury from inflammatory response like diabetes mellitus (Agca et al., 2014). PPAR-γ is identified as a primary regulator of gene expression for inflammation and a pharmacological receptor of insulin-sensitizing drugs (Choi et al., 2014).
As summed up in Table 3, the current study status demonstrate that Ber from RC exert the most comprehensive effect compared with other constituents form RR and RS, pathway molecules from upstream to downstream, including CaMKII, LKB1, PPAR-γ (Legendre et al., 2007), AMPK (Lu et al., 2010), Nrf2 and HO-1(Mo et al., 2014) are all verified to be the effective targets of Ber. In addition, Emo (Yang Z. et al., 2014; Wang T. et al., 2015), Bai and Bae (Lim et al., 2012; Ma et al., 2012; Feng et al., 2013; Tsai et al., 2014) as well affect some of those molecules. Given this investigation situation, it seems that constituents from either RR, RS, or RC can block AMPK pathway by cross-talk regulating pathway molecules.
Table 3
| Target | Animal or cell culture | Model building | Control (P or N) | Drug | Dose | Treat time | Result |
|---|---|---|---|---|---|---|---|
| CaMK-II | BV2 microglial cell | LPS or IFN-γ | Vehicle | Ber | 10 μM | 2 h | CaMKII (Thr286) phosphorylation↑ Lu et al., 2010 |
| LKB1 | BV2 microglial cell | LPS or IFN-γ | Vehicle | Ber | 10 μM | 2 h | LKB1 phosphorylation↑ Lu et al., 2010 |
| AMPK | BV2 microglial cell | LPS or IFN-γ | Vehicle | Ber | 10 μM | 2 h | AMPK (Thr172) phosphorylation↑ Lu et al., 2010 |
| Hela cell | None | Compound C | Bai | 1 μM | 3 h | AMPK phosphorylation↑ Ma et al., 2012 | |
| HO-1 | PM | LPS | Vector | Ber | 10 μM | 24 h | HO-1 mRNA expression↑ Mo et al., 2014 |
| SD rats | LPS | Vehicle | Bae | 20 mg/kg | 7 h | HO-1 protein expression↑ Tsai et al., 2014 | |
| BALB/c mice | Dox | Vehicle | Bae | 25 mg/kg | 24 d | HO-1 protein expression↑ Sahu et al., 2016 | |
| C57BL/6 mice | OVA | Dex | Emo | 10 mg/kg | 3 d | HO-1 mRNA expression↑ Wang T. et al., 2015 | |
| Nrf2 | PM | LPS | Vector | Ber | 10 μM | 24 h | Nrf2 translocation↑ Mo et al., 2014 |
| SD rats | LPS | Vehicle | Bae | 20 mg/kg | 7 h | Nrf2 nuclear translocation↑ Tsai et al., 2014 | |
| BALB/c mice | Dox | Vehicle | Bae | 25 mg/kg | 24 d | Nrf2 protein expression↑ Sahu et al., 2016 | |
| PPAR -γ | 3T3-L1 cell | TNF-a | Pioglitazone | WE | 30 mg/L | 24 h | PPAR-γ mRNA expression↑Yuan et al., 2014 |
| SD rats | LPS | SR-202 | Bai | 25 mg/kg | 3 d | intestinal PPAR-γ level↓ Feng et al., 2013 | |
| Fischer 344 rats | Aged | TZD;GW9662 | Bai | 10 mg/kg | 3 d | PPAR-γ protein expression↓ Lim et al., 2012 | |
| HBZY-1 | HG | SB203580 | Emo | 30–60 μM | 24 h | PPAR-γ protein expression↑ Li et al., 2009 | |
| MEC | LPS | Rosiglitazone | Emo | 10 μg/ml | 1 h | PPAR-γ activation↑ Yang Z. et al., 2014 |
Effect of the active constituents on molecules in AMPK pathway.
Effect of the active constituents on molecules in JAK/STAT pathway
The activation of JAK catalyze Tyr phosphorylation so that STAT can be combined with receptor protein, then transported into nucleus to regulate transcription. It has been reported that STAT1 and STAT5, the downstream molecules of IFN-γ, are also likely to be implicated in inflammation (Chmielewski et al., 2015; Li X. et al., 2015). Akt functions as emerging crucial regulator of multiple cellular processes, such as apoptosis, differentiation, survival, etc., (Piao et al., 2015). Moreover, recent studies indicate PI3K/Akt can lead to an elevated expression level of COX-2 and iNOs in inflammatory macrophages (Liou et al., 2014). Further activated mTOR can regulate cell growth, differentiation as well as transcription and it tends to perform abnormally in diabetes models (Hua and Hu, 2015).
For JAK/STAT pathway, constituents from RC, RS and RR are all showing inhibitory activity, typical targets include JAK (Kim et al., 2011; Qi et al., 2013; Subramaniam et al., 2013), STAT (Cui et al., 2009; Liu et al., 2010; Kim et al., 2015) and Akt (Lou et al., 2011; Hu et al., 2014; Wang A. W. et al., 2014), all of which are proved to be influenced by Ber, Bae, Bae, Emo or Aem in either in-vivo or in-vitro models (Table 4). On the other hand, results in the study concerning about downstream molecular present main RR constituent's effect-weakness on targets like Tyk2. Apparently, RS and RC cover the shortfalls of RR's poor activity in downstream pathway, which partly supports the synergistic theory of drug combination aiming at promoting curative effect.
Table 4
| Target | Animal or cell culture | Model building | Control (P or N) | Drug | Dose | Treat time | Result |
|---|---|---|---|---|---|---|---|
| JAK1 | Raw264.7 cell | LPS | Vehicle | Bae | 20–80 μM | 2 h | JAK1 phosphorylation↓ Qi et al., 2013 |
| NOP2 cells | IL-6 | None | Bae | 50 μM | 1 h | JAK1 phosphorylation↓ Liu et al., 2010 | |
| JAK2 | Raw264.7 cell | LPS | Vehicle | Bae | 20–80 μM | 2 h | JAK2 phosphorylation↓ Qi et al., 2013 |
| HepG2 | None | Vehicle | Emo | 50 μM | 12 h | JAK2 phosphorylation↓ Subramaniam et al., 2013 | |
| JAK3 | Nb2 cell | IL-2 | Vehicle | Ber | 1–10 μM | 1 h | JAK3 phosphorylation↓ Kim et al., 2011 |
| STAT1 | NOD rats CD4+ T cell | None | Vehicle | Ber | 200 mg/kg 5, 10 μM | 2 w | STAT1 phosphorylation↓ Cui et al., 2009 |
| BALB/c mice | LPS | Yohimbine | Ber | 50 mg/kg | 3 d | Spleen STAT1 phosphorylation↓ Li et al., 2012 | |
| U266 cells | IL-6 | None | Bae | 12.5–50 μM | 1 h | STAT1 phosphorylation↓ Liu et al., 2010 | |
| STAT3 | NOD rats CD4+ T cell | None | Vehicle | Ber | 200 mg/kg 5, 10 μM | 2 w | STAT3 phosphorylation↓ Cui et al., 2009 |
| U266cells | IL-6 | None | Bae | 50,100 μM | 1 h | STAT3 phosphorylation↓ Liu et al., 2010 | |
| GSCs | None | Vehicle | Emo | 5 μM | 24 h | p-STAT3 phosphorylation↓ Kim et al., 2015 | |
| RPMI8266 | IL-6 | Dox | Emo | 50 μmol/L | 12 h | STAT3 phosphorylation↓ Muto et al., 2007 | |
| STAT5 | Nb2 cell | IL-2 | Vehicle | Ber | 1,3,7,10 μM | 1 h | STAT5 phosphorylation↓ Kim et al., 2011 |
| STAT4 | NOD rats CD4+ T cell | None | Vehicle | Ber | 200 mg/kg 5, 10μM | 2 w | STAT4 phosphorylation↓ Cui et al., 2009 |
| Arthritis mice | kaolin | Prednisolone | Ber | 10–50 mg/kg | 6 d | synovial expression STAT4↓ Kim et al., 2011 | |
| STAT6 | Arthritis mice | kaolin | Prednisolone | Ber | 10–50 mg/kg | 6 d | synovial expression STAT6↓ Kim et al., 2011 |
| Tyk2 | BALB/c mice | LPS | Yohimbine | Ber | 50 mg/kg | 3 d | Spleen Tyk2 phosphorylation↓ Li et al., 2012 |
| NOP2 cells | IL-6 | None | Bae | 25 μM | 1 h | Tyk2 phosphorylation↓ Liu et al., 2010 | |
| Src-P | HT-29/B6 cell | TNF-α | BAY11-7082, Genistein | Ber | 50 μM | 26 h | Src-P phosphorylation↓ Amasheh et al., 2010 |
| Akt | HT-29/B6 cell | TNF-α | BAY11-7082, Genistein | Ber | 50 μM | 26 h | Akt phosphorylation↓ Amasheh et al., 2010 |
| HepG2 cell | Paimitate | PD98059,SS, BAY11-7082 | Ber | 0.1–10 μM | 30 min | Akt phosphorylation↓ Lou et al., 2011 | |
| NOP2 cells | IGF-1 | None | Bae | 10 μM | 30 min | Akt phosphorylation↓ Liu et al., 2010 | |
| HUVECs | CoCl2 | Vehicle | Rhe | 50 μM | 6 h | p-Akt activation↓ Fernand et al., 2011 | |
| Raw264.7 cell | LPS | LY294002 | Aem | 10,20 μM | 4 h | Akt phosphorylation↓ Hu et al., 2014 | |
| C57BL/6 mice | Ang II | Vehicle | Bae | 25 mg/kg | 14 d | p-Akt expression↓ Wang A. W. et al., 2014 | |
| SD rats | Adjuvant | Ibuprofen | Rhe | 50 mg/kg | 21 d | p-Akt/Akt level↓ Cong et al., 2012 | |
| PI3K | HUVECs | CoCl2 | Vehicle | Rhe | 50 μM | 6 h | PI3K activation↓ Fernand et al., 2011 |
| HT-29/B6 cell | TNF-α | BAY11-7082, Genistein | Ber | 50 μM | 26 h | PI3K activation↓ Amasheh et al., 2010 | |
| mTOR | CRC cells | None | Vehicle | Ber | 15–60 μM | 24 h | mTOR phosphorylation↓ Li W. et al., 2015 |
| C57BL/6 mice | Ang II | Vehicle | Bae | 25 mg/kg | 14 d | p-mTOR expression↓ Wang A. W. et al., 2014 |
Effect of the active constituents on molecules in JAK/STAT pathway.
Pharmacokinetic level
Traditional Chinese medicines are frequently orally administrated and the absorption of active constituents are confirmed to be influenced by efflux pumps and intestinal transporters (ITs) (Park et al., 2012; Zumdick et al., 2012). In general, ITs widely distribute in intestinal membrane and can be divided into two categories. One accounts for external substance's intracellular transport, such as OCTs and SGLT1 (Moran et al., 2014; Couroussé and Gautron, 2015). The other one, like P-gp, MRP and BCRP, is functioning as efflux pump to make drug or toxin back to lumen (Yamagata et al., 2007; Juan et al., 2010; Zeng et al., 2015). There are many isolate reports showing SHXXT's main constituents have an unexpectedly low concentration in plasma with oral administration, making it challenged to explain its positive effects in inflammatory therapies.
In-vitro research on the efflux pump and ITs normally use Caco-2 cell or MDCK cell for they both have similar structure of differential intestinal epithelial cell with apical side and basolateral side (Chen et al., 2013; Schexnayder and Stratford, 2015; Obringer et al., 2016). Currently, it is verified that Bai from RS is the substrate of both MRP2 and BCRP (Kalapos-Kovács et al., 2015), and another RS constituent Bae is also pumped out by MRP (Zhang et al., 2007). Rhe, Emo and Aem from RR are substrate of BCRP, MRP and P-gp respectively (Wang J. et al., 2011; Liu et al., 2012; Ye et al., 2013), those ITs at least partly reduce the bioavailability of SHXXT constituents by diminishing their intracellular transport. Similarly, the absorption of Ber, Pal, Cop and Jat form RC is reported to be promoted by OCTs while inhibited by P-gp (Chen et al., 2008; Zhang et al., 2011; Sun et al., 2014). In addition to OCTs, SGLT1 also contributes to uptake (Zhang et al., 2012). Thus, any constituents in SHXXT which suppress the MRP2, BCRP, and P-gp activation or, on the other hand, up-regulate OCTs and SGLT1 activation may be considered to exert mutual reinforcement property by promoting bioavailability.
In return, constituents in SHXXT show retroaction on those efflux pump or ITs. Depicted in Figure 2, Firstly, P-gp, which reduces the absorption of Ber, Pal, Cop, Jar, and Aem, is proved to be inhibited by Bae treatment (Cho et al., 2011). Secondly, Rhe can suppress MRP's activation which may lead the increasing uptake of Aem, Bai, and Bae (Shia et al., 2013). Last but not least, Ber can as well decrease BCRP activation, which is capable of promoting the intracellular concentrations of Bai, Emo, and Rhe (Tan et al., 2013).
Figure 2
Discussion
TCM normally used as prescription so as to recruit active contents from different herbals. Modern mutual reinforcement theory believes pharmacodynamics effect after herbal combination is not simply equal to the summing up of each herbal, but to a certain extent, should be more than that. Under most circumstances, a prescription can bring out more advantages in regards of safety and efficacy aspects than a single herb does (Song et al., 2013). Apart from expanding effect on one specific part, the combination of several herbals can also give rise to respective effect on different parts, which in other words, supplement other herbals' disadvantages or helping other herbals to perform their property in a better way.
Inflammatory signal transduction is quite complex network, and suppression on any intersection can partly contribute to the prevention of inflammation process. SHXXT have been high-lighted based on their widely appearance in inflammation-associated treatment for centuries. Clinically, SHXXT is a preferred drug for “coexistence of cold and heat” (Zhang et al., 2013c). With the constantly deepen researches, it is widely used in the treatment for anti-pathogens, anti-inflammation, gastric mucosal protection, hemostasis, anti-diabetes and so on (Li and Guo, 2010). As depicted in Figure 1, target with three colored “cross” is to be influenced by constituents form all three compositions (TLR-4, ERK, JNK, p38, Akt, etc.), which lead a fold increase of the final effect. On the other hand, target with less than three “cross” suggest at least one composition was not valid at this part. For example,
Ber from RC is reported to affect TAK1 and interaction between LPS and TLR-4, while RR and main RS constituents barely mentioned.
Bae from RS and Ber from RC inhibit Tyk2 phosphorylation, while no main RR constituent has similar effect.
Rhe from RR and Ber from RC reduce IRF3 phosphorylation level, while the effect of main constituent of RS isn't that clear, etc.
The connotative meaning of synergism at pharmacodynamics level is to enhance the effect on a certain target, as well as to expand target-affecting scope, just like what SHXXT constituents have performed. As for the pharmacokinetic level, shown in Figure 2, Ber form RS, Rhe form RR and Bae form RC is capable of improving the uptake or reducing the efflux of constituents from the other composition, which ultimately reaches the goal of synergistically influence inflammatory processes and eventually make this formula's anti-inflammatory action stronger and wider.
Nowadays, elevated attention has been paid to dose-effect relationship. There is a complicated process which can be expressed as “theory-methodology-formulation-medication-dosage” in TCM clinical therapeutics, showing how important for a formula prescription to have a specific herbal dosage (Zha et al., 2015). Basically for western medicine, these is a positive correlation between dose and toxicity. However, TCM at a large dosage tends to have good therapy efficacy with slight side effect (Wang et al., 1983). The dosage of Chinese herbals in clinical cases or experimental studies is usually at a relatively higher level than that documented in ancient TCM records (Peng, 2003; Sun, 2007). RR as an example, the dosage to treat cholestasis in clinical is more than four times the regular dose recommended in the Chinese pharmacopeia (Zhang et al., 2016). For now, the widespread explanation is that drug should be administrated to the patient with the correct disorder indications, otherwise it will produce dosage variety and individual detrimental effect (Zhao et al., 2015). As displayed in Table 5, dosage of constituents from SHXXT has a big range with no obvious rule to follow, it is possibly due to different tested animals or cells may have different drug sensitivities, but still need further clarification.
Table 5
| Constituent | Model | Dose lower limit | Dose upper limit |
|---|---|---|---|
| Ber | Cells | 0.1 μM Lou et al., 2011 | 90μM Jiang et al., 2011 |
| Mice | 3 mg/kg Domitrović et al., 2013 | 50mg/kg Li et al., 2011 | |
| Rats | 50 mg/kg Li et al., 2012 | 200 mg/kg Muto et al., 2007 | |
| Bai | Cells | 1 μM Ma et al., 2012 | 100 μM Dong et al., 2015 |
| Mice | 100 mg/kg Feng et al., 2014 | 375 mg/kg Wan et al., 2014 | |
| Rats | 10 mg/kg Lim et al., 2012 | 25 mg/kg Feng et al., 2013 | |
| Bae | Cells | 10 μM Fan et al., 2013 | 80 μM Qi et al., 2013 |
| Mice | 25 mg/kg Sahu et al., 2016 | 100 mg/kg Wang W. et al., 2015 | |
| Rats | 10 mg/kg Lee et al., 2011 | 40 mg/kg Mao et al., 2014 | |
| Emo | Cells | 1 μM Lu et al., 2013 | 182.5 μM Meng et al., 2010 |
| Mice | 1 mg/kg Li D. et al., 2013 | 100 mg/kg Xiao et al., 2014 | |
| Rats | 10 mg/kg Li A. et al., 2013 | 30 mg/kg Wu et al., 2013 | |
| Alo | Cells | 5 μM Hu et al., 2014 | 20 μM Hu et al., 2014 |
| Mice | Not reported | Not reported | |
| Rats | Not reported | Not reported | |
| Rhe | Cells | 10 μM Domagala et al., 2006 | 200 μM Fernand et al., 2011 |
| Mice | 20 mg/kg Yu et al., 2015 | 80 mg/kg Yu et al., 2015 | |
| Rats | 100 mg/kg Ji et al., 2005 | 400 mg/kg Hou et al., 2012 |
The dose range of SHXXT constituent used in-vivo and in-vitro.
Conclusions
It is easy to find out not all the SHXXT constituents receive deep-enough investigation on their anti-inflammatory effect, the interaction between main SHXXT constituents and targets outside the nucleus get most focus. Besides, any drug elevating the absorption of Rhe, Ber, and Bae can be employed to promote oral bioavailability of SHXXT. Even though evidence shows P-gp, BCRP, and MRP really are inhibited while reports rarely cover the effect of SHXXT constituents on OCTs or SGLT. Hence, further investigation at these two levels is required to fully explain the mutual reinforcement relationship of RR, RC, and RS.
Statements
Author contributions
JW: Prepare the manuscript; YH and LX: Search for the literatures; SL and YY: Draw the figures; XC and YZ: Do the summing work and accomplish the tables; WH: Polish language; XM and PW: Corresponding authors.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81073118, 81274111 and 81473419).
Conflict 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.
- ADM
adriamycin amycin
- Akt
Protein kinase B; extracellular signal-regulated kinase
- AMPK
5′ AMP-activated protein kinase
- Ang II
angiotensin II
- AP-1
activator protein 1
- ATF
Activating transcription factor
- BCRP
breast cancer resistance protein
- CaMK
Calcium/calmodulin- dependent kinase
- CHOP
C/EBP homologous protein 10
- CK
ginsenoside metabolite compound K
- CMC-Na
caboxy methyl cellulose
- CREB
cAMP response element-binding protein
- Dex
Dexamethasone
- Dox
Doxorubicin
- DSS
dextran sulfate sodium
- ERK
extracellular signal-regulated kinase
- GSK3β
Glycogen synthase kinase 3 beta
- HCM
hypercholesterolemic
- HG
high glucose
- HO-1
HMOX1heme oxygenase (decycling) 1
- I/R
ischemia/reperfusion
- IKK
IκBα kinase
- IκBα
inhibitor of nuclear factor κBα
- iNOS
inducible nitric oxide synthase
- IRAK
Interleukin-1 receptor-associated kinase
- IRF3
Interferon regulatory factor 3
- IRS-1
Insulin receptor substrate 1
- JAK
junas kinase
- JNK
c-Jun NH2-terminal kinase
- LKB1
liver kinase B1
- LPS
lipopolysaccharide
- MAPK
mitogen-activated protein kinase
- MAPKAPK2
MAP kinase-activated protein kinase 2
- MEK
Mitogen-activated protein kinase kinase
- MRP
multidrug resistance associated protein
- mTOR
mammalian target of rapamycin 2
- MyD88
Myeloid differentiation primary response gene 88
- NIK
NF-κB inducing kinase
- Nrf2
Nuclear factor (erythroid-derived 2)-like 2
- OCT
organic cation transporter
- OGD
oxygen–glucose deprivation
- PDTC
Pyrrolidine dithiocarbamate
- P-gp
P-glycoprotein
- PI3K
phosphoinositide 3-kinase
- PMA
Phorbol-12-myristate-13-acetate
- Poly(I:C)
Polyinosinic:polycytidylic acid
- PPAR-γ
peroxisome proliferator-activated receptor γ
- Raf
RAF proto-oncogene serine/threonine-protein kinase
- SAP
severe acute pancreatitis
- SGLT1
Na+-dependent glucose transporter
- SO
sham operation
- SS
sodium salicylate
- ST
sodium taurocholate
- STAT
signal transducer and activator of transcription
- TAK1
transforming growth factor-b-activated kinase
- TLR-4
toll-like receptor
- TNBS, 2, 4
6-trinitrobenzene sulfonic acid
- TNFR1
tumor necrosis factor receptor 1
- TRADD
Tumor necrosis factor receptor type 1-associated death domain protein
- TRAF
TNF receptor associated factors
- TRM
epilepsy-like tremor
- Tyk2
Non-receptor tyrosine-protein kinase 2
- VSMC
vascular smooth muscle cell
- WKY
Wistar-Kyoto
- WT
wild type.
Abbreviations
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Summary
Keywords
San-Huang-Xie-Xin-Tang, constituents, anti-inflammatory, NF-κB, MAPK, JAK/STAT, intestinal transporter
Citation
Wu J, Hu Y, Xiang L, Li S, Yuan Y, Chen X, Zhang Y, Huang W, Meng X and Wang P (2016) San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review. Front. Pharmacol. 7:448. doi: 10.3389/fphar.2016.00448
Received
07 September 2016
Accepted
09 November 2016
Published
28 November 2016
Volume
7 - 2016
Edited by
Pietro Minuz, University of Verona, Italy
Reviewed by
Satish Ramalingam, Chettinad Academy of Research and Education, India; Ennio Lubrano, University of Molise, Italy
Updates
Copyright
© 2016 Wu, Hu, Xiang, Li, Yuan, Chen, Zhang, Huang, Meng and Wang.
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) or licensor 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: Xianli Meng xlm9999@hotmail.com
This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology
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