Front. Pharmacol. Frontiers in Pharmacology Front. Pharmacol. 1663-9812 Frontiers Media S.A. 10.3389/fphar.2016.00448 Pharmacology Review San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review Wu Jiasi 1 Hu Yingfan 1 Xiang Li 1 Li Sheng 2 Yuan Yi 1 2 Chen Xiaomei 3 Zhang Yan 1 Huang Wenge 1 Meng Xianli 1 * Wang Ping 1 * 1Chengdu University of Traditional Chinese Medicine Chengdu, China 2Chengdu Institute of Biology, Chinese Academy of Sciences Chengdu, China 3Hainan Medical University Hainan, China

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

*Correspondence: Xianli Meng xlm9999@hotmail.com

Ping Wang viviansector@aliyun.com

This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

 28 11 2016 2016 7 448 07 09 2016 09 11 2016 Copyright © 2016 Wu, Hu, Xiang, Li, Yuan, Chen, Zhang, Huang, Meng and Wang. 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.

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.

 San-Huang-Xie-Xin-Tang constituents anti-inflammatory NF-κB MAPK JAK/STAT intestinal transporter 81073118 81274111 National Natural Science Foundation of China10.13039/501100001809 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.

Effect of the active constituents on molecules in NF-κB pathway.

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

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.

The effect of SHXXT alkaloids on inflammatory pathway molecules. 1. The green ellipse represents kinase. 2. The purple ellipse represents transcription factor. 3. The red ellipse represents GTpase. 4. The brown ellipse represents phosphatase. 5. The solid arrow represents direct stimulatory modification. 6. The dotted arrow represents translocation. 7. The dotted “T” represents direct inhibitory modification. 8. The red, yellow and blue cross represents the target influenced by RC, RS, and RR constituents, respectively.

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).

Effect of the active constituents on molecules in MAPK pathway.

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 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.

Effect of the active constituents on molecules in AMPK pathway.

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 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.

Effect of the active constituents on molecules in JAK/STAT pathway.

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
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).

The effect of SHXXT constituents on ITs. Ber, berberine; Cop, coptisine; Pal, palmatine; Jat, jatrorrhizine; Bai, baicalin; Bae, baicalein; Emo, emodin; Aem, aloe-emodin; Rhe, rhein.

 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.

The dose range of SHXXT constituent used in-vivo and in-vitro.

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
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.

 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.

Conflict of interest statement

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.

This work was supported by the National Natural Science Foundation of China (Nos. 81073118, 81274111 and 81473419).

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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.