Cellular stress response mechanisms of Rhizoma coptidis: a systematic review
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Rhizoma coptidis has been used in China for thousands of years with the functions of heating dampness and purging fire detoxification. But the underlying molecular mechanisms of Rhizoma coptidis are still far from being fully elucidated. Alkaloids, especially berberine, coptisine and palmatine, are responsible for multiple pharmacological effects of Rhizoma coptidis. In this review, we studied on the effects and molecular mechanisms of Rhizoma coptidis on NF-κB/MAPK/PI3K–Akt/AMPK/ERS and oxidative stress pathways. Then we summarized the mechanisms of these alkaloid components of Rhizoma coptidis on cardiovascular and cerebrovascular diseases, diabetes and diabetic complications. Evidence presented in this review implicated that Rhizoma coptidis exerted beneficial effects on various diseases by regulation of NF-κB/MAPK/PI3K–Akt/AMPK/ERS and oxidative stress pathways, which support the clinical application of Rhizoma coptidis and offer references for future researches.
KeywordsRhizoma coptidis Alkaloids Pathways Diseases
myeloid differentiation primary response protein
inhibitor of nuclear factor kappa-B kinase
NF-κB inhibitor alpha
toll like receptor 4
lipopolysaccharide binding protein
interleukin 1 receptor associated kinase
intercellular adhesion molecule-1
vascular cell adhesion molecule-1
urokinase plasminogen activator
receptor activator for nuclear factor-κ B ligand
mammalian target of rapamycin
mitogen-activated protein kinase kinase 1/2
apoptosis signal-regulating kinase 1
early growth response protein-1
TGFβ-activated kinase 1
monocyte chemoattractant protein-1
cAMP-response element binding protein
brain-derived neurotrophic factor
transforming growth factor beta 1
intercellular cell adhesion molecule-1
activating transcription factor-2
CREB-regulated transcription co-activator 2
gastric inhibitory polypeptide
liver kinase B1
eukaryotic translation elongation factor 2
sterol regulatory element-binding transcription factor-1c
peroxisome proliferator-activated receptor γ
activating protein 2
fatty acid synthase
insulin receptor substrate
insulin-like growth factor-1
hypoxia inducible factor-1α
reactive oxygen species
phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase
focal adhesion kinase
eukaryotic initiation factor 2α
C/EBP homologous protein
CCAAT/enhancer binding protein alpha
glucose-regulated protein 78
AMP-dependent transcription factor 4
nuclear factor-erythroid 2 related factor 2
NAD(P)H quinone dehydrogenase 1
nicotinamide adenine dinucleotide phosphate-oxidase
When the body is under external pressure, cells produce stress responses, defense reactions to resist pressure damage, including NF-κB, MAPK, Akt, AMPK, ERS and oxidative stress signaling pathways [11, 12, 13, 14]. NF-κB pathways are associated with immunity, inflammation and cell survival. MAPK pathways refer to various cellular functions, including cell proliferation, differentiation and migration. Akt pathways have effects on apoptosis, protein synthesis, metabolism and cell cycle. AMPK pathways are energy regulation pathways. AMPK pathways inhibit biosynthetic pathways with energy consumption, such as protein, fatty acid and glycogen synthesis. ERS pathways are triggered by the unbalance of ER environment, including hypoxia, disturbance of Ca2+ homeostasis and glucose starvation. Oxidative stress pathways are caused by the imbalance of oxidation and antioxidation in body. Oxidative stress pathways regulate redox balance by Nrf2 and other ways.
The theory of traditional Chinese medicine is more from experience and inference, still lack of sufficient scientific basis, and cannot provide a modern scientific basis for overseas popularization and clinical use. Traditional Chinese medicine has multi-components, multi targets. Their complex components have different pharmacokinetic characteristics and complex interactions. The mechanism of Chinese medicine is complex and systematic. As a traditional Chinese medicine, Rhizoma coptidis has excellent therapeutic effects on various diseases, but the underlying systematic molecular mechanisms are still far from being fully elucidated. In this review, we sorted out the relationship of Rhizoma coptidis among components, diseases and NF-κB/MAPK/PI3K/Akt/AMPK/ERS/oxidative stress pathways, systematically studying on how Rhizoma coptidis exerts beneficial effects to various diseases, which supported the clinical application of Rhizoma coptidis and provided references for the future researches.
The effects of Rhizoma coptidis on NF-κB/MAPK/PI3K–Akt/AMPK/ERS and oxidative stress pathways
Molecular mechanisms of Rhizoma coptidis inhibiting NF-κB pathways
NF-κB pathways, expressing in all nucleated cells, participate in various diseases by regulation of cellular immunity, proliferation, differentiation and apoptosis, etc. . NF-κB pathways can be mainly activated by two pathways. The canonical pathways are triggered by TNF-α, IL-1β or viral infections. The activation of IKK and the degradation of IκB-α play key roles in the regulation of canonical pathways. TNF-α, IL-1β or LPS activate IKK and lead the degradation of IκB-α and p50/p65 NF-κB dimer entering the nucleus for DNA transcription . In atypical pathways, the activation of NF-κB is shown to be independent from the phosphorylation of IKK and the degradation of IκB-α .
Molecular mechanisms of Rhizoma coptidis inhibiting MAPK pathways
MAPK (Mitogen activated protein kinases) pathways play important roles in inflammatory response, cell proliferation, differentiation and apoptosis, etc., mainly through three pathways, ERK (extracellular regulated protein kinases), JNK (c-Jun N-terminal kinase) and p38 MAPK [20, 21]. The activations of MAPK pathways are very conservative. Each MAPK is activated by a specific MAPK kinase. MAPK are the pivots of each pathways. MAPKK kinase (MAP3K or MKKK) and MAPK kinase (MAP2K or MKK) of three pathways have different substrates and intermolecular interconnections, as well as scaffolding proteins [22, 23]. The ERK pathway is activated by mitogen, such as growth factor, platelet-derived growth factor and insulin, and plays important roles in regulating cell growth, survival and differentiation. JNK and p38MAPK pathways weakly activated by mitogen, but can be strongly activated by stress signals, including TNF-α, IL-1β and ultraviolet irradiation, causing inflammatory responses and participating in cell apoptosis . Three pathways can be adjusted specifically. For example, berberine can effectively inhibit the activation of ERK in LPS or IFN-γ induced BV-2 microglia, but it has no impact on the phosphorylation of p38 and JNK .
Molecular mechanisms of Rhizoma coptidis regulating AMPK pathways
AMPK pathways exist in most of eukaryotic cells and metabolism related tissues and organs . AMP-activated protein kinase (AMPK) plays important roles in multiple metabolic pathways, including regulating movement, nutrition and hormonal signals at cellular level, so as to control energy consumption and substrate utilization of whole body and maintain the balance of energy metabolism [32, 33]. AMPK promotes glucose uptake and transport by regulating the expression of GLUT4, including promoting GLUT4 translocation and unlocking GLUT4 gene expression [34, 35]. AS160 is a downstream target of AMPK. Phosphorylation of AS160 promotes the translocation of GLUT4 and glucose uptake . PFK (6-phosphofructo-2-kinase) is a speed limiting enzyme of glycolysis. AMPK regulates the phosphorylation of PFK2 . AMPK also can inhibit the activation of FAS, ACC, etc., to inhibit gluconeogenesis and glycogen formation [38, 39]. AMPK participates in the regulation of lipid metabolism, which is related to SREBP1C . AMPK plays a major role in the development of insulin resistance . AMPK can regulate the secretion of insulin and homeostasis of pancreatic β cells . AMPK also plays significant roles in various inflammatory diseases with the function of anti-inflammation .
Molecular mechanisms of Rhizoma coptidis regulating PI3K–Akt pathways
The full activations of the PI3K–Akt pathways are complex processes. Akt (protein kinase B) can be phosphorylated by PDK1 and PDK2, or directly phosphorylated by phosphatidylinositol 3′-kinase (PI3K) in residues Thr-308 and Ser-473 . Once the Akt is activated, it can regulate the expressions of downstream factors. Akt can inhibit GSK-3β activity by increasing its phosphorylation and there has shown that GSK-3β plays an important role in cellular survival and metabolism . Akt inhibits cell apoptosis by regulating the expressions of BAD (Bcl-2-associated death promoter), Bcl-2, procaspase-9, and caspase-9 [50, 51]. Akt regulates cell growth by controlling the expression of mTORC1 (mTOR complex 1) that controls the initiation of translation and synthesis of ribosome . Akt participates in the process of nutrient absorption and metabolism, such as by regulation of GLUT4 and HIF-1α to mediate insulin stimulation and glucose absorption. Akt is also involved in angiogenesis and cell migration [53, 54, 55, 56].
Molecular mechanisms of Rhizoma coptidis regulating ERS pathways
Molecular mechanisms of Rhizoma coptidis regulating oxidative stress pathways
Low levels of ROS/RNS are necessary for cell proliferation and differentiation. Excessive levels of ROS/RNS directly destruct of cell membrane, DNA and proteins, resulting in cell function damage, proliferation inhibition and apoptosis . ROS are radical species, including O2−, H2O, OH•, peroxylradicals, etc. RNS are radical species, including NO and ONOO−, etc. [71, 72]. Under normal condition, antioxidant proteins, such as glutathione (GSH), ROS metabolic enzymes, including glutathione peroxidase, catalase and superoxide dismutase (SOD), are in balance. When this redox homeostasis is unbalanced, oxidative stress will be activated and participate in the occurrence and development of various diseases .
Oxidative stress interacts with other pathways . NF-κB, MAPKs, AP-1, HIF, PI3K/Akt are redox-sensitive transcription factors. ROS activates NF-κB pathways through activation of IκB kinase, regulation of the chromatin remodeling, coactivator recruitment and DNA binding ability of NF-κB [72, 73]. Berberine down regulates ROS-related ASK1, p38/JNK, and NF-κB pathways in osteoarthritis synovial fibroblasts . Berberine also prevents ROS dependent and JNK driven apoptosis in bone marrow mesenchymal stem cells .
Nrf2 is an important transcription factor that regulates the balance of redox in cells. Under normal physiological conditions, Nrf2 binds to Keap1 in cytoplasm. After activation, Nrf2 separates from Keap1 and binding to ARE site to activate the downstream promoters and proteins, including NQO1, HO-1, GST, thioredoxin [75, 76]. In SH-SY5Y cells, Nrf2 siRNA abolished BBR-induced HO-1, neurite outgrowth and ROS decrease, which indicates that berberine is a Nrf2 activator against glucose neurotoxicityas . Also, berberine, a PI3K activator, can regulate the oxidative stress by regulating the PI3K–Akt–Nrf2 pathway. PI3K–Akt and MAPKs pathways are important for BBR to induce Nrf2 translocation and HO-1 expression [21, 49, 64]. Coptisine also can activate Nrf2 and its upstream targets, including Akt and JNK, thus to regulate expressions of NQO1, ROS, GSH SOD and GPx in HepG2 cells .
Therefore, Rhizoma coptidis can regulate oxidative stress partly as Additional file 6: Table S6. Rhizoma coptidis can regulate oxidative stress by following: (1) regulation of ROS/RNS radical species, including H2O2, ONOO−; (2) regulation the productions of antioxidant proteins, including ROS metabolic enzymes; (3) regulation the expressions of redox-sensitive transcription factors, including NF-κB, MAPKs, AP-1, HIF, PI3K/Akt; (4) stimulating the translocation activity and nuclear accumulation of Nrf2, as well as promoting the Nrf2-DNA binding activity.
NF-κB/MAPK/AMPK/PI3K–Akt/ERS/oxidative stress pathways in disease states
Rhizoma coptidis has significant effects on the main pathogenic factors of cardiovascular diseases, including anti-atherosclerosis, lipid lowering and anti-ischemia reperfusion injury. These properties have been attributed to alkaloid components of Rhizoma coptidis, including berberine, coptisine, palmatine, epiberberine, jatrorrhizine and magnoflorine [78, 79].
Rhizoma coptidis has therapeutic effects on ischemia–reperfusion injury by regulation of Akt/AMPK/p38/ERS/oxidative stress pathways as follows: (1) regulation of Ak/GSK3β/CREB as well as JNK/ERK1/2 to reduce ischemic brain injury ; (2) activation of PI3K–Akt, enhancement the accumulation of HIF-1α and promoting of HIF-1α mediated Sphk2 transcriptional to protect endogenous nerves ; (3) activation of AMPK, phosphorylation of Akt, thus exerting protective effects on the non-ischemic regions of the diabetic heart ; (4) activation of AMPK and PI3K–Akt–eNOS pathways to reduce myocardial apoptosis induced by ischemia/reperfusion in diabetic rats ; (5) regulation of lactate dehydrogenase (LDH), creatine phosphokinase (CK), superoxide dismutase and catalase (CAT) and other antioxidant enzyme activities ; (6) P38MAPK is crucial in myocardial ischemia and reperfusion . Rhizoma coptidis also inhibits ischemia–reperfusion injury by blocking the activity of p38MAPK.
Berberine, epiberberine, coptisine, palmatine, and magnoflorine can inhibit the lipid accumulation significantly in a dose-dependent manner in 3T3-L1 cells. They can down regulate the expression of adipocyte marker proteins, including C/EBP-α and PPAR-γ. The inhibition ability is as follows: coptisine > berberine > epiberberine > palmatine > magnoflorine .
AMPK and SREBP-1c are the main therapeutic targets for the treatment of metabolic diseases. AMPK is a kinase responsible for the phosphorylation of SREBP-1c in adipocytes. SREBP-1c is a transcription factor associated with the promoter region of a number of genes related to fat formation. SREBP-1c plays an important role in increasing triglyceride synthesis by increasing numbers of adipose producing genes related to FAS, also by promoting the expression of PPAR-γ . Berberine can induce SREBP-1c phosphorylation by AMPK/Akt phosphorylation, thus inhibiting protein hydrolysate, nuclear translocation and DNA binding ability of SREBP-1c and reduce the expressions of lipogenic genes including FAS, LPL, PPAR-γ, C/EBP-α and ACC1 in a dose-dependent manner . Epiberberine can inhibit lipid accumulation by regulating the expressions of AMPK/Akt and cellular differentiation mediated Raf/MEK1/ERK1/2, and then down regulating the main transcription factors of adipose formation, such as PPAR-c, C/EBP-α, SREBP-1c, and FAS in 3T3-L1 adipocytes . Jatrorrhizine can also down regulate the expressions of SREBP-1c and FAS in the liver of high-fat diet-induced obesity mouse model .
Diabetes and its complications
Berberine, epiberberine, magnoflorine, palmatine, jatrorrhizine and coptisine have antidiabetic potential [87, 88]. Jatrorrhizine, palmatine and magnoflorine have potential therapeutic effects on diabetic complications such as retinopathy, cataract, neuropathy, and kidney disease .
Insulin resistance and glucose metabolism disorder
Rhizoma coptidis plays a therapeutic role in insulin resistance partly by regulating the TLR4/JNK/NF-κB pathways and Akt/AMPK/GLP-1/ERS pathways. In the insulin resistance models, Rhizoma coptidis acts on the TLR4/JNK/NF-κB inflammatory pathways and inhibits the activities of MCP-1, IL-6, TNF-α, JNK and NF-κB [9, 90, 91, 92, 93]. AMPK also plays an important role in Rhizoma coptidis’s treatments on diabetes . Rhizoma coptidis up-regulates the expression of LKB1, AMPK and inhibits the translocation of TOCR2 into the nucleus in the liver of diabetic rats . Berberine regulates the expression of GLUT4 in insulin-resistant cells with AMPK dependent and Akt independent ways. Akt is an important kinase that mediates glucose metabolism stimulated by insulin, and the deficiency of Akt can lead to glucose metabolism disorder. Rhizoma coptidis acts on Akt pathways by modifying IRS, phosphorylation of downstream Akt and activating PKC to improve insulin signaling cascade [66, 95, 96]. Protein kinase C (PKC) is expressed by the insulin receptor. Berberine can decrease insulin resistance by activating PKC, and inhibitor of PKC can eliminates InsR activation and InsR mRNA transcription induced by berberine . IRS-1 is the principal link between inflammation and insulin resistance . Berberine can improve the IRS-1 level in the brain and restore the expressions of GLUT1 and GLUT3 in the treatment of diabetic animals . Berberine also improves insulin resistance in nonalcoholic fatty liver disease by regulating the expression levels of IRS-2 . Akt induces GLUT translocation to the plasma membrane and regulates downstream targets involved in glycogen synthesis including GSK-3β and glucokinase . Berberine activates Akt and GCK in liver and adipose tissue. The activity of GSK-3β in the liver was also inhibited by berberine [90, 96, 99]. Recent studies have shown that ERS play important roles in obesity, insulin resistance and T2DM. Rhizoma coptidis treats on insulin resistance partly by acting on the ERS pathways, including JNK, PERK, eIF2α and ORP150 to protect cells from ER stress injury .
Rhizoma coptidis also treats insulin resistance by activation of GLP-1. Berberine may regulate the secretion of GLP-1 by regulating AMPK . GLP-1 plays an important role in stimulating glucose dependent insulin secretion, inhibiting glucagon release, promoting β cell proliferation, and gastric emptying and food intake . Rhizoma coptidis can increase the expression of GLP in type 2 diabetic rats to stimulate glucose consumption and lower the levels of blood glucose . Berberine also promotes the secretion of GLP-1 by activating TGR5 and bitterer receptor subtype TAS2R38. TGR5 plays an important role in regulating glycolipid metabolism, inhibiting inflammation, and improving kidney disease [101, 102].
Glucose transportation is the speed limiting step of glucose metabolism and can be activated in the peripheral tissue by two different ways: (1) IRS-1/PI3K signal transduction stimulated by insulin; (2) activation of muscle contraction through AMPK . Berberine can improve glucose metabolism by insulin independent way in insulin sensitive cells including HepG2, C2C12, L6, 3T3-L1 cells [91, 104]. Berberine can increase the ratio of AMP/ATP and activate AMPK and Akt pathways to promote acute insulin mediated glucose transportation [101, 103].
Diabetic nephropathy (DN) is one of the microvascular complications of diabetes and is the main cause of end-stage diabetes . Oxidative stress, ERS and inflammation play important roles in the treatment of DN with Rhizoma coptidis. The levels of AGEs, P-PKC-β and TGF-β increased in injured kidneys. Berberine significantly reduced these levels, but the specific mechanisms remain to be further studied .
Rhizoma coptidis can treat diabetic nephropathy by AMPK/NF-κB/MAPK/Akt/oxidative stress/ERS pathways in diabetic nephropathy. (A) Under high glucose conditions in glomerular mesangial cells, berberine activates TGR5 and inhibits NF-κB/AP-1/MAPK pathways, decreasing the expressions of fibronectin (FN), ICAM-1, TGF-β1 and the phosphorylation levels of c-Jun/c-Fos [101, 107, 108]. High glucose can induce the over expressions of TGF-β1 in diabetic animals and patients, leading to renal fibrosis. However, berberine can reduce the expression of TGF-β1 by NF-κB pathways . At the same time, berberine suppresses the p38MAPK pathways to inhibit the formation of fibronectin and collagen, which participate in renal fibrosis . (B) Under high glucose conditions in renal tubular epithelial cells, berberine activates the PI3K/Akt pathways, reducing the expressions of apoptosis related proteins including Bax, cytochrome c, caspase3 and caspase9. Berberine also has effects on the oxidative stress pathways by reducing ROS production, promoting the expressions of GSH, SOD, Nrf2 and OH-1 to protect the renal tubular epithelial cells from apoptosis . In dorsal root ganglion neurons, Berberine can reduce ROS production and rescue mitochondrial dysfunction induced by high glucose by increasing the expression of p-AMPK and Nrf2 . (C) The sertoli cells arrange at the height of the glomerular basement membrane, and the lack of sertoli cells in regeneration is the main restriction of glomerular healing. Berberine can prevent Aldo induced sertoli cells injury and apoptosis by inhibiting the expressions of ERS related protein GRP78 and CHOP .
Discussion and conclusion
As a traditional Chinese medicine, Rhizoma coptidis is widely cultivated in China. It can be employed in infectious diseases, cardiovascular diseases, diabetes and so on. Its new efficacy is also constantly being discovered. In this paper, we summarized its mechanisms from the relationships of effective components, diseases and pathways. We found that various pharmacological effects of Rhizoma coptidis were due to its overall effects on multiple targets and pathways. The single component of the Rhizoma coptidis can act on several pathways at the same time. Multiple effective components of Rhizoma coptidis also play synergistic roles in pathways. In Osteoarthritis articular chondrocytes, berberine activates Akt/p70S6K/S6 pathway to promote protein synthesis, cell survival and matrix production, and also strongly induces differentiation through PI3K/Akt and p38 kinase pathway [111, 112]. Berberine also regulates the formation of osteoclasts through the negative feedback of AK1 and the activation of AMPK . Coptisine inhibits NF-kB activation and the expression of COX-2, MMP-3, MMP-13 in Osteoarthritis articular chondrocytes . Palmatine may attenuate osteoclast differentiation by inhibiting the expressions of OPG, RANK and RANKL [115, 116].
The related signaling pathways of Rhizoma coptidis are complex. It has been studied from the point of network pharmacology and revealed some mechanisms from the body system. But the activations of the corresponding biomarkers are caused by which components, which components regulate the networks or targets and whether there are synergistic/antagonistic effects between these components remain to be further studied. How to integrate the components, pharmacological actions and targets of Rhizoma coptidis is the focus and difficulty of future researches.
Therefore, in order to make full use of Rhizoma coptidis, we should use the modern technical means, such as the combination of the composition-activity relationship with metabolomics, to find the material basis and system mechanisms of Rhizoma coptidis. It will provide important bases for clinical application and comprehensive utilization of Rhizoma coptidis.
QWH is corresponding author on the study. JW and QR contribute equally as first author and were responsible for collecting materials, writing the paper. HRZ and LW helped organizing the information and edited in the article pictures. CJH and QWH analyzed the article and made recommendations. All authors read and approved the final manuscript.
We are indebted to our alma mater, Chengdu University of Traditional Chinese Medicine for provided convenience in the collection of documents. Thanks for all the help from everyone in our lab. Thanks Hongyi Qi (College of Pharmaceutical Sciences, Southwest University, Chongqing, China) for critical reading of this manuscript and Wei Peng (College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China) for helpful advice.
The authors declare that they have no competing interests.
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This work is financially supported by the national Chinese medicine standardization project (Code: ZYBZH-Y-CQ-46); project of administration of traditional Chinese medicine of Sichuan province (Code: 2018JC011).
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