A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications

Figures & data

Figure 1. Radix Bupleuri (a) and its pieces (b).

Figure 2. Bupleurum chinense DC. (a) Shows the compound umbels and simple, long, slender leaves, (b) shows the yellowish bisexual flowers of compound umbels.

Figure 3. The structures of SSa, SSd, SSc and SSb₂.

Table 1. The various pharmacological activities, mechanisms, models, and applications of SSa.

Pharmacologicalactivities of SSa	Tissue	Models/cells	In vivo/vitro	Mechanisms	Applications	References
Anti-inflammatory activity	Adipocytes	3T3-L1	In vitro	SSa inhibits the expression of inflammatory associated genes and is a potent inhibitor of NF-κB activation.	Obesity-associated inflammation	(Kim et al. 2015)
	Ileum	Male Wistar rats	In vivo	SSa suppresses the production of TNF-α and IL-6 and inhibits the nucleotide-binding oligomerization domain 2 (NOD2)/NF-κB signalling pathway.	Sepsis	(Zhao et al. 2015a)
	Liver	LX-2	In vitro	SSa down-regulates BMP-4 expression and inhibits hepatic stellate cell activation.	Liver fibrosis	(Wang et al. 2013b)
	Macrophages	RAW 264.7	In vitro	SSa regulates inflammatory mediators and suppresses the MAPK and NF-κB signalling pathways.	Lipopolysaccharide (LPS) -induced inflammation	(Zhu et al. 2013)
	Macrophages	RAW264.7	In vitro	SSa inhibits receptor activator of the nuclear factor-κBligand (RANKL)-induced IκBα phosphorylation, p65phosphorylation and NF-κB luciferase activity	Osteoporosis	(Zhou et al. 2015)
	Vascular tissue	HUVECs	In vitro	SSa dose-dependently inhibits the production of ROS,TNF-α, IL-8, COX-2 and iNOS in LPS-stimulated HUVECs.	Oxidative damage	(Fu et al. 2015)
	Liver	HSC-T6	In vitro	SSa decreases the expressions of ERK1/2, PDGFR, TGF-β1R, α-smooth muscle actin, and connective tissue growth factor to inhibit proliferation and activation of HSCs.	Liver inflammation and fibrogenesis	(Chen et al. 2013b)
	Macrophages	RAW264.7	In vitro	SSa inhibits the activation of NF-κB, iNOS, COX-2 and pro-inflammatory cytokines TNF-α and IL-6.	LPS-induced inflammation	(Lu et al. 2012a)
	Inflammatory tissue	HMC-1	In vitro	SSa decreases the expression of IL-6, IL-1β and TNF-α and suppresses NF-κB signal pathway.	Anti-inflammation	(Han et al. 2011)
	Liver	Sprague-Dawley rats	In vivo	SSa inhibits the expression of hepatic proinflammatory cytokines and NF-κB signal pathway and increases the expression of anti-inflammatory cytokine IL-10.	Inhibition of liver injury	(Wu et al. 2008, 2010)
	Human monocytic leukemia cells	THP-1	In vitro	SSa inhibits oxLDL-induced activation of AKT and NF-kappaB, assembly of NLRP3 inflammasome and production of pro-inflammatory cytokines.	Atherosclerosis	(He et al. 2016)
Neuroregulation	Hippocampal tissue	Sprague-Dawley rats	In vivo	SSa inhibits NMDA receptor current and persistent sodium current.	Epilepsy	(Yu et al. 2012)
	CA1 neurons	Sprague-Dawley rats	In vivo	SSa exerts selectively enhancing effects on I A.	Epilepsy	(Xie et al. 2013)
	Spinal cord tissues	Chronic constriction injury rats	In vivo	SSa inhibits the activation of p38 MAPK and NF-κB signalling pathways in spinal cord.	Chronic constriction injury	(Zhou et al. 2014)
	Hippocampus	Sprague-Dawley rats	In vivo	SSa attenuates cocaine-reinforced behaviour throughactivation of GABA(B) receptors.	Morphine-reinforced behaviour	(Yoon et al. 2012, 2013)
	Nervous tissue	Sprague-Dawley rats	In vivo	SSa counteracts the inflammatory response and neurological function deficits via an anti-inflammatory response and inhibition of the MAPK signalling pathway.	Nerve injury	(Mao et al. 2016)
	Nervous tissue	Sprague-Dawley rats	In vivo	SSa inhibits this addiction by regulating GABA(B) receptor system.	Drug addiction	(Maccioni et al. 2016)
Antitumor activity	Different cancer cells	A549, SKOV3, HeLa and Siha	In vitro	SSa sensitizes cancer cells to cisplatin through ROS -mediated apoptosis.	Cancer cell cytotoxicity	(Wang et al. 2010a)
	Glioma	C6 glioma cells	In vitro	SSa enhances the enzymatic activities of GS and CNP.	C6 glioma cells proliferation	(Tsai et al. 2002)
Antiviral activity	Human fetal lung fibroblasts	Human coronavirus 229E	In vitro	SSa intervenes in the early stage of viral replication, such as absorption and penetration.	Coronavirus infection	(Cheng et al. 2006)
	Lung tissue	Influenza A virus infected A549	In vitro	SSa attenuates viral replication, aberrant pro-inflammatory cytokine production and lung histopathology.	Pathological influenza virus infections	(Chen et al. 2015)
Immunoregulation	Lymphoid tissue	Sprague-Dawley rats	In vivo	SSa inhibits the proliferation and activation of T cells and causes the G0/G1 arrest as well as the induction of apoptosis via mitochondrial pathway.	Inflammatory andautoimmune diseases	(Sun et al. 2009)

Figure 4. The molecular mechanisms of the anti-inflammatory activity of SSa. (a) shows the NF-κB pathway, (b) shows the MAPK pathway.

Table 2. The various pharmacological activities, mechanisms, models, and applications of SSd.

Pharmacological activities of SSd	Tissue	Models/cells	In vivo/vitro	Mechanisms	Applications	References
Antitumor activity	Liver	Sprague Dawley rats	In vivo	SSd inhibits the activation of CCAAT/enhancer binding protein β (C/EBPβ) and COX-2.	Human hepatocellular carcinoma	(Lu et al. 2012b)
	Thyroid	ARO, 8305C, SW1736	In vitro	SSd promotes cell apoptosis and induced G1-phase cell cycle arrest.	Human undifferentiated thyroid carcinoma	(Liu & Li 2014)
	Liver	SMMC7721	In vitro	SSd suppresses the expression of COX-2 through the p-STAT3/hypoxia inducible factor-1α (HIF-1α) pathway.	Human hepatocellular carcinoma	(He et al. 2014)
	Prostate carcinoma cells	DU145	In vitro	SSd has effects on induction of apoptosis and cell cycle arrest at G0/G1 phase.	Prostate carcinoma	(Yao et al. 2014)
	Different cancer cells	HeLa, HepG2	In vitro	SSd suppresses TNF-α-induced NF-κB activation and its target genes expression to inhibit cancer cell proliferation, invasion, angiogenesis and survival.	As a combined adjuvant remedy with TNF- α for cancer patients	(Wong et al. 2013a)
	Lung carcinoma	A549	In vitro	SSd induces apoptosis and blocked cell cycle progression by activating Fas/FasL pathway in the G1 phase in A549 cells.	Human non-small cell lung cancer	(Hsu et al. 2004a)
	Liver	HepG2, 2.2.15	In vitro	SSd induces the apoptosis through the activation of caspases-3 and caspases-7.	Human hepatocellular carcinoma	(Chiang et al. 2003)
	Liver	Hep3B	In vitro	SSd induces apoptosis in Hep3B cells through the caspase-3 -independent pathways.	Human hepatocellular carcinoma	Zhou 2003
	Breast carcinomas tissue	MCF-7	In vitro	SSd activates oestrogen response element (ERE)-luciferase activity via the ER α-mediated pathway.	Acting as a weak phytoestrogen.	(Wang et al. 2010a)
	Liver	SMMC-7721, HepG2	In vitro	SSd has a radiosensitizing effect on hepatoma cells under hypoxic conditions by inhibiting HIF-1α expression.	Radiotherapy sensitizer in hepatoma radiotherapy	(Wang et al. 2014a, 2014b)
	Different cancer cells	HeLa, MCF-7	In vitro	SSd induces autophagy through the formation of autophagosomes by inhibiting SERCA.	Apoptosis-resistant cancer cells	(Wong et al. 2013b)
Anti-inflammatory activity	Inflammatory tissue	RAW264.7	In vitro	SSd has inhibitory effects on NF-κB activation and iNOS, COX-2 and pro-inflammatory cytokines including TNF-α and IL-6.	LPS-induced inflammation	(Lu et al. 2012a)
	Hepatic stellate cells	HSC-T6	In vitro	SSd decreases the expressions of extracellular matrix-regulated kinase 1/2 (ERK1/2), PDGFR, TGF-β1R, α-smooth muscle actin, TGF-β1 and connective tissue growth factor.	Liver inflammation and fibrogenesis	(Chen et al. 2013a)
	Human acute monocytic leukaemia cells	THP-1	In vitro	SSd inhibits selectin-mediated cell adhesion.	L-selectin-mediated cell adhesion	(Jang et al. 2014)
	Liver	C57/BL6 rats	In vivo	SSd down-regulates NF-κB and STAT3-mediated inflammatory signal pathway.	Hepatotoxicity and liver injury	(Liu et al. 2014a)
	Liver	Hepatic fibrosis rats	In vivo	SSd down-regulates liver TNF-α, IL-6 and NF-κB p65 expression and increases IκB-α activity.	Hepatic fibrosis	(Dang et al. 2007)
	Kidney	LLC-PK1	In vitro	SSd increases the activity and expression of anti-oxidant enzymes (SOD, CAT, GPx) and HSP72.	Oxidative damage in the kidney	(Zhang et al. 2014)
	Nervous tissue	C6 rat glioma cells	In vitro	SSd possesses a dual effect: an inhibition of PGE2 production without a direct inhibition of cyclooxygenase activity and an elevation of [Ca^2+]i.	Inflammation in C6 rat glioma cells	(Kodama et al. 2003)
	Lung	VILI rats	In vivo	SSd decreases the expression of pro-inflammatory cytokines including MIP-2, IL-6 and TNF-α and elevates the expression of anti-inflammatory mediators, such as TGF-β1 and IL-10.	Lung injury	(Wang et al. 2015)
	Renal tubular epithelial cells	NRK-52E	In vitro	SSd attenuates oxidative injury via upregulation of SirT3.	High glucose induced kidney injury	(Zhao et al. 2015b)
	Kidney	HK-2	In vitro	SSd represses ROS-mediated activation of MAPK and NF-κB signal pathways.	DDP-induced kidney injury	(Ma et al. 2015)
Immunoregulation	Lymphoid tissue	Mouse T cells	In vitro	SSd inhibits the T cell proliferation and activation through the NF-κB, NF-AT and AP-1 signal pathways, and it also inhibits the cytokine secretion and IL-2 receptor expression.	T cell-mediated autoimmune conditions	(Wong et al. 2009)
	Monocyte-derived dendritic cells	DCs	In vitro	SSd reduces the differentiation of human DCs and promotes DCs maturation and increases the function of mature DCs.	Condylomata acuminata	(Ying et al. 2014)
Anti-allergic activity	Lymphoid tissue	Rat basophilic leukemia-2H3 cells	In vitro	SSd suppresses the intracellular calcium mobilization and tyrosine phosphorylation, thereby prevents gene activation of Cdc42 and c-Fos.	Soybean allergy	(Hao et al. 2012)
Neuroregulation	Neuronal cells	PC12	In vitro	SSd regulates mitochondrial and nuclear GR translocation, partial reversal of mitochondrial dysfunction, inhibition of the mitochondrial apoptotic pathway, and selective activation of the GR-dependent survival pathway.	Against corticosterone-induced apoptosis	(Li et al. 2014b)
	Neuronal cells	PC12	In vitro	SSD reduces PC12 cells apoptosis by removing ROS and blocking MAPK-dependent oxidative damage.	Neuronal oxidative stress	(Lin et al. 2016)

Figure 5. The molecular mechanisms of the anti-tumor activity of SSd.

Table 3. The similarities and differences of SSa and SSd in mechanisms of anti-inflammation.

The possible mechanisms of anti-inflammation	SSa	SSd
Inhibiting pro-inflammatory cytokines and promoting anti-inflammatory cytokines	✓	✓
Inhibiting activity of enzymes associated with inflammation	✓	✓
Inhibiting activation of NF-κB pathway	✓	✓
Inhibiting activation of MAPK pathway	✓	✗
Inhibiting selectin-mediated cell adhesion	✗	✓
Inhibiting PGE2 production and elevating Ca^2+ level intracellular	✗	✓

Table 4. The pharmacological activities and mechanisms of extracts from different Bupleurum species.

Species	Extractive fractions	Extraction method	Activities	Mechanisms	References
B. chinenes	Aqueous extracts	Water decoction, 3 h	Antitumor activity	Enhancing 5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cells and protecting normal blood lymphocytes.	(Kang et al. 2008)
		Water decoction, 3 h	Antiviral activity	Suppressing the effect on regulated activation normal T-cell expressed (RANTES) secretion.	(Wen et al. 2011)
		Water decoction, 3 h	Affect drug distribution	Inhibiting the activity of β-glucuronidase.	(Chen et al. 2014)
	Methanol TSS extracts	Methanol, reflux, 4 h	Neuroregulation	Suppressing the abnormal activation of hippocampal astrocyte through inhibiting the overexpression of glial fibrillary acidic protein.	(Xie et al. 2006)
		95% methanol 5% pyridine, reflux, 4 h		TSS antagonizes the reserpine-induced akinesia, and ptosis in mice.	(Liu et al. 2014a)
B. falcatum	Ethanol extracts	70% ethanol, reflux, 6 h	Anti-inflammatory activity	Inhibiting the expression and activation of both metal matrix proteinase (MMP)-2 and MMP-9 after spinal cord injury (SCI) and the mRNA expressions of TNF-α, IL-1β, COX-2, and iNOS.	(Lee et al. 2010)
		80% ethanol, reflux, 6 h	Anti-depressant activity	Reducing depression and anxiety-like behaviors, possibly through central adrenergic mechanism.	(Lee et al. 2012a)
		80% ethanol, reflux, 6h	Memory improvement	Attenuating IMO stress-induced loss of cholinergic immunoreactivity in the hippocampus.	(Lee et al. 2009)
	Methanol extracts	Methanol, reflux, 4 h	Anti-depressant activity	The mechanism of this activity involves the serotonergic and noradrenergic systems.	(Kwon et al. 2010)
		Methanol, reflux, 4 h	Anti-inflammatory activity	Decreasing the content of alanine transaminase (ALT) in blood serum of the liver injury rats.	(Nakahara et al. 2011)
	Aqueous extracts	Water decoction, 3 h	Anti-hyperthyroidism	Attenuating LT4-induced hyperthyroidisms and normalizing LT4-induced liver oxidative stresses and reducing liver and epididymal fat pad changes.	(Kim et al. 2012b)
B. scorzonerifolium	Acetone extracts	Acetone, reflux, 4 h	Antitumor activity	Inducing tubulin polymerization, and activates caspase-3 and caspase-9 in A549 cells, and these effects are related to ERK 1/2 activation and the apoptosis.	(Chen et al. 2005; Cheng et al. 2005)
		Acetone, reflux, 4 h		Inhibiting telomerase activity and activation of apoptosis.	(Cheng et al. 2003)
B. marginatum	Methanol extracts	Methanol, reflux, 6 h	Anti-infective and antitumor activities	Methanol extracts show a significant anti-trypanosomal activity and moderate activity against Streptococcus pyogenes and have the cytotoxicity inducing apoptosis.	(Ashour et al. 2014)
B. longiradiatum	Ethyl acetate extracts	Ethyl acetate, reflux, 4 h	Antiangiogenic activity	It has an inhibitory effect on the tube-like formation of HUVECs.	(You et al. 2002)
B. yinchowense	Ethanol TSS extracts	60% ethanol 0.5% ammonia reflux, 6 h	Neuroregulation	The neuroprotective mechanism relates with inhibiting the ER stress and the mitochondrial apoptotic pathways.	(Li et al. 2013)
B. kaoi	Methanol TSS extracts	Methanol, reflux, 4 h	Antitumor activity	The activity of the Fas/Fas ligand apoptotic system participates in the antiproliferative activity of TSS in A549 cells.	(Hsu et al. 2004b)
		Methanol, reflux, 4 h		Extracts from B. kaoi show potent antiproliferative effects on human A375.S2 melanoma cells.	(Hu et al. 2016)

Table 5. The preparations from Bupleuri Radix approved by CFDA.

Components	Dosage forms	China Approved Drug Names (CADN)	Batch number	Approval date	Drug standard code
Radix Bupleuri extract, poly yamanashi ester-80, sodium chloride	Injection	Chai Hu Injection	Z61021126	07/2013	86902434000703
Radix Bupleuri dry extract	Tablet	Chai Hu Cough Tablets	Z42020845	06/2015	86901876000227
Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice and jujube	Tablet	Xiao Chai Hu Tablets	Z20023393	10/2015	86903050000405
Radix bupleuri, polyethylene glycol	Dripping Pill	Chai Hu Dripping Pills	Z20020053	07/2015	86900941000063
Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice and jujube	Decoction Pill	Xiao Chai Hu Decoction Pills	Z41021830	06/2015	86903082001340
Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice, jujube	Particle	Xiao Chai Hu Particles	Z34020723	05/2015	86904366000721
Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice, jujube	Capsule	Xiao Chai Hu Capsules	Z20090882	08/2014	86904641002884
Radix Bupleuri, scutellaria, rhubarb, immature bitter orange, pinellia, paeoniae, jujube, ginger	Particle	Da Chai Hu Particles	Z20080007	02/2013	86901622002642
Radix Bupleuri, tangerine peel, ligustici, rhizoma cyperi, hoveniadulcis, paeoniae, licorice	Pill	Chai Hu Shu Gan Pills	Z20073333	07/2015	86901174000103
Radix Bupleuri extract	Oral Liquid	Chai Hu Oral Liquid	Z20020107	06/2010	86903099000244
Radix Bupleuri, sileris, tangerine peel, paeoniae, licorice, ginger	Particle	Zheng Chai Hu Yin Particles	Z20003013	06/2015	86901622002086
Radix Bupleuri, sileris, tangerine peel, paeoniae, licorice, ginger	Capsule	Zheng Chai Hu Yin Capsules	Z20040013	07/2015	86904398000362
Radix Bupleuri, sileris, tangerine peel, paeoniae, licorice, ginger	Mist	Zheng Chai Hu Yin Mixture	Z20090749	06/2014	86901622002666
Radix Bupleuri, scutellaria, pinellia, dangshen, ginger, licorice and jujube	Effervescent tablet	Xiao Chai Hu Effervescent Tablets	Z20060458	11/2011	86900042000085
Radix Bupleuri extract, acetaminophen	Injection	Paracetamol and Bupleurum Injection	H52020518	09/2010	86905510000024

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