key: cord-0944584-xqieyhc0 authors: Yang, Min; Wang, Cong-cong; Wang, Wen-le; Xu, Jian-ping; Wang, Jie; Zhang, Chun-hong; Li, Min-hui title: Saposhnikovia divaricata—An Ethnopharmacological, Phytochemical and Pharmacological Review date: 2020-04-21 journal: Chin J Integr Med DOI: 10.1007/s11655-020-3091-x sha: 115ee6e98ba9fd2153e357d93441938750b56890 doc_id: 944584 cord_uid: xqieyhc0 Saposhnikovia divaricata (Turcz.) Schischk., a perennial herb belonging to the family Umbelliferae, is widely distributed in Northeast Asia. Its dried root (Radix Saposhnikoviae) is used as a Chinese herbal medicine for the treatment of immune system, nervous system, and respiratory diseases. Phytochemical and pharmacological studies have shown that the main constituents of S. divaricata are chromones, coumarins, acid esters, and polyacetylenes, and these compounds exhibited significant anti-inflammatory, analgesic, antioxidant, antiproliferative, antitumor, and immunoregulatory activities. The purpose of this review is to provide comprehensive information on the botanical characterization and distribution, traditional use and ethnopharmacology, phytochemistry, and pharmacology of S. divaricata for further study concerning its mechanism of action and development of better therapeutic agents and health products from S. divaricata. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (Appendixes 1–10) is available in the online version of this article at 10.1007/s11655-020-3091-x. comprehensive analysis of ancient herbal books showed northward movement of S. divaricata-producing areas in China with changes in dynasties, for which natural resources have been destroyed by the expansion of cultivated land with a growth in population. (10) At present, S. divaricata is mainly produced in Northeastern China, Inner Mongolia, Shanxi, Hebei, Shandong, and Shaanxi provinces. S. divaricata cultivation has regained momentum as its high medicinal and dietary value and became more apparent in recent years. Heilongjiang Province, China is the major producing region of cultivated S. divaricate and has the largest output. (11) S. divaricata is classified according to its quality in different regions. S. divaricata produced in Heilongjiang, Jilin, Liaoning, and Inner Mongolia (East) is of the best quality and is known as Guanfangfeng or Dongfangfeng. By contrast, S. divaricata produced in Inner Mongolia (West), Hebei (Chengde, Zhangjiakou), and Shanxi, known as Xifangfeng, and that produced in Hebei (Baoding, Tangshan) and Shandong, known as Shanfangfeng, Huangfangfeng, and Qingfangfeng, are of inferior quality. (12) Traditional Uses and Ethnopharmacology S. divaricata was fi rst recorded in Shen Nong's Materia Medica (Shen Nong Ben Cao Jing) written in 300 A.D. China with signifi cant therapeutic properties against common cold, headache, rheumatic diseases, arthralgia, rubella, pruritus, and tetanus. It was ranked as a premium-grade herb in this ancient pharmaceutical monograph. (3) Its dried roots possess the property of pungent, sweet and slight warm, which are widely used clinically for treating exterior syndromes including migraines and headaches caused by common cold and internal diseases including Bi syndrome and rosacea in CM. (13) Various traditional preparations containing the roots of S. divaricata are listed in Appendix 2. Phytochemical studies have revealed that there are approximately 100 compounds with different structural patterns isolated from S. divaricata, including chromones, coumarins, acid esters, polyacetylenes, volatile oils, polysaccharides, and inorganic elements (1, 4, (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) as shown in Appendixes 3-9. Chromones, a subclass of fl avonoids, are a class of oxygen-containing heterocyclic compounds having a benzo-cyclized γ-pyrone ring. They are the primary active components of S. divaricata, and research on these compounds has been well studied than that on other components. To date, 17 chromones have been identifi ed (Appendix 3), which are ledebouriellol (1), hamaudol (2) (17). (15) Despite their simple structure, they have good anti-inflammatory, free radical-scavenging, and immunostimulatory effects. (16) (17) (18) Among them, compounds 3, 7-10 are the primary chromones, which are abundant in S. divaricata, in particular, compounds 7 and 8. (19, 20) Coumarins Coumarins, a type of benzopyrones containing a benzene ring fused to a pyrone ring, are the most abundant chemical constituents of S. divaricata. They have extremely diverse structures, which are divided into simple coumarins, pyranocoumarins, furanocoumarins, and other coumarins. (1, 21, 22) At present, a total of 35 coumarins, primarily furanocoumarins and pyranocoumarins, have been identified from S. divaricata (Appendixes 4 and 5). Among them, the 17 furanocoumarins isolated include bergapten (18) , byakangelicin (19) , deltoin (20) , imperatorin (21) , isoimperatorin (22) , isobergapten (23) , marmesin (24), methoxy-8-(3-hydroxymethylbut-2-enyloxy)-psoralen (25) , nodakenetin (26) , oxypeucedanin hydrate (27) , phellopterin (28) , psoralen (29) , sapodivarin (30) , xanthotoxin (31), 5-hydroxy-8-methoxypsoralen (32), nodakenin (33) , and xanthoarnol (34) . (23) Five simple coumarins isolated from the herb, including fraxidin (35), isofraxidin (36) , scopoletin (37) , umbelliferone (38) and 5-methoxy-7-(3, 3-dimethylallyloxy)-coumarin (39) , have simple structures but show a variety of biological activities such as dispelling phlegm and antitumor activity. Lastly, 13 pyranocoumarins have also been identified from S. divaricata, including anomalin (40) , decursinol (41) , decursinol angelate (42) , divaricoumarin A (43), divaricourmarin B (44), divaricourmarin C (45), praeruptorin B (46), praeruptorin F (47), cis-3', 4'-disenecioylkhellactone (48) , cis-3'-isovaleryl-4'-acetylkhellactone (49) , cis-3'-isovaleryl-4'-senecioylkhellactone (50), (-)-ciskhellactone (51), and (3'S)-hydroxydeltoin (52) . (24) (25) (26) (27) Recently, compounds 43, 44 and 45, with the molecular formulas C 25 H 32 O 12 , C 25 H 30 O 12 , and C 25 H 30 O 12 , respectively (Appendix 6), were found to be effective against the porcine epidemic diarrhea virus (PEDV). (28) Compound 44 has the strongest inhibitory effect on PEDV in Vero cells. In vitro studies showed that compound 44 inhibits viral replication during the protein synthesis stage, thus, demonstrating its antiviral properties for potential application in intractable human diseases caused by coronavirus. (28) Acid Esters Nineteen fatty acids, 2 organic acids, and 9 methyl ester derivatives of organic acids have been isolated from supercritical CO 2 extract, fatty acid extract, and ethanol extracts of S. divaricata roots, respectively. Among them, a phenylpropanoid fatty acid ester, identified as (±)-2-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-3-methoxypropyl nervonic acid ester (53) , signifi cantly suppressed nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages. (16) Another acid ester, lindiol (54) , has also been isolated from S. divaricata roots (Appendix 7). Five polyacetylene compounds, including panaxynol (55), falcarindiol (56), (8E)-heptadeca-1,8-dien-4,6-diyn-3,10-diol (57), (9Z )-1-methoxy-9-heptadecene-4,6-diyn-3-ol (58) , and (8E )-10hydroperoxy-1,8-heptadecadiene-4,6-diyn-3-ol (59) have been isolated from the fibrous roots of S. divaricata (Appendix 8). (29) There are a series of other compounds isolated from S. divaricata, such as adenosine (60), daucosterol (61), β-sitosterol (62), marmesinin (63), fangfengalpyrimidine (64), clemiscosin A (65), bitter glycoside (66), melanochrome (67), tectochrysin (68), glycerol monolinoleate (69), glycerol monooleate (70), stigmasterol (71), and 8'-epicleomiscosin A (72), shown in Appendix 9. (23) To date, 45 inorganic elements have been detected in S. divaricata by inductively coupled plasma atomic emission spectroscopy. High levels of Zn, Sr, Cr, and Ni are found in the root of S. divaricata, especially those of Zn and Sr, with average values being 29.4 and 25.8 μg/g, respectively. (4) Essential oils, which are relatively complex, have also been isolated from S. divaricata. In recent years, nearly 70 volatile compounds have been identifi ed by gas chromatography-mass spectrometry from the roots and fruits of the plant, including panaxynol, α-pinene, β-eudesmol, β-bisabolene, hexanal, pentanol, hexanol, octanal, octanol, nonanal, α-muurolene, acetophenone, 7-octen-4ol, naphthalene, octadecadienoic acid, falcarinol, cyclohexene, calacorene, decenal, and decadienal, which have been isolated from the roots. Essential oils isolated from the fruit of S. divaricata primarily include n-heptane, n-octane, n-caproaldehyde, 2-heptanone, 2-octanone, benzaldehyde, n -nonane, myrcene caprylic aldehyde, heptanal, α-thujene, α-pinene, β-pinene, and camphene. (30, 31) The compositions and quantities of essential oils in S. divaricata vary greatly depending on the extraction method, production area, and mineral elements in the rhizosphere soil. Polysaccharides are another class of compounds in S. divaricata. Three homogenous polysaccharides, saponikovan A, B, and C (relative molecular masses, 5.4×10 4 , 2.8×10 5 , and 1.32×10 5 , respectively), have been isolated from S. divaricata. Furthermore, two other acidic Saposhnikovia polysaccharides (SPSs), SPSa and SPSb, have been isolated from the dried root and rhizome of S. divaricata by DEAE-sepharose fast fl ow column chromatography. SPSa is primarily composed of galactose, arabinose, rhamnose, and galacturonic acid in the molar ratio of 1:2.3:0.15:4.8. While SPSb is primarily comprised of galactose, arabinose, rhamnose, xylose, and galacturonic acid in the molar ratio of 1:1.5:0.8:0.2:10.2, respectively. (32) SPSa and SPSb are novel acidic polysaccharides isolated from S. divaricata. Previous studies have demonstrated that S. divaricate exhibits a broad range of pharmacological activities, including anti-inflammatory, analgesic, a n t i o x i d a n t , a n t i p r o l i f e r a t i v e , a n t i t u m o r , i m m u n o r e g u l a t o r y , a n t i a l l e r g i c , a n t i p y r e t i c , a n t i c o a g u l a n t , b l o o d c i r c u l a t i o n -p r o m o t i n g , anticonvulsive, antileukemia, anti-atherosclerosis, and hepatoprotective effects (Appendix 10). (18, (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) Many reports have demonstrated that the extract of S. divaricata (SDE) and several of its constituents, including sec -O -glucosylhamaudol, cimifugin, prim -O -glucosylcimifugin, 4'-O -β -D-glucosyl-5-O -methylvisamminol, 5-O -methylvisamminol and anomalin, exhibit significant anti-inflammatory and analgesic activities. (33) (34) (35) (36) (37) (38) (39) Chun, et al (42) reported that SDE extracted with 70% ethanol demonstrated an anti-inflammatory and anti-osteoarthritis activities through in vitro and in vivo studies. They examined the levels of 4 proinfl ammatory cytokines in LPS-stimulated RAW 264.7 cells to evaluate the anti-infl ammatory activity of SDE in vitro, and found that it significantly inhibited the production of NO, prostaglandin E 2 (PGE 2 ), tumor necrosis factor (TNF), and interleukin-6 (IL-6) at a concentration of 200 or 400 μg/mL. A monosodium iodoacetate (MIA)induced osteoarthritis model was used to investigate the anti-osteoarthritic activity of SDE in vivo. The results of the hind paw weight-bearing assay in rats showed that the weight-bearing distribution reduced rapidly in the group with MIA injection while it decreased only slightly in the group treated orally with SDE (200 mg/kg) and indomethacin (IM, 2 mg/kg). The serum levels of IL-1β, IL-6, TNF-α, and PGE 2 increased in the MIA group but decreased in the SDE-and IM-treated groups. Following MIA injection, the expression of cytokine and inflammatory mediator mRNAs increased while the expression of the cytokine decreased in the SDEand IM-treated groups. The results showed that SDE maintained normal weight-bearing in MIA-induced osteoarthritis rats, suggesting that SDE could be used to treat osteoarthritis. All of above results indicated that the SDE attenuated stiffness, inhibited the production of proinflammatory cytokines and mediators, and protected cartilage and subchondral bone tissue in the rat model. (50, 51) Chromones isolated from S. divaricata, including prim -O -glucosylcimifugin, 4'-O -β -D-glucosyl-5-O -methylvisamminol, 5-O -methylvisamminol, and cimifugin also have anti-inflammatory properties, which can significantly reduce pain and swelling in arthritic rats. (33) Prim-O-glucosylcimifugin was found to inhibit the pathways of mitogen activated protein kinase (MAPK) phosphorylated-extracellular signalregulated kinase, c-Jun Nterminal kinase (JNK), p38, and p-JNK which was the most effectively suppressed among the MAPK subtypes. (37) Compared with prim-Oglucosylcimifugin, cimifugin and 5-O-methylvisamminol had a stronger inhibitory effect on NO and inducible NO synthase (iNOS) production. (35) Anomalin, a coumarin compound isolated from S. divaricata, is an active compound against hyperalgesiaassociated inflammation. (52) Khan, et al (38) investigated the effect of anomalin on the production of infl ammatory molecules in LPS-stimulated murine macrophages to clarify the cellular signaling mechanisms underlying the anti-infl ammatory action of anomalin. Cells were treated with various concentrations of anomalin (1, 10, and 50 μmol/L). The results suggested that anomalin can block the protein synthesis and phosphorylation of inhibitor of nuclear factor kappa-B (NF-κB) α (IκBα) and deactivate the transcription of NF-κB by inhibiting iNOS, cyclooxygenase-2, TNF-α and IL-6 in RAW 264.7 cells. The analgesic and antinociceptive activities of S. divaricata are the results of synergistic actions of its various chemical components, including chromones, coumarins and polyacetylenes, although the content and potency of these compounds differ. Oral administration of the sec-O-glucosylhamaudol and cimifugin at 40 and 80 mg/kg, respectively, induced significant analgesia. (33) Another study showed that the aglycone part of sec-O -glucosylhamaudol and cimifugin significantly increased the potency at doses of 1, 5 and 10 mg/kg. (33) Interestingly, the non-glycosylated dihydropyran C-ring may play an important role in the analgesic effect of chromones. (33) The pain threshold tail writhing test also showed that spasmodic pain was effectively reduced when intramuscular injections of prim-O-glucosylcimifugin and 4'-O-β-D-glucosyl-5-O-methylvisamminol at doses of 100 mg/kg were administered in murine models. The study also demonstrated that chromones including divaricatol, ledeouriellol, and hamaudol exhibited the strongest analgesic effect when administered orally at a dose of 1 mg/kg in rats. (33) Antioxidant Activities Oxidative stress is implicated in the pathogenesis of numerous diseases. (53) Polysaccharides and various individual compounds such as cimifugin, 5-O-methylvisamminol, imperatorin, and deltoin isolated from S. divaricata possess significant antioxidant activities. (54, 55) SPS scavenged free radicals and inhibited lipid peroxidation, and the effects on scavenging 1,1-diphenyl-2-trinitrobenzene hydrazine (DPPH) and hydroxyl radical (OH) were especially signifi cant. (18) Acid SPS, the potential primary active ingredient in SPS, was isolated from S. divaricata by hot water extraction and ethanol precipitation method; this compound had strong antioxidant activity. The total reducing power, scavenging effect on superoxide anion (O 2-), OH, and DPPH, and inhibitory effect on lipid peroxidation induced by Fe 2+ of different SPS was measured in vitro in chemical-simulated systems to evaluate the antioxidant activity. The scavenging rate of acid SPS for DPPH and OH approached 70% with the concentration of 8 mg/mL, which is considered to have a better effect among different SPS. (43) Li, et al (56) prepared different extracts using ultrasound-assisted extraction for different times, temperatures, and solvents, and determined the antioxidant activity of the different extracts by the DPPH assay. Their study results showed that the 80% ethanol extract (prepared after 120 min extraction time) exhibited strong antioxidant activity in the DPPH assay. Furanocoumarins including imperatorins and deltoin isolated from S. divaricata also showed antioxidant potential. (39) The inhibitory mechanism involved weakening the activation of IκB kinase and janus kinase, blocking the nuclear translocation of NF-κB and Stat-1 and eliminating the induction of iNOS. The undiluted ethanolic SDE had substantial antioxidant activity determined by the 2,2'-azinobis [3-ethylbenzothiazoline-6-sulfonic acid] (ABTS) hydroxyl radicalscavenging assay; the antioxidant activity values of two batches in different dried roots from S. divaricata were equivalent to 6.9 and 7.6 μmol/L trolox, respectively. (18) Animal studies on transplanted S180 tumor strains in vivo have shown that polysaccharides from S. divaricata possess antineoplastic function. Li, et al (44) combined the S180 oncocyte with celiac macrophagocyte (Mф) of immunized mice to vaccinate the mice, and at the same time, blocked the function of Mф by silica gel to observe the effect on the antineoplastic function of S. divaricata in vivo. The results showed that S. divaricata in vivo could inhibit S180 tumor growth by 52.92%. The antineoplastic activity increased upon vaccination with the combination of S180 oncocyte and celiac Mф of immunized mice (P<0.01). However, the antineoplastic function of S. divaricata greatly decreased after Mф function was blocked by silica gel, and the tumor inhibitory rate decreased from 52.92% to 11.82%. The study indicated that the antineoplastic effect of S. divaricata was closely related to Mф, and the enhancement of the antitumor activity of Mф could be related to the promotion of the secretion of lysosomal enzymes or cytotoxic cytokines. 50 values at the dilutions of 1/300, 1/400, 1/250, and 1/600, respectively. The results indicated that the combination of SDE with a lower concentration of CAM or PTX could achieve the same antiproliferative activity as shown by a high concentration of CAM or PTX. (18) Panaxynol, another active component of the root of S. divaricata, was found to suppress the proliferation of K562, Raji, Wish, HeLa, Calu-1, and Vero cells by 30.0%±4.1%, 34.0%±5.6%, 19.4%±3.2%, 32.0%±8.5%, 14.5%±16.8%, and 8.9%±3.2%, respectively, at 25 μmol/L. (41) It induced G0/G1 to S and G2/M phase cell cycle arrest at a concentration of 100 μmol/L in vitro. Therefore, its effect may be related to the blocking of cyclin E mRNA expression. Kuo, et al (41) also showed that the ethanol SDE potently inhibited the proliferation of various tumor cells; while a study reported that coumarins showed antitumor activities at concentrations >100 μg/mL. (57) Immunoregulatory Activities Besides the antioxidant and antitumor activities, polysaccharides from the roots of S. divaricata also show immunostimulatory activity. Liu, et al (58) used a marked test to observe spleen cell proliferation and spleen index as well as the macrophage and phagocytic rate in mice to study the immunoregulatory effects of these polysaccharides. The lymphocyte subset ratio for CD3 + CD4 increased from 27.28%±2.30% to 45.82%±1.54% at doses of 250-1000 mg/kg, while the ratio for CD3 + CD8 + was significantly higher at 17.44%±1.78% (250 mg/kg), but decreased by 13.22%±1.34% (1,000 mg/kg). Polysaccharides increase the release of IL-1 and IL-8 from macrophages in vivo and improve the proliferation and lethality of immune cells. (49) Another study showed that SDNP-2 (a purifi ed native polysaccharide) from the water extract of S. divaricata exhibited signifi cant antagonistic effect against immunosuppression as shown by the cell viability of the culture supernatants of melanoma cells on RAW 264.7 macrophages. (49) The percentage of mouse peritoneal macrophage phagocytosis was 20.8%±2.2% in the control group and 30.7%±3.1% in the experimental group treated daily for 4 days with 20 g/kg polysaccharide, and the phagocytosis index of the experimental group was 1.7 times higher than that of the control group. (46) Others S. divaricata also showed an antiallergic effect. Controlled trials for the antiallergic effect showed that S. divaricata group (2.90±0.45 mg) was significantly lower than the control group (4.88±0.78 mg, P<0.05) in body temperature in mice, indicating that S. divaricata could inhibit the delayed hypersensitivity induced by 2,4-dinitrochlorobenzene (DNCB). (46) Yang, et al (59) studied the antipyretic effect of SDE prepared by CO 2 supercritical extraction depending on 2,4-dinitrophenol (DNP). The results showed that the antipyretic effect in the low-and middle-dose groups was lower than that in the aspirin control group, while the effect in the highdose group was similar to that in the control group. S. divaricata also has anticoagulant, blood circulationpromoting, and blood stasis-removing effects. Its n-butanol extract can prolong bleeding and coagulation times in mice, which may play a role in activating blood circulation and removing blood stasis by affecting the quantity and function of erythrocytes and fibrinogen. (59) Volatile oils isolated from S. divaricata can significantly prolong the coagulation time in Kunming mice and have a good anticoagulant effect. (60) A previous study demonstrated that an intragastric dose of S. divaricata extract exhibited a 60% reduction in albino mice experiencing electroshock convulsions. Chen, et al (61) reported that the water SDE showed significant anticonvulsant effects. Additional effects such as antileukemia, anti-atherosclerosis, and hepatoprotective have been observed in vivo. (45, (62) (63) (64) Toxicity To evaluate the infl uence of S. divaricata extract in rats, Shang, et al (65) conducted a study on the acute toxicity of the water extract and water extracting-alcohol precipitating extract of the root of S. divaricata. After 20-30 min of administration, the mice suffered from lassitude, shortness of breath accompanied by sound, urinary incontinence, other phenomena indicative of poisoning, and death due to generalized convulsions. The test results showed that the water extract and water extracting-alcohol precipitating extract of S. divaricata, which had a long history of clinical use, could induce a toxic reaction in mice. The median lethal dose of the water extract of the root of S. divaricata was 184.03 g/kg, while that of the water extractingalcohol precipitating extract was 118.14 g/kg. The acute toxicity of the water extract is less than that of the water extracting-alcohol precipitating extract. (65) The viability assay based on neutral red incorporation showed that S. divaricata had a signifi cant protective effect on LPS-activated RAW 264.7 cells, with no cytotoxicity observed in cells at 1/10,000, 1/5,000 and 1/2,000 dilutions (P<0.05). The extract still had no cytotoxic effect, although it reduced viability of the LPS-activated cells at a dilution of 1/1,000 (P<0.05). (1) Although this review makes a systematic and detailed summary of this species, there are some knowledge gaps that require elucidation. Potential future research should address the following. (1) The wild variety of S. divaricata cannot fulfill the increasing market demand due to the limitations associated with reduction in plant growth. Overexploitation of wild varieties is a direct consequence of a decline in their wild populations. At the local level, there is no effective managing strategy for S. divaricata loss, which may lead to a decline in seed germination in the following year before the seeds maturation. (2) Not only the root but also the leaves, fl owers and fruits of S. divaricata were used to cure diseases in ancient times. (57) It is imperative to study the medicinal value of the aboveground parts of S. divaricata in order to make full use of the resource. (3) There are limited clinical studies on pharmacokinetics for this plant, and the scientific evidence is insuffi cient to explain the specifi c mechanism underlying the plant's biological activity. Pharmacokinetic and clinical studies should be conducted to assess the possible therapeutic effect on target organs and the active ingredients responsible for it. (4) The toxicity of S. divaricata has not been thoroughly analyzed and described. Systemic evaluation of toxicity for this plant has not been conducted; similarly, it remains known whether this herb causes serious side effects. Therefore, physiological data are needed to study its toxicity. And the toxicity of S. divaricata should be studied in line with its pharmacological potential. Overall, S. divaricata is a valuable herb, which deserves further attention due to its wide applicability and biological activities. Although research on S. divaricate is far from being fl awless, we have reviewed the latest research results. This article highlights the ethnopharmacological potential of S. divaricata and provides a foundation for its utilization. There are no conflicts of interest. Saposhnikoviae divaricata: a phytochemical, pharmacological, and pharmacokinetic review Committee for the Pharmacopoeia of PR China. Pharmacopoeia of PR China (Part Ⅰ) Herbal textual research on the Saposhnikovia divaricata Advance in study on chemical constituents of Saposhnikovia divaricata and their pharmacological effects Chinese Academy of Sciences Flora Republicae Popularis Sinicae Editorial Committee Hohhot: Inner Mongolia People's Publishing House Effects of drought stress on the antioxidant system, osmolytes and secondary metabolites of Saposhnikovia divaricata seedlings Effect of drought stress on physiological characteristics and quality of Saposhnikovia divaricata Physical and ecological impacts of chromones of fresh root of Saposhnikovia divaricata exposure to high temperature Herbalogical studies of the Chinese drug Saposhnikovia divaricata Investigation on the planting situation of Gentianae Radix et Rhizoma and Saposhnikoviae Radix in Heilongjiang Province A survey of the research on Saposhnikovia divaricata Molecular mechanism of infl ammatory signaling and predominant role of Saposhnikovia divaricata as antiinfl ammatory potential Two new chromone glycosides from the roots of Saposhnikovia divaricata Ultra-performance convergence chromatography method for the determination of four chromones and quality control of Saposhnikovia divaricata (Turcz.) Schischk Anti-infl ammatory constituents from the roots of Saposhnikovia divaricata Analgesic components of saposhnikovia root Saposhnikovia divaricata Anti-proliferative and antioxidant activities of Saposhnikovia divaricata Application of response surface methodology to optimise ultrasonic-assisted extraction of four chromones in Radix Saposhnikoviae Simultaneous determination of six major constituents in the roots of Saposhnikovia divaricata by HPLC Isolation and structure identifi cation of chemical constituents from Saposhnikovia divaricata Isolated perfused lung extraction and HPLC-ES-MSn analysis for predicting bioactive components of Saposhnikoviae Radix Chemical constituents of Saposhnikovia divaricata Chemical constituents of roots of Saposhnikovia divaricata Rapid characterisation and identifi cation of compounds in Saposhnikoviae Radix by high-performance liquid chromatography coupled with electrospray ionisation quadrupole timeof-fl ight mass spectrometry Characterization of compounds from the roots of Saposhnikovia divaricata by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry A sensitive liquid chromatography-mass spectrometry method for simultaneous determination of two active chromones from Saposhnikovia root in rat plasma and urine Three new coumarins from Saposhnikovia divaricata and their porcine epidemic diarrhea virus (PEDV) inhibitory activity Chemical constituents of the roots and rhizomes of Saposhnikovia divaricata and their cytotoxic activity GC-MS analysis of essential oils from the roots of Saposhnikovia divaricata (Turcz.) Schischk, Libanotis laticalycina Shan et Sheh, Seseli yunnanense Franch. and Peucedanum dielsianum Fedde ex Wolff GC-MS Analysis of essential oil from the root of Sapsohnikovia Divaricata (Turcz.) Schischk Research for the chemical constituent of Saposhnikovia Divaricata (Turcz.) Schichk polysaccharides A pharmacodynamic research on chromone glucosides of Saposhnikovia divaricata Ultrafi ltration LC-ESI-MSn screening of MMP-2 inhibitors from selected Chinese medicinal herbs Smilax glabra Roxb., Smilax china L. and Saposhnikovia divaricata (Turcz.) Schischk as potential functional food ingredients Prime-O-glucosylcimifugin attenuates lipopolysaccharide-induced acute lung injury in mice The suppressive effects of Saposhnikovia divaricata (Fangfeng) chromone extract on rheumatoid arthritis via inhibition of nuclear factor-κB and mitogen activated proteinkinases activation on collagen-induced arthritis model Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury Suppression of LPS-induced inflammatory and NF-κB responses by anomalin in RAW 264.7 macrophages Inducible nitric oxide synthase inhibitor of the Chinese herb Ⅰ. Saposhnikovia divaricata Imperatorin attenuates LPS induced infl ammation by suppressing NF-κB and MAPKs activation in RAW 264.7 macrophages A tumor cell growth inhibitor from Saposhnikovae divaricata Anti-inflammatory and antiosteoarthritis effects of Saposhnikovia divaricata ethanol extract: in vitro and in vivo studies Studies on the antioxidative activity of polysaccharides from Radix Saposhnikoviae Effect of polysaccharide of Radix Sileris on enhancing macrophagocyte's antineoplastic function Reactions of macrophage and lymphocyte subsets in normal mice to Radix Saposhnikoviae polysaccharide Pharmacological studies on the root of Saposhnikovia divaricata Effect of Saposhnikovia divaricata polysaccharide JBO-6 on immune function and anti-tumor effect in mice Pharmacological study on antiinfl ammatory and hemostatic effects of Saposhnikovia divaricata volatile oil Structural characterization of polysaccharides from Saposhnikovia divaricata and their antagonistic effects against the immunosuppression by the culture supernatants of melanoma cells on RAW264.7 macrophages Research progress on Saposhnikovia divaricata at home and abroad Effects of volatie oil of Schizonepeta tenuifolia Briq herb and Saposhnikovia divaricata Schischke root on proinflammatory cytokine expression and regulation Mechanism underlying antihyperalgesic and anti-allodynic properties of anomalin in both acute and chronic infl ammatory pain models in mice through inhibition of NF-κB, MAPKs and CREB signalling cascades Oxidative stress: oxidants and antioxidants Biotransformation of prim-Oglucosylcimifugin by human intestinal flora and its inhibition on NO production and DPPH free radical Antimicrobial and antioxidant activity of Saposhnikovia divaricata, Peucedanum japonicum and Glehnia littoralis Anti-oxidant activities of chromones from Saposhnikovia divaricata Immunological and antitumor effects of coumarin and some derivatives Study on apoptosis of K562 cell in vitro induced by Saposhnikovia divaricata polysaccharide Study on pharmacodynamics of CO 2 swpercritical fluid extraction of Radix saposhinikovise Experimental study of pharmacological action of active composition of Radix Saposhnikoviae Experimental study on antiallergic effect of Saposhnlkovia divarlcata (Turcz.) Schischk and Tribulus terrestris L Comparative studies on the febrifugal analgesic and anticonvulsive activities of water extracts from cultivated and wild Saposhnikovia divaricata Experimental study on anti-atherosclerotic inflammatory response of Saposhnikovia divaricata of active components. Beijing: China Academy of Chinese Medical Sciences Protective effect of Saposhnikovia divaricata extract on liver Research on acute toxicity of water extract and water extracting-alcohol precipitating extract from Radix Saposhnikoviae