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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 7
| Issue : 3 | Page : 287-298 |
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The distribution, uses, and characteristic components of gentianaceae plants in China
Han Cheng1, Yue-Bin Ge1, Jun Li1, Yan Zhang2, Xian-Ju Huang1, Guo-Xun Chen3
1 Department of Pharmacology, College of Pharmacy, South-Central University for Nationalities, Wuhan, China
2 Department of Gatroenterology, Affiliated Puren Hospital of Wuhan University of Science and Technology, Wuhan, Hubei, China
3 Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA
| Date of Submission | 15-Jun-2020 |
| Date of Acceptance | 02-Sep-2020 |
| Date of Web Publication | 24-Mar-2021 |
Correspondence Address:
Prof. Guo-Xun Chen
229 Jessie Harris Building, 1215 West Cumberland Avenue, Knoxville, Tennessee 37996
USA
Prof. Xian-Ju Huang
182 Minyuan Road, Wuhan 430074
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/wjtcm.wjtcm_14_21
Extracts of Gentianaceae herbs have been widely used as food additives, teas, or medicinal remedies for various human diseases and disorders. Iridoids, secoiridoids, and analogs glycosides, mainly include gentiopicroside, sweroside, swertiamarin, and loganic acid, are the characteristic compounds found in the Gentianaceae plants. The uses of the medicinal herbs containing these secoiridoids have been described in Chinese Materia Medica. Herbal extracts containing iridoids, secoiridoids, and analogs could exert protective effects in multiple human tissues and cells. Some of these medicinal herbs have been studied using modern pharmacological means. The results indicate that they have analgesic, liver protective, anti-inflammatory, antiallergic, anti-pathogeny, and anti-bacterial functions. This review was aimed to summarize the use of Gentianaceae herbs for disease treatments and pharmacokinetic characteristics of the active compounds. In so doing, we hope to demonstrate that Gentianaceae herbs and bioactive compounds in them may have abilities to affect inflammation, hepatic metabolism and cell signaling. In addition, we would like to bring this to the attention of the field about the use and study of compounds derived from Gentianaceae herbs.
Keywords: Analogs, gentiopicroside, iridoids, phytomedicines, secoiridoids
How to cite this article:
Cheng H, Ge YB, Li J, Zhang Y, Huang XJ, Chen GX. The distribution, uses, and characteristic components of gentianaceae plants in China. World J Tradit Chin Med 2021;7:287-98 |
How to cite this URL:
Cheng H, Ge YB, Li J, Zhang Y, Huang XJ, Chen GX. The distribution, uses, and characteristic components of gentianaceae plants in China. World J Tradit Chin Med [serial online] 2021 [cited 2022 Jan 19];7:287-98. Available from: https://www.wjtcm.net/text.asp?2021/7/3/287/323493 |
| Introduction | |  |
With the prolonged life expectancy, a series of age-related metabolic diseases has become an epidemic and one of the major health issues throughout the world. Metabolic diseases are caused by metabolic disorders, including diabetes, diabetic ketoacidosis, and gout.[1]
Many metabolic patients choose therapeutic herbal or traditional Chinese medicine (TCM) along with the mainstream anti-metabolic drugs, thus making alternative therapy for metabolic disease a popular remedy. The gentian family consists of 99 genera with a total of about 1736 species. Most of them are plants with medicinal uses in folk medicine to treat various diseases include metabolic disorders. Gentianaceae plants are extensively consumed as medicine or tea for curative purposes. For example, the consumption of bitter gentian teas is very popular among the nomadic people of Siberia.[2] These teas have been widely used as a remedy to treat various digestive disorders associated with the food consumptions.[3] Gentiopicroside and sweroside have been detected as specific components in gentian herb teas. Gentian root extract, a bitter food additive registered and used in Japan, also contains sweroside and gentiopicroside with the later one as one of two major components.
Gentiopicroside and sweroside have the most and second to the most bitterness indexes (14,500 and 9500, respectively) in the gentian teas.[3] The structure of gentiopicroside and its role as the principal bitter molecule in gentian are proposed in 1961.
This review was aimed to summarize the distribution, uses and characteristic components of Gentianaceae plants in China.
| Distribution of Genus Gentian in China | | |
A total of 417 species of genus Gentian are identified in China, and they are distributed in all provinces and regions. Among them, Tibet, Qinghai, Gansu, Sichuan, Yunnan, and other southwestern provinces have the most species. A cluster analysis of some medicinal resources of gentian has been conducted to analyze the internal transcribed spacer sequences,[4] which establishes a scientific reference for the identification of these medicinal resources. According to its morphology, the genus Swertia under the gentian family has also been reclassified.[5]
Gentianaceae plants are widely used in the clinical practice of TCM, such as “Di Da,” one of the representative medicinal materials with Tibetan medicine characteristics. “Di Da” does not refer to a certain kind of medicine, but a general term for drugs used to treat liver and gallbladder diseases. The ancient and modern Tibetan medicine literature shows that “Di Da” includes a variety of medicinal materials that are extremely complex on the origin, and lots of gentian plants.
In an attempt to understand the bioactive compounds in Veratrilla baillonii Franch, a medicinal herb used commonly in southwestern area of China for the treatments of pyrexia, inflammation, gastro spasm, and aconite root poison, we found that gentiopicroside and sweroside in the plant are the responsible bioactive compounds with capability to regulate gene expression and to active components of insulin signal transduction cascade in hepatoma cells, indicating their effects on the hepatic metabolism.[6]
| Characteristic Components in Gentianaceae Herbs | | |
Secoiridoids mainly as gentiopicroside, sweroside, and swertiamarin are the characteristic components of the medicinal plants of Gentianaceae used in the practice of TCM. As shown in [Table 1], the presence of one, two or all three of these secoiridoids has been demonstrated in a variety of medicinal herbs, which are not limited to the genus of Gentianaceae. Gentiopicroside is also identified in aerial parts of Gentiana gelida. Other than Gentianaceae, secoiridoids can be found in Swertia, Veratrilla, Centaurium, Gentianella Moench, Gentianopsis, Halenia Borkh, and Cornus. It is reasonable to observe the wide distribution of these secoiridoids as gentiopicroside and sweroside are the components responsible for the bitter taste as indicated in. | Table 1: The reported genus, and species of medicinal herbs used in traditional Chinese medicine that contain gentiopicroside, sweroside, swertiamarin or their combinations
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A total 53 of iridoids, secoiridoids, and analogs from 50 Gentianaceae exist in Chinese Materia Medica,[7] which include 29 iridoids and secoiridoids, and 24 analogs glycosides [Figure 1]. | Figure 1: All the structures of the studied compounds 29 iridoids, seco-iridoids and analogss for CYP3A4 and CYP2D6
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Secoiridoids are a type of monoterpenes that have the general form of cyclopentanopyran with one of the rings open as shown in [Figure 2]. Early tracer experiments using radio-labeled acetate and mevalonate had established the biosynthesis scheme of monoterpenes.[8],[9] The roots of Swertia caroliniensis Kuntze contain relatively abundant (about 2.5%) gentiopicroside.[8] The administration of radio labeled mevalonate (mevalonate-2-14C) through a cotton wick inserted in the stem of a Swertia plant shows the incorporation of radioactivity in gentiopicroside at a rate of 0.04%. Removal of the glucose moiety of the radiolabeled gentiopicroside reveals that all the radioactivity was presented in the aglucone, suggesting that a cyclopentanoid monoterpene may be a precursor for the biosynthesis of gentiopicroside in Swertia caroliniensis Kuntze.[8] It was concluded that gentiopicroside, a monoterpene is synthesized from mevalonate in Swertia caroliniensis Kuntze.[9] Originally, the secoiridoid synthesis was thought to be initiated from isoprenoid biosynthesis through mevalonate to geranyl pyrophosphate, which is then converted to monoterpene iridoid loganin.[13] Iridoid loganin will undergo ring cleavage to afford secoiridoid monoterpene.[13] | Figure 2: Original and generation of secoiridoids sweroside, swertiamarin and geniopicroside in plants. Starting from mevalonate, isoprenoid biosynthesis leads to the synthesis of oxogeranial, which is converted to iridoid loganin eventually. Loganin undergoes ring cleavage reaction to generate sweroside. Sweroside will be converted into swertiamarin, and then gentiopicroside. Gentiopicroside can be further modified to form indole alkaloids
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The secoirdoids mentioned here seem to be present in a variety of medicinal herbs that used in different cultures and geographic locations. This phenomenon indicates that these bioactive compounds in the medicinal herbs are responsible for the treatment activities of those plants. The function of a medicinal plant can be replaced by another one or other plants if the content and amount of the bioactive compounds are present. Interestingly, oleuropein, another secoiridoid synthesized in olives fruit, has been shown to attenuate the hepatic steatosis in mice fed a high-fat diet.[21] The oleuropein treatment reduces the expression levels of genes responsible for oxidative stress and pro-inflammatory cytokines.[8],[9] It will be interesting to compare the bioactive compounds in medicinal herbs that can be used to treat similar diseases, and identify the common one or more components for further analysis of their biological and pharmacological activities.
Another interesting point deserves to be noted is about the relationship between iridoids and secoiridoids. Iridoids, the precursors of secoiridoid biosynthesis,[9],[10], [11,[12],[13],[14] have some of the same activities discussed here. For example, loganin, an iridoid and the precursor of secoiridoids, at doses of 0.02 and 0.1 g/kg attenuates diabetic nephropathy in STZ-induced diabetic C57BL/6J mice.[8] In STZ-induced diabetic male SD rats, loganin at 5 mg/kg or 10 mg/kg (i. g.) attenuates the diabetic nephropathy through the reduction of connective tissue growth factor level, but does not reduce the blood glucose level.[9] The treatment of loganin extracted from Corni Fructus (20 or 100 mg/kg body weight/day, p. o.) for 8 weeks reduces the hepatic oxidative stress in db/db mice and blood glucose slightly in the 100 mg/kg group, showing its hepatic protective function.[10] If both iridoids and secoiridoids can have antidiabetic activities, there might be pathways responding to these monoterpenes in cells and animals. Further investigation of these pathways may help the prevention and treatment of diabetes and other metabolic diseases. In addition, whether any enzymatic system contributes to the conversion of iridoids to secoiridoids or vice versus in mammals is an interesting topic that deserves to be investigated.
| Pharmacokinetics of Gentiopicroside, Sweroside, and Swertiamarin | | |
Gentiopicroside
Studies are designed to determine the pharmacokinetic parameters of gentiopicroside or crude extract preparations containing significant amount of gentiopicroside using rabbits, rats or Beagle dogs as shown in [Table 2]. In studies using the pure gentiopicroside and rats, the values of the time to attain the maximum plasma concentration (Tmax) of two doses 50 mg/kg and 78.2 mg/kg are 0.25 and 0.57 h, and the maximum plasma concentration (Cmax) are 16.5 and 6.2 μg/ml in the blood, respectively.[46] These results are comparable to the one using total iridoid glucosides administrated similarly as described in.[47] These data indicate a quick absorption and achievement of sufficient concentration for therapeutic purposes. If administrated intravenously, the plasma concentration of gentiopicroside can achieve as high as 163.5 μg/ml in Beagle dogs receiving the pure compound[48] and 45 μg/ml in rats receiving a crude extract.[49],[50],[51],[52],[53] The presence of other components in the crude extracts seems to affect the Tmax, but not the Cmax as indicated in the studies comparing the gentiopicroside and extracts with equal amount of it.[54] Compared with gentiopicroside alone, as judged by the area under concentration-time curve values, studies demonstrate the marked variability in pharmacokinetics and bioavailability of the active component from different herbal preparations. In mice, a single intravenous administration can distribute gentiopicroside in tissues and organs to achieve concentrations with therapeutic effects.[55]
Metabolites of gentiopicroside have been detected in rat plasma after oral gavage.[56] Erythrocentaurin and gentiopicral, two metabolites of gentiopicroside, can reach 600 ng/ml and 150 ng/ml, respectively, after oral administration of gentiopicroside at a dose of 200 mg/kg.[57] The potential pathways leading to their productions have been proposed.[58] This observation was supported by another pharmacokinetic study using purified gentiopicroside.[47] Gentiopicroside and two of its metabolites can be detected after a single oral dose at 150 mg/kg in rats, showing the absorption and conversion in vivo.[50]
Fifteen catabolic products of gentiopicroside have also been identified in human urine, indicating their metabolism in human body.[59] Erythrocentaurin and gentiopicral can also be identified after gentiopicroside is incubated with strains of human intestinal bacteria.[60] Whether these bioactive compounds are absorbed first and modified by the hosts or modified in the gut by the bacteria first and then taken by the hosts remains to be studied.
Swertiamarin
Noncompartmental model method was successfully applied to determine the pharmacokinetic properties of swertiamarin in rats after an oral administration at a dose of 20 mg/kg. The following pharmacokinetic parameters are obtained (mean): Cmax 1.92 μg/mL; Tmax 0.95 h; T1/2 1.10 h; Cl 5.64 L/h/kg; and V 9.64 L/kg.[33] Swertiamarin shows rapid absorption and elimination, and its absolute bioavailability is low at 10.3%.[34] Some studies have also been designed to determine the pharmacokinetic parameters of swertiamarin from extracts or preparations using normal or pathological rats. The presence of other components in the administrated samples seems to affect the pharmacokinetic parameters of swertiamarin comparing with the swertiamarin alone.[31],[32],[33],[34]
Sweroside
The pharmacokinetics of sweroside is evaluated in rats. Sweroside could be eliminated quickly after oral (T1/2 64.34 min) and intravenous (T1/2 23.27 min) administration. The absolute bioavailability is estimated to be very low (0.31%). The lower oral bioavailability might be due to the first-pass metabolism and intestinal bacterial biotransformation.[11] A few studies have been designed to determine the pharmacokinetic parameters of sweroside from extracts or preparations in rats.[21],[31] The presence of other components in the administrated samples seems to affect the pharmacokinetic parameters of sweroside.[31]
After the intravenous administration of REDuNing, sweroside is mainly excreted in the urine without any modification. Its elimination half-time is 0.4 h with 0.7 h of mean residence time, indicating a short half-life.[35]
After a single dosage (10 mg/kg) by gavage, sweroside is distributed in the liver, kidney, spleen, lung and brain (possibly be able to cross the blood–brain barrier), indicating its potential targets.[35] It is mainly metabolized in the liver, whereas free form of sweroside still can be found in urine, feces, and bile.[35] Another study using much higher dosage of sweroside (500 mg/kg) only detected in rat plasma 30 min after a single oral administration, suggesting a low bioavailability.[36] In addition, a significant amount of free sweroside can be detected in bile indicating the role of hepatobiliary route for sweroside excretion.[36] When sweroside is administrated orally in rats, 11 metabolites can be identified.[37] Only 4 of those 11 metabolites can be attributed as direct metabolites of sweroside and the rest ones are considered hydrolytic products of gut microbiome.[37]
| Effects of Gentianaceae Herbs on Animals and Cells | | |
The uses of the aforementioned medicinal herbs in TCM have been described in Chinese Materia Medica,[7] which are summarized in [Table 3]. These medicinal herbs have been used to treat a variety of symptoms ranging from alleviating fever and pain to eliminating rheumatic arthralgia, etc. The processing methods and dosages vary depending on whether the herbs are used orally or topically. Some of these medicinal herbs have been studied using modern pharmacological means. The results indicate that they have analgesic, liver protective, anti-inflammatory, antiallergic, anti-pathogeny, and anti-bacterial functions. Whether all these actions are mediated by secoiridoids or not remain to be determined. Nevertheless, the effects of secoiridoids should not be over-looked. | Table 3: The clinical use, dosage and modern pharmacological studies of some of the Gentiana medicinal herbs used in traditional Chinese medicine as described in Chinese Materia Medica
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Antidiabetic effects
With the rise of number of diabetic patients, it has become urgent to look for any potential drugs from traditional medicinal herbs for the prevention and treatment of diabetes. Plants in Gentiana sect. Cruciata have been used in the Tibetan traditional folk medicine to treat a variety of symptoms that overlap with those being treated by Veratrilla baillonii Franch.[38] Both gentiopicroside and sweroside have been found in the roots of species belonging to Gentiana sect. Cruciata (Gentianaceae) also known as Qinjiao in TCM.[18] In addition, gentiopicroside, swertiamarin, and sweroside are also found in methanol extract of Swertia corymbosa, a plant in the family Gentianaceae and used in traditional medicine to treat diabetes in Indian.[39] In that study, the methanol extract of Swertia corymbosa has been shown to improve blood glucose levels in streptozotocin (STZ)-induced diabetic rats in a 28-day study, probably through the inhibition of α-glucosidase and α-amylase activities.[39] Our research results have shown the treatments of gentiopicroside, sweroside and a mixture of these two can cause phosphorylation of Akt and Erk in HL1C hepatoma cells,[8] demonstrating their abilities to cause changes of signal transduction pathways.
The ethanol and n-butanol extracts of Swertia macrosperma, a medicinal herb used in traditional folk medicine “Di da” in several southwestern provinces in China, also demonstrate activities to lower the plasma levels of glucose and triacylglycerols in STZ-induced diabetic rats, which is accompanied by the induction of glucokinase and reduction of glucose 6-phosphatase activities in the liver and improvement of morphology of pancreatic islets.[40] The ethanol extract of Swertia kouitchensis (called “Guizhou Zhangyacai,” “Shuihuanglian,” or “Silengcao”) has been shown to inhibit α-amylase and α-glucosidase.[41] This extract was effective to reduce blood glucose levels in STZ-induced diabetic mice.[41]
Plants in the genus anthocleista of the Gentianaceae family have been used for the treatment of diabetes.[42] Sweroside and gentianine are observed as components in some of those plants.[42] Furthermore, gentiopicroside and sweroside are identified in methanol extract of the milled aerial parts of the dried plant of Centaurium erythraea, which at 250 mg/kg body weight has been shown to reduce hyperglycemia and hyperlipidemia in STZ-induced diabetic rats.[43] Although in that study, the name of sweroside was typed as “sveroside” in the article.
Swertiamarin, isolated from Enicostemma littorale, has been shown to have antidiabetic activity.[44] Swertiamarin administrated orally at doses of 15, 25, and 50 mg/kg for 28 days reduced plasma glucose and lipid levels in STZ-induced diabetic rats with improvement of pancreatic β-cell regeneration.[44] The treatments of aqueous extract of E. littorale 1 g/kg, p. o. and swertiamarin 50 mg/kg, p. o. daily for 3 weeks improved diabetic nephropathy in STZ-induced diabetic rats.[45] In hyperglycemia rats induced by one administration of nicotinamide and STZ, swertiamarin at 50 mg/kg/day administrated orally for 40 days reduced plasma glucose and triacylglycerol levels.[46] Swertiamarin at 50 mg/kg/day administrated intraperitoneally for 6 weeks resulted in reduction of plasma triacylglycerol, and cholesterol and low-density lipoprotein levels in diabetic animals.[47] It seems that swertiamarin regulates both glucose and lipid metabolism in diabetic animals.
Liver protection effects
Among many Chinese herbal extracts with hepatoprotective activity, the extracts of gentian plants are hepatoprotective and uniquely advantageous in the prevention and rescue of liver injury.[12],[13] Monoterpenes, gentiopicroside, sweroside, and swertiamarin have been found in medicinal herbs that protect liver functions. Sweroside has been used in China to reduce serum alanine transaminase (ALT, glutamic pyruvic transaminase) in patients with hepatitis.[48]
Our laboratory recently investigated the potential effects of the material basis from gentian on acontine-induced hepatotoxicity in HepG2 cells and obtained metabolic data of drug-biotarget interactions. The docking scores of 53 components were calculated using computer-assisted docking simulation to determine the free energy of ligand-protein complexes. After comprehensive evaluation, six of those compounds, i.e., gentiopicroside, sweroside, swertiamarin, loganic acid, 6-O-β-D-glucosyl-gentiopicroside, and amarogentin were selected to evaluate their hepatoprotective effects. The result shows that amarogentin displays the most obvious inductive effect on CYP3A4 mRNA levels in HepG2 cells. The hepatoprotective effects are caused by facilitation of drug metabolism, amelioration of mitochondrial dysfunction, and reduction of oxidative stress.[49]
It has been shown that the methanol extracts of Gentiana cruciata L. aerial parts and roots, which contain high concentrations of sweroside and gentiopicrin (gentiopicroside), attenuates carbon tetrachloride-induced liver injury in Wistar rats.[50] At 400 mg/kg body weight, these methanol extracts completely normalize the elevated levels of serum aspartate aminotransferase aspartate transaminase, and alkaline phosphatase. The protective effects of these extracts are attributed to their antioxidative properties.[50] In addition, methanol extracts of Gentiana asclepiadea L. aerial parts and roots also exerted the same protective effects on tetrachloride-induced liver injury in Wistar rats.[51] These extracts also contained high concentrations of sweroside, and gentiopicroside.[51]
Swertiamarin (100 and 200 mg/kg, ig) attenuates hepatotoxicity induced by carbon tetrachloride treatment in rats.[52] Qing Ye Dan (200 and 100 mg/kg/d, ig), a Chinese herbal medicine derived from the whole plant of Swertia mileensis, and its main component, swertiamarin (16 mg/kg/d, ig), inhibit benign prostatic hyperplasia in rats.[53] This is mediated by the reduced expression levels of genes involved in inflammation and oxidative stress.[53] At 15 and 20 mg/kg, swertiamarin (ig) attenuates hepatic fibrosis in rats treated with dimethylnitrosamine.[54] This is through the swertiamarin-mediated inhibition of Ang II-induced proliferation and activation in hepatic stellate cells.[54]
In mice, two of the three protective activities of n-butanol extract of Swertia japonica Makino to D-galactosamine/lipopolysaccharide (LPS)-induced liver injury are attributed to gentiopicroside and sweroside in the plant, which works at the range of 25–50 mg/kg.[55] Gentiopicroside from Gentiana macrophylla Pall roots at 30–60 mg/kg/day has been shown to attenuate the chloroform- and LPS/bacillus Calmette-Guerin-induced liver injuries in mice.[56] Sweroside attenuates carbon tetrachloride-induced liver injury in mice.[57]
Gentianella turkestanerum contains significant amount of secoiridoid compounds (sweroside, swertiamarin, and gentiopicrin).[20] Its extracts protect the liver to toxicities induced by carbon tetrachloride in mice.[20] Sweroside (120 mg/kg/d, ig) protects cholestatic liver injury induced by α-naphthylisothiocyanate in mice through the attenuation of inflammatory responses.[58] Erythrocentaurin and gentiopicral, two derivatives of gentiopicroside aglucone after being treated with β-glucosidase, protect human embryonic hepatocytes (L02 cells) from cytotoxicity of hydrogen peroxide.[59]
Anti-inflammation effects
A TCM called Huo Luo Xiao Ling Dan is a mixture of 11 herbs, and has been used to treat experimental arthritis in rats.[60] The treatment of its extract at 2.3 g/kg for 23 days suppresses the arthritis development in rats.[61] In rat pharmacokinetic studies with extracts from the 11 herbs, T1/2 and Cmax are respectively 1.4 h and 5.8 mg/L for gentiopicroside, 2.7 h and 99 μg/L for swertiamarin, and 2.3 h and 14 μ/L for sweroside.[31] The methanol extract of Gentiana macrophylla Pall., one of the 11 herbs, contains gentiopicroside, sweroside and swertiamin, and demonstrates anti-inflammatory activities in rats and cultured cells.[17] The chloroform extract of Gentianae Scabrae Radix has been shown to have anti-inflammatory activity by inhibiting the interleukin-6 production in RAW264.7 cells treated with LPS.[62] The extract contains gentiopicroside and sweroside. Sweroside IC50 is 58 μM.[62]
The anti-inflammatory effect of gentiopicroside is not limited to the liver. Gentiopicroside (2.5 mg/kg i. p) reduces bleomycin-induced inflammation and fibrosis in mice.[63] The treatment of gentiopicroside (20, 40, and 80 mg/kg, ig) for 3 days significantly attenuates 70% ethanol-induced gastric mucosal injury in mice, which is probably through reductions of cytokines and oxidative stress.[64] The n-butanol fraction of ethanol extract of Gentiana macrophylla contains iridoid glycosides, mainly loganic acid, swertiamarin, gentiopicroside, and sweroside. This iridoid extract at 15 mg/kg or 30 mg/kg (ig) attenuates rheumatoid arthritis induced by intradermal injection of the complete bovine collagen Type II in male SD rats.[18] Gentiopicroside (200, 100, and 50 mg/kg, ig) once a day for 7 days reduces colitis induced by dextran sulfate sodium in mice through downregulation of inflammatory pathways.[65]
Smooth muscle movement
Gentiopicroside at 80 and 160 mg/kg has been shown to significantly induce the gastrointestinal motility in SD rats.[66] The amount of gentiopicroside can reach 2.73 and 3.99% in Gentianae scabrae radix.[67] On the other hand, chloroform/methanol (1/1) extract of Gentiana spathacea and the purified gentiopicroside from it inhibit the spontaneous contraction of isolated guinea-pig ileum and contraction induced by other compounds such as acetylcholine and histamine.[68] This shows the effects of gentiopicroside on the smooth muscle.
In cultured rat aortic smooth muscle cells, aqueous root extracts of Gentiana lutea plant at a concentration of 1 mg/ml are able to reduce the cell proliferation and nitric oxide production induced by platelet-derived growth factor (PDGF)-BB treatment.[69] This is attributed to isovitexin-mediated inhibition of Erk1/2 induced by PDGF-BB.[69] Gentiopicroside is also present in the extract.[69]
Antinociceptive activity
The methanol extract of Gentiana lutea ssp. symphyandra roots at 250 and 500 mg/kg administrated through the intraperitoneal route increases swimming endurance test and shows analgesic activity in mice.[70] The Gentiana lutea extract contains 10.5% and 0.9% w/w of gentiopicroside and sweroside, respectively.[70] Gentiopicroside has antinociceptive effects (50 and 100 mg/kg) through the changes of behaviors in mice and electrophysiological parameters in neurons.[71]
Antibacteria and virus
Gentiopicroside isolated from the methanol extract of Centaurium erythraea aerial parts has antibacterial activity with minimum inhibitory concentrations at about 0.006–0.1 mg/ml, and antioxidant activities.[72] In addition, antimicrobial activity of gentian tea preparations is attributed to gentiopicroside.[3] Gentiopicroside from gentian tea preparations inhibits bacterial growth, and relieves digestive discomfort in nomadic people of Siberia who only consume high-fat and protein foods.[3]
Gentiopicroside derivatives after the modification of its sugar moiety have demonstrated anti-influenza A/WSN/33(H1N1) virus activity in MDCK cells, but not anti-hepatitis C virus activity in pseudo particle entry assay using Huh-7 cells.[73] Sweroside is in Chinese herbal medicine, ReDuNing, used for the treatment of viral upper respiratory tract infections.[35]
Anti-cancer and others
Gentiopicroside is in Chinese medicinal preparation Sann-Joong-Kuey-Jian-Tang,[74] which has been shown to inhibit Hep-G2 human hepatoma cells growth.[75] Aqueous extract of Gentiana veitchiorum protects bleomycin-induced pulmonary injuries in rats.[19] Gentiana veitchiorum contains 1.97% gentiopicroside.[19] In HL-60 Human leukemia cells, sweroside extracted from Lonicera japonica induces apoptosis through the activation of caspase 3.[76] Gentiopicroside (50 mg/kg, i. p.) reduces the depressive behaviors induced by LPS in mice, which is due to the decrease of tryptophan degradation in the mouse brain.[77]
Swertiamarin at 2, 5, and 10 mg/kg (ig) attenuates bone erosion in rats with adjuvant induced arthritis.[78] This is attributed to the direct effects of swertiamarin on osteoclasts and osteoblasts.[79] Sweroside as a major component in Fructus Corni has been shown to promote growth of human MG-63 and rat osteoblast cells.[80],[81],[82],[83],[84],[85]
| Conclusion | | |
As reviewed in this paper, sweroside, swertiamarin, and gentiopicroside are produced sequentially in a variety of Gentianaceae herbs. Some activities of those medicinal herbs can be attributed to the presence of one, two, or three of them. These secoiridoids as a group of molecules with a unique molecular structure demonstrate biological or pharmacological activities in both in vivo and in vitro studies. These activities are mediated by various mechanisms ranging from signal transduction cascade to metabolic pathways.
With the rise of number of patients with diabetes and other metabolic diseases, more and more efforts will be devoted to find potential leads in medicinal herbs for the treatments of these diseases. We hope that our review here will bring some attention to secoiridoids, which may help the combat against those diseases.
Acknowledgments
We gratefully acknowledge financial support from Research project of the National Natural Science Foundation of China (No. 81873090 and 81374064) and the Fundamental Research Funds for the Central Universities, South-Central University for Nationalities (CZP20002).
Financial support and sponsorship
We gratefully acknowledge financial support from Research project of the National Natural Science Foundation of China (No. 81873090 and 81374064) and the Fundamental Research Funds for the Central Universities, South-Central University for Nationalities (CZP20002).
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Deng X, Wang P, Yuan H. Epidemiology, risk factors across the spectrum of age-related metabolic diseases. J Trace Elem Med Biol 2020;61:126497.  |
| 2. | Pan Y. Study for Gentiana rigescens Based on Fingerprints of Characteristic Ingredients. Master Thesis: Yunnan University of Chinese Traditional Medicine; 2015. p. 35-6. |
| 3. | Olennikov DN, Kashchenko NI, Chirikova NK, Tankhaeva LM. Iridoids and flavonoids of four siberian gentians: Chemical profile and gastric stimulatory effect. Molecules 2015;20:19172-88. |
| 4. | Liu C, Zhang YX, Liu Y, Chen YL, Fan G, Xiang L, et al. The textual criticism on resource, property and efficiency of Tibet medicine “Tida”. China J Chin Materia Med 2016;41:567-71. |
| 5. | He TN, Liu SW, Chen SL. New classified outline of the genus Swertia under the gentian family. Plant Diversity and resources 2013;35:386-92. |
| 6. | Huang XJ, Li J, Mei ZY, Chen G. Gentiopicroside and sweroside from Veratrilla baillonii Franch induced phosphorylation of Akt and suppressed Pck1 expression in hepatoma cells. Biochem Cell Biol 2016;30:270-99. |
| 7. | Editorial Board of the State Administration of Traditional Chinese Medicine. Chinese Materia Medica. 1 st ed. Shanghai: Shanghai Science and Technology Publishing House; 1999. |
| 8. | Coscia CJ, Guarnaccia R. Biosynthesis of gentiopicroside, a novel monoterpene. J Am Chem Soc 1967;89:1280-1. |
| 9. | Coscia CJ, Guarnaccia R, Botta L. Monoterpene biosynthesis. I. Occurrence and mevalonoid origin of gentiopicroside and loganic acid in Swertia caroliniensis. Biochemistry 1969;8:5036-43. |
| 10. | Horn MM, Drewes SE, Brown NJ, Munro OQ, Meyer JJ, Mathekga AD. Transformation of naturally-occurring 1,9-trans-9,5-cis sweroside to all trans sweroside during acetylation of sweroside aglycone. Phytochemistry 2001;57:51-6. |
| 11. | Chen QL, Zhang WJ. The progress in the study of the secoiridoids. World Phytomed (Chinese) 2003;18:58-63. |
| 12. | Zhou H. Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China. 9 th ed. Beijing: China Medical Science and Technology Press; 2010. p. 89-90. |
| 13. | Zhao ZL, Zhang JY, Jin H, Yang MQ, Yang WZ, Yang Y, et al. Species and ecological control of disease on cultivated Gentiana rigescens in Yunnan. Zhong Yao Cai 2012;35:6-11. |
| 14. | Caliş I, Rüegger H, Chun Z, Sticher O. Secoiridoid glucosides isolated from gentiana gelida. Planta Med 1990;56:406-9. |
| 15. | Amakura Y, Yoshimura M, Morimoto S, Yoshida T, Tada A, Ito Y, et al. Chromatographic evaluation and characterization of components of gentian root extract used as food additives. Chem Pharm Bull (Tokyo) 2016;64:78-82. |
| 16. | Canonica L, Pelizzoni F, Manitto P, Jommi G. Structure of gentiopicroside. Tetrahedron 1961;16:192-200. |
| 17. | Jia N, Li Y, Wu Y, Xi M, Hur G, Zhang X, et al. Comparison of the anti-inflammatory and analgesic effects of Gentiana macrophylla Pall. and Gentiana straminea Maxim., and identification of their active constituents. J Ethnopharmacol 2012;144:638-45. |
| 18. | Jia N, Chu W, Li Y, Ding L, Duan J, Cui J, et al. Iridoid glycosides from the flowers of Gentiana macrophylla Pall. ameliorate collagen-induced arthritis in rats. J Ethnopharmacol 2016;189:1-9. |
| 19. | Liang X, Tian Q, Wei Z, Liu F, Chen J, Zhao Y, et al. Effect of feining on bleomycin-induced pulmonary injuries in rats. J Ethnopharmacol 2011;134:971-6. |
| 20. | Yang J, Zhu D, Ju B, Jiang X, Hu J. Hepatoprotective effects of Gentianella turkestanerum extracts on acute liver injury induced by carbon tetrachloride in mice. Am J Transl Res 2017;9:569-79. |
| 21. | Duan B, Fang H, Chen J, Shang F, Li L, Wang F. Determination of contents of three Iridoid glycosides in Bai National Herb of Veratrilla baillonii Franch. J Chin Med Material 2014;37:1012-4. |
| 22. | Feng B, Zhu HY, Guan J, Hao CY, Dua JC, Gu JK. Comparative study on pharmacokinetics of gentiopicroside and gentianae radix extract in rats. J Chin Med Materials 2013;36:783-6. |
| 23. | Cui C, Tang Z, Guo D, Eng C, Ang B. Pharmacokinetics of gentiopicroside in total iridoid glucosides extracted from Gentiana macrophylla in rats. Chin J Exp Tradit Med Formulae 2012;18:176-9. |
| 24. | Feng YJ, Yang FZ, Guo WB, Gu Y, Sun JA. Study on pharmacokinetics studies of gentiopicroside in beagle dogs. Tradit Chin Drug Res Clin Pharmacol 2004;15:333-5. |
| 25. | Ye L, Jiang YX, Ma XQ, Li YQ, Gao YL. HPLC determination of gentiana gentiopicrin content and pharmacokinetic study. Ningxia Med J 2009;31:1113-4. |
| 26. | Wang CH, Wang ZT, Annie BW, White K, White C. Pharmacokinetics and tissue distribution of gentiopicroside following oral and intravenous administration in mice. Eur J Drug Metabol Pharmacokinet 2004;29:199-203. |
| 27. | Wang Z, Tang S, Jin Y, Zhang Y, Hattori M, Zhang H, et al. Two main metabolites of gentiopicroside detected in rat plasma by LC-TOF-MS following 2,4-dinitrophenylhydrazine derivatization. J Pharm Biomed Anal 2015;107:1-6. |
| 28. | Xiong K, Gao T, Zhang T, Wang Z, Han H. Simultaneous determination of gentiopicroside and its two active metabolites in rat plasma by LC-MS/MS and its application in pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci 2017;1065-1066:1-7. |
| 29. | Han H, Xiong AZ, He CY, Liu Q, Yang L, Wang ZT. Combination of UHPLC/Q-TOF-MS, NMR spectroscopy, and ECD calculation for screening and identification of reactive metabolites of gentiopicroside in humans. Anal Bioanal Chem 2014;406:1781-93. |
| 30. | Elsedawy AI, Hattori M, Kobashi K. Metabolism of gentiopicroside (gentiopicrin) by human intestinal bacteria. Chem Pharm Bull 1989;37:2435-7. |
| 31. | Wu Y, Ai Y, Wang F, Ma W, Bian Q, Lee DY, et al. Simultaneous determination of four secoiridoid and iridoid glycosides in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application to a comparative pharmacokinetic study. Biomed Chromatogr 2016;30:97-104. |
| 32. | Lu CM, Lin LC, Tsai TH. Determination and pharmacokinetic study of gentiopicroside, geniposide, baicalin, and swertiamarin in Chinese herbal formulae after oral administration in rats by LC-MS/MS. Molecules 2014;19:21560-78. |
| 33. | Bai MR, Na BG, Mujila LX. Pharmacokinetics study of swertiamain of mongolian medicine DIGEDA-4 decoction in acute liver lesion rat. Chin J Exp Tradit Med Formulae 2012;18:125-8. |
| 34. | Li S. Study on the transformation process of swertiamain in medicine to coumarins. J Jiangxi Univ Tradit Chin Med 2016;27:70-2. |
| 35. | Cheng C, Du F, Yu K, Xu F, Wang F, Li L, et al. Pharmacokinetics and disposition of circulating iridoids and organic acids in rats intravenously receiving reduning injection. Drug Metab Dispos Biol Fate Chem 2016;44:1853-8. |
| 36. | Luo YD, Chen J, Cao J, Wen XD, Li P. Determination of sweroside in rat plasma and bile for oral bioavailability and hepatobiliary excretion. Chem Pharm Bull 2009;57:79-83. |
| 37. | Han H, Zeng W, He C, Bligh SW, Liu Q, Yang L, et al. Characterization of metabolites of sweroside in rat urine using ultra-high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry and NMR spectroscopy. J Mass Spectrom 2014;49:1108-16. |
| 38. | Yang YB, Zhou J. Studies on the xanthones of Veratrilla baillonii Franch. I. Structures of veratriloside and veratrilogenin. Acta Pharma Sin 1980;15:625-9. |
| 39. | Mahendran G, Thamotharan G, Sengottuvelu S, Narmatha BV. Anti-diabetic activity of Swertia corymbosa (Griseb.) Wight ex C.B. Clarke aerial parts extract in streptozotocin induced diabetic rats. J Ethnopharm 2014;151:1175-83. |
| 40. | Wang YL, Xiao ZQ, Liu S, Wan LS, Yue YD, Zhang YT, et al. Antidiabetic effects of Swertia macrosperma extracts in diabetic rats. J Ethnopharmacol 2013;150:536-44. |
| 41. | Wan LS, Chen CP, Xiao ZQ, Wang YL, Min QX, Yue Y, et al. In vitro and in vivo anti-diabetic activity of Swertia kouitchensis extract. J Ethnopharm 2013;147:622-30. |
| 42. | Anyanwu GO, Nisar UR, Onyeneke CE, Rauf K. Medicinal plants of the genus Anthocleista-A review of their ethnobotany, phytochemistry and pharmacology. J Ethnopharm 2015;175:648-67. |
| 43. | Stefkov G, Miova B, Dinevska-Kjovkarovska S, Stanoeva JP, Stefova M, Petrusevska G, et al. Chemical characterization of Centaurium erythraea L. and its effects on carbohydrate and lipid metabolism in experimental diabetes. J Ethnopharm 2014;152:71-7. |
| 44. | Dhanavathy G. Immunohistochemistry, histopathology, and biomarker studies of swertiamarin, a secoiridoid glycoside, prevents and protects streptozotocin-induced b-cell damage in Wistar rat pancreas. J Endocrinol Invest 2015;38:669-84. |
| 45. | Sonawane RD, Vishwakarma SL, Lakshmi S, Rajani M, Padh H, Goyal RK. Amelioration of STZ-induced type 1 diabetic nephropathy by aqueous extract of Enicostemma littorale Blume and swertiamarin in rats. Mol Cell Biochem 2010;340:1-6. |
| 46. | Patel TP, Soni S, Parikh P, Gosai J, Chruvattil R, Gupta S. Swertiamarin: An active lead from Enicostemma littorale regulates hepatic and adipose tissue gene expression by targeting PPAR-g and improves insulin sensitivity in experimental NIDDM rat model. Evid Based Complement Alternat Med 2013;2013:358673-84. |
| 47. | Vaidya H, Prajapati A, Rajani M, Sudarsanam V, Padh H, Goyal RK. Beneficial effects of swertiamarin on dyslipidaemia in streptozotocin-induced type 2 diabetic rats. Phytother Res 2012;26:1259-61. |
| 48. | Zhou J. Bioactive glycosides from Chinese medicines. Mem Inst Oswaldo Cruz, Rio de Janeiro1991;86:231-4. |
| 49. | Dai K, Yi XJ, Huang XJ, Muhammad A, Li M, Li J. Hepatoprotective activity of iridoids, seco-iridoids and analogs glycosides from gentianaceae on HepG2 cells via CYP3A4 induction and mitochondrial pathway. Food Funct 2018;9:2673-83. |
| 50. | Mihailovic V, Katanic J, Misic D, Stankovic V, Mihailovic M, Uskokovic A, et al. Hepatoprotective effects of secoiridoid-rich extracts from Gentiana cruciata L. against carbon tetrachloride induced liver damage in rats. Food Funct 2014;5 1795-803. |
| 51. | Mihailovic V, Mihailovic M, Uskokovic A, Arambasic J, Misic D, Stankovic V, et al. Hepatoprotective effects of Gentiana asclepiadea L. extracts against carbon tetrachloride induced liver injury in rats. Food Chem Toxicol 2013;52:83-90. |
| 52. | Wu T, Li J, Li Y, Song H. Antioxidant and hepatoprotective effect of swertiamarin on carbon tetrachloride-induced hepatotoxicity via the Nrf2/HO-1 pathway. Cell Physiol Biochem 2017;41:2242-54. |
| 53. | Wu X, Gu Y, Li L. The anti-hyperplasia, anti-oxidative and anti-inflammatory properties of Qing Ye Dan and swertiamarin in testosterone-induced benign prostatic hyperplasia in rats. Toxicol Lett 2017;265:9-16. |
| 54. | Li S, Wang Q, Tao Y, Liu C. Swertiamarin attenuates experimental rat hepatic fibrosis by suppressing angiotensin II-Angiotensin Type 1 receptor-extracellular signal-regulated kinase signaling. J Pharmacol Exp Ther 2016;359:247-75. |
| 55. | Hase K, Li JF, Basnet PF, Xiong QF, Namba TF, Kadota S. Hepatoprotective principles of Swertia japonica Makino on D-galactosamine/lipopolysaccharide-induced liver injury in mice. Chem Pharm Bull 1998;29:1823-7. |
| 56. | Kondo Y, Takano F, Hojo H. Suppression of chemically and immunologically induced hepatic injuries by gentiopicroside in mice. Planta Med 1994;60:414-6. |
| 57. | Jie L, Yaping L, Klaassen CD. The effect of Chinese hepatoprotective medicines on experimental liver injury in mice. J Ethnopharmacol 1994;42:183-91. |
| 58. | Yang Q, Yang F, Gong J, Tang X, Wang G, Wang Z, et al. Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses. Acta Pharmacol Sin 2016;37:1218-28. |
| 59. | Zeng W, Han H, Tao Y, Yang L, Wang Z, Chen K. Identification of bio-active metabolites of gentiopicroside by UPLC/Q-TOF MS and NMR. Biomed Chromatogr 2013;27:1129-36. |
| 60. | Lao L, Fan AY, Zhang RX, Zhou A, Ma ZZ, Lee DY, et al. Anti-hyperalgesic and anti-inflammatory effects of the modified Chinese herbal formula Huo Luo Xiao Ling Dan (HLXL) in rats. Am J Chin Med 2006;34:833-44. |
| 61. | Zhang RX, Fan AY, Zhou AN, Moudgil KD, Ma ZZ, Lee DY, et al. Extract of the Chinese herbal formula Huo Luo Xiao Ling Dan inhibited adjuvant arthritis in rats. J Ethnopharmacol 2009;121:366-71. |
| 62. | He YM, Zhu S, Kazuma K, Kazuma KF, Zou KF, Cai SQ, et al. The anti-inflammatory secoiridoid glycosides from Gentianae scabrae Radix: The root and rhizome of Gentiana scabra. J Nat Med 2015;69:303-12. |
| 63. | Chen C, Wang Y, Wang Y, Cheng M, Yin J, Zhang X, et al. Gentiopicroside ameliorates bleomycin-induced pulmonary fibrosis in mice via inhibiting inflammatory and fibrotic process. Biochem Biophys Res Commun 2018;495:2396-403. |
| 64. | Yang Y, Wang Z, Zhang L, Yin B, Lv L, He J, et al. Protective effect of gentiopicroside from Gentiana macrophylla Pall. in ethanol-induced gastric mucosal injury in mice. Phytother Res 2017;32:259-66. |
| 65. | Niu YT, Zhao YP, Jiao YF, Zheng J, Yang WL, Zhou R, et al. Protective effect of gentiopicroside against dextran sodium sulfate induced colitis in mice. Int Immunopharmacol 2016;39:16-22. |
| 66. | Ruan M, Yu B, Xu L, Zhang L, Long J, Shen X. Attenuation of stress-induced gastrointestinal motility disorder by gentiopicroside, from Gentiana macrophylla Pall. Fitoterapia 2015;103:265-76. |
| 67. | Tanaka R, Hasebe Y, Nagatsu A. Application of quantitative 1H-NMR method to determination of gentiopicroside in Gentianae radix and Gentianae scabrae radix. J Nat Med 2014;68:630-5. |
| 68. | Rojas A, Bah M, Rojas JI, Gutiérrez DM. Smooth muscle relaxing activity of gentiopicroside isolated from Gentiana spathacea. Planta Med 2000;66:765-7. |
| 69. | Kesavan R, Potunuru UR, Nastasijevic BT, Joksic G, Dixit M. Inhibition of vascular smooth muscle cell proliferation by Gentiana lutea Root extracts. PLoS One 2013;8:e61393-406. |
| 70. | Öztürk N, Can Baser KH, Aydin S, Öztürk Y, Çali I. Effects of Gentiana lutea ssp. symphyandra on the central nervous system in mice. Phytother Res 2002;16:627-31. |
| 71. | Liu N, Li YX, Gong SS, Du J, Liu G, Jin SJ, et al. Antinociceptive effects of gentiopicroside on neuropathic pain induced by chronic constriction injury in mice: A behavioral and electrophysiological study. Can J Physiol Pharmacol 2016;94:769-78. |
| 72. | Kumarasamy Y, Nahar L, Sarker SD. Bioactivity of gentiopicroside from the aerial parts of Centaurium erythraea. Fitoterapia 2003;74:151-4. |
| 73. | Wu S, Yang L, Sun W, Si L, Xiao S, Wang Q, et al. synthesis and biological evaluation of gentiopicroside derivatives as potential antiviral inhibitors. Eur J Med Chem 2017;130:308-19. |
| 74. | Lin SJ, Tseng HH, Wen KC. Determination of gentiopicroside, mangiferin, palmatine, berberine, baicalin, wogonin and glycyrrhizin in the traditional Chinese medicinal preparation Sann-Joong-Kuey-Jian-Tang by high-performance liquid chromatography. J Chromatogr A 1996;730:1-7. |
| 75. | Chen YL, Yan MY, Chien SY. Sann-Joong-Kuey-Jian-Tang inhibits hepatocellular carcinoma Hep-G2 cell proliferation by increasing TNF-α, caspase-8, caspase-3 and Bax but by decreasing TCTP and Mcl-1 expression in vitro. Mol Med Rep 2013;7:1487-93. |
| 76. | Han XL, Li JD, Wang WL, Yang C, Li ZY. Sweroside eradicated leukemia cells and attenuated pathogenic processes in mice by inducing apoptosis. Biomed Pharmacother 2017;95:477-86. |
| 77. | Deng YT, Zhao MG, Xu TJ. Gentiopicroside abrogates lipopolysaccharide-induced depressive-like behavior in mice through tryptophan-degrading pathway. Metab Brain Dis 2018:33:1-8. |
| 78. | Hairul-Islam MI, Saravanan S, Thirugnanasambantham K, Chellappandian M, Simon Durai Raj C, Karikalan K, et al. Swertiamarin, a natural steroid, prevent bone erosion by modulating RANKL/RANK/OPG signaling. Int Immunopharmacol 2017;53:114-24. |
| 79. | Sun H, Li L, Zhang A, Zhang N, Lv H, Sun W, et al. Protective effects of sweroside on human MG-63 cells and rat osteoblasts. Fitoterapia 2013;84:174-9. |
| 80. | Alagna F, Geu-Flores F, Kries H, Panara F, Baldoni L, O'Connor SE, et al. Identification and characterization of the iridoid synthase involved in oleuropein biosynthesis in olive ( Olea europaea) Fruits. J Biol Chem 2016;291:5542-54. |
| 81. | Kim Y, Choi Y, Park T. Hepatoprotective effect of oleuropein in mice: Mechanisms uncovered by gene expression profiling. Biotechnol J 2010;5:950-60. |
| 82. | Park S, Choi Y, Um SJ, Yoon SK, Park T. Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice. J Hepatol 2011;54:984-93. |
| 83. | Liu K, Xu H, Lv G, Liu B, Lee MK, Lu C, et al. Loganin attenuates diabetic nephropathy in C57BL/6J mice with diabetes induced by streptozotocin and fed with diets containing high level of advanced glycation end products. Life Sci 2015;123:78-85. |
| 84. | Jiang WL, Zhang SP, Hou J, Zhu HB. Effect of loganin on experimental diabetic nephropathy. Phytomedicine 2012 19:217-22. |
| 85. | Park CH, Tanaka T, Kim JH, Cho EJ, Park JC, Shibahara N, et al. Hepato-protective effects of loganin, iridoid glycoside from Corni Fructus, against hyperglycemia-activated signaling pathway in liver of type 2 diabetic db/db mice. Toxicology 2011;290:14-21. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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