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Molecules 2017, 22(10), 1689; doi:10.3390/molecules22101689

Review
A Review on the Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology of Geniposide, a Natural Product
Mingqiu Shan 1,*Orcid, Sheng Yu 1, Hui Yan 1, Sheng Guo 1, Wei Xiao 2, Zhenzhong Wang 2, Li Zhang 1, Anwei Ding 1, Qinan Wu 1 and Sam Fong Yau Li 3
1
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China
2
National Key Laboratory of Pharmaceutical New Technology for Chinese Medicine, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang 222001, China
3
Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
*
Correspondence: Tel.: +86-025-8581-1519; Fax: +86-025-8581-1524
Received: 25 August 2017 / Accepted: 10 October 2017 / Published: 10 October 2017

Abstract

:
Iridoid glycosides are natural products occurring widely in many herbal plants. Geniposide (C17H24O10) is a well-known one, present in nearly 40 species belonging to various families, especially the Rubiaceae. Along with this herbal component, dozens of its natural derivatives have also been isolated and characterized by researchers. Furthermore, a large body of pharmacological evidence has proved the various biological activities of geniposide, such as anti-inflammatory, anti-oxidative, anti-diabetic, neuroprotective, hepatoprotective, cholagogic effects and so on. However, there have been some research articles on its toxicity in recent years. Therefore, this review paper aims to provide the researchers with a comprehensive profile of geniposide on its phytochemistry, pharmacology, pharmacokinetics and toxicology in order to highlight some present issues and future perspectives as well as to help us develop and utilize this iridoid glycoside more efficiently and safely.
Keywords:
geniposide; iridoid glycoside; natural product; pharmacokinetics; pharmacology; phytochemistry; toxicology

1. Introduction

Iridoid glycosides are phytochemicals which naturally occur in many plants belonging to the families Scrophulariaceae, Rubiaceae, Gentianaceae and Caprifoliaceae, including some Traditional Chinese Medicines (TCMs). Among them, geniposide (methyl (1S,4aS,7aS)-1-(β-d-gluco-pyranosyloxy)-7-(hydroxylmethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate; C17H24O10; GS; Figure 1) is particularly well known. In view of its chemical structure, this component is also considered as a glycoside consisting of one molecule each of genipin and glucose. To date, this natural product has been isolated and identified in nearly 40 plants, most of which are traditional phytomedicines and/or come from the family Rubiaceae. As far as bioactivities are concerned, GS exerts many pharmacological functions, including anti-inflammatory [1], antidiabetic [2], anti-oxidative [3], neuroprotective [4], hepatoprotective and choleretic effects [5]. GS is recorded as a characteristic component for the quality control of Gardenia jasminoides Ellis (G. jasminoides) fruits in the 2000–2015 editions of the Chinese Pharmacopoeia [6,7,8,9]. According to the national standard, this phytomedicine with a GS content above 1.8% could be considered as having adequate quality. Additionally, in the 2015 edition, GS as also listed as the quantitative component for quality evaluation of about twenty Chinese Patent Medicine preparations containing G. jasminoides fruits, such as Bazheng mixture, Longdan Xiegan pills, Qingkailing soft capsules, Niuhuang Shangqing soft capsules and Zhizi Jinhua pills [10]. On the other hand, in recent years, there have been many new findings on the hepatotoxicity and nephrotoxicity of the natural product [11,12], which may limit its usage as a candidate drug with good performance in some diseases.
Although a large number of studies on GS have been carried out and a considerable amount of relevant literature has been reported, a comprehensive review that provides a complete profile on the phytochemistry, pharmacology, pharmacokinetics and toxicology of the active component is still lacking. In the present study, with the help of some scientific search engines and databases, including Google Scholar, Web of Science, Pubmed and Chinese National Knowledge Infrastructure (CNKI), we summarize the recent research progress of the above aspects. In addition, some further studies and future perspectives were also proposed. We hope that this review would prove helpful to researchers to ensure that the GS will have an effective and safe application.

2. Sources

To our knowledge, researchers isolated and identified GS from Gardenia jasminoides forma grandiflora (Lour.) Makino as an iridoid glycoside-type natural product in the 1960s [13]. Since then, this compound has been found in nearly 40 plants, the majority of which belong to the Rubiaceae (Table 1). Some of the plants are famous phytomedicines that have been used in the clinic for thousands of years in China and Southeast Asia, such as G. jasminoides (Zhizi), Rehmannia glutinosa Libosch. (Dihuang), Eucommia ulmoides Oliv. (Duzhong) and Achyranthes bidentata Blume (Niuxi). Among them, G. jasminoides is a fundamental plant source of GS with a considerable content (3.3–8.56%) found in the fruits of dry weight (DW) [14]. This iridoid glycoside has been found and isolated from various parts of this phytomedicine, including leaves, flowers, fruits and tubers. Furthermore, there were also several varieties of the species G. jasminoides containing GS, including Gardenia jasminoides cv. fortuneana Hara, Gardenia jasminoides forma grandiflora (Lour.) Makino and Gardenia jasminoides var. radicans (Thunb.) Makino. There were also some studies on the GS contents in other herbal medicines from different production areas, which report various amounts such as 0.2035–0.4381% (DW) for Rehmannia glutinosa Libosch. roots [15], 0.0699–0.1135% (DW) for Scrophularia ningpoensis Hemsl. roots [16], and 0.0173–0.5811% (DW) for Eucommia ulmoides Oliv. barks [17].

3. Natural Derivatives

We know that approximately 90 derivatives have been found present in natural plants along with GS. Table 2 lists their names and Figure 2 shows the structures of the representative derivatives. The compounds listed here are all iridoid glycosides. Some are the substitution derivatives on the various positions of GS, such as geniposidic acid, scandoside and daphylloside. Some, including alpinoside, majoroside and monotropein, are derivatives of the structural isomers of GS with different double bond positions. Some are the biosynthetic products of GS, such as galioside, gardenoside, 6α-hydroxygeniposide and 6β-hydroxygeniposide [145].
As for its chemical structure, GS is regarded as an iridoid glycoside, namely genipin 1-O-β-d-glucopyranoside. From another point of view, this component is also regarded as a C11 methyl ester of geniposidic acid, which is a common derivative of GS found in Nature. Due to the bioactivities and high content in the phytomedicine, geniposidic acid was recorded as the chemical marker for the quality evaluation of Plantaginis Semen in the Chinese Pharmacopoeia [146]. Other derivatives commonly found in natural plants are 6α-hydroxygeniposide and 6β-hydroxygeniposide with their own derivatives. These two natural components are characterized by a α-OH or β-OH on the C6 position of GS. These hydroxyl groups and that on the C10 position are often esterified with some organic acids, such as acetic acid, ferulic acid, caffeic acid, cinnamic acid, succinic acid and p-coumaric acid. In addition, there are also some other derivatives with a C6–C7 double bond (e.g., gardenoside, galioside and monotropein) or a C8–C9 double bond (e.g., alpinoside and majoroside), which differ from the C7–C8 double bond of GS.
In terms of glycoside-moiety numbers, the above mentioned natural derivatives are mono-glycosides. Apart from these components, some diglycosides have also been discovered in the plants. For example, genipin gentiobioside is a diglycoside with a gentiobiose on the C1 position, while genipin isomaltoside has an isomaltose moiety on the C1 position. These two compounds are considered as 6′-O-β-d-glucosylgeniposide and 6′-O-α-d-glucosylgeniposide. The substitutions with different acids mentioned above are also found on the C6′ or C6′′ position of genipin gentiobioside. Furthermore, genipin 1,10-di-O-β-d-glucopyranoside is another diglycoside with two glucose molecules on C1 and C10, which is also known as 10-O-β-d-glucosylgeniposide.

4. Analytical Methods

Due to its higher separation efficiency, shorter analysis time and less sample consumption, liquid chromatography (LC) is considered as an accepted and effective analytical method to separate mixtures in the natural products research field. To determine the GS content in the different plant sources and medical preparations, high performance liquid chrpmatography (HPLC) or ultra performance liquid chromatography (UPLC) is usually employed, coupled with some detectors, such as an ultraviolet detector (HPLC-UV), diode array detector (HPLC-DAD) or evaporative light scattering detector (HPLC-ELSD) [9,10,14,147,148]. Since the GS content is much lower and some endogenous interfering substances are present in the plasma or other biological samples, a mass spectrometry detector (MSD) is much preferable, especially in multiple-reaction monitoring (MRM) mode when pharmacokinetic studies are involved [149,150,151].
Like HPLC, capillary electrophoresis (CE) is also characterized by high efficiency and high selectivity. Han et al. quantitatively analyzed GS along with other four phytochemicals in Rehmannia glutinosa Libosch. roots. Sodium borate (60 mM) was used as buffer solution (5% methanol, pH 9.5), the separation voltage was set at 20 kV, and the temperature was maintained at 20 °C [15]. Micellar electrokinetic chromatography (MEKC) is a CE mode used to separate either neutral or charged components. Along with other nine bioactive compounds, GS was successfully separated and determined in Eucommia ulmoides Oliv. barks by MEKC using 50 mM boric acid (pH 9.5) as the buffer solution, with 50 mM sodium dodecylsulfate and 4% 1-butanol [152].
Aside from the chromatographic methods mentioned above, the near-infrared spectroscopy (NIRS) technique has also been used for quantitative analysis of GS in Gardenia jasminoides Ellis fruits with a partial least squares (PLS) method in the spectral regions of 8660–7500 cm−1, 6650–5600 cm−1 and 4900–4000 cm−1 [153].

5. Pharmacology

With the rapid development of modern pharmacology, an increasing amount of evidence has emerged for the multiple bioactive functions of GS, including its anti-inflammatory, antitumor, anti-oxidative, neuroprotective, hepatoprotective and cholagogic effects.

5.1. Hepatoprotective and Cholagogic Effects

As a major component in G. jasminoides fruits, GS also has a hepatoprotective effect similar to the phytomedicine and has been considered as a potential drug for liver diseases. After a CCl4 challenge in mice in vivo, serum levels of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) increased markedly, while in the liver homogenate, the level of glutathione (GSH) and activity of antioxidant enzymes (SOD and CAT) decreased significantly. Furthermore, deformability, irregular arrangement and rupture of hepatocytes were observed in the liver. These biochemical parameters and histopathological examination results indicated liver damage, which were all ameliorated by a peroral GS treatment of 400 mg/kg [154]. In terms of liver damage induced by Tripterygium glycosides, GS (i.g.; 20, 40, 80 mg/kg) also had protective effects in vivo, which may be involved in alleviating oxidative stress and inflammationin in addition to facilitating tissue repair and regeneration [155]. Furthermore, GS (i.g.; 20, 40, 80 mg/kg) could ameliorate alcohol-induced oxidative stress damage in the liver in vivo through upregulating the expression of the main antioxidant enzymes, including GSH, glutathione-S-transferase (GST), glutathione peroxidase (GPx), copper-and zinc-containing superoxide dismutase (CuZn-SOD) as well as catalase (CAT) [156]. Liver fibrosis is known to cause the destruction of the hepatic parenchyma and the liver structure. GS (20 μM) was able to inhibit epithelial-mesenchymal transition (EMT), which was induced by transforming growth factor β1 (TGF-β1) in hepatic fibrosis. This in vitro effect may be related to the inhibition of the TGFβ/Smad and external signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathways [157].
The homeostasis of bile acids between uptake, efflux and biosynthesis is essential. Once the balance is broken, cholestasis will occur and result in damage to the liver. In a related pharmacological investigation, α-naphthylisothiocyanate (ANIT)-induced rats were used to characterize the effect of GS on this disorder. Subsequently, associated with some regulation of enzymes and transporters contributing to the homeostasis of bile acids, such as organic anion transporting polypeptide 2, bile acids export pump and organic solute transporter β, the active component (i.g.; 25, 50, 100 mg/kg) was observed to reduce the uptake and biosynthesis of bile acids; to increase canalicular secretion; and to downregulate bile acids in plasma in vivo [5]. In another study, GS of 50 mg/kg (i.g.) also inhibited ANIT-induced cholestasis and liver damage in ICR mice in vivo, which was related to the downregulation of signal transducers and activators of transcription-3 (STAT3) and nuclear factor-κB (NF-κB) signaling [158].

5.2. Anti-Inflammation

In an anti-inflammatory study, the mouse mastitis model and the primary mouse mammary epithelial cells, both induced by lipopolysaccharide (LPS), were used to investigate the anti-mastitis effect of GS. The results suggested that GS (2.5, 5, 10 mg/kg in vivo; 25, 50, 100 μg/mL in vitro) could alleviate mammary gland apoptosis through the modulation of Toll-like receptor 4 (TLR4) and apoptosis-related factors, such as p53, Bax, BcI-2 and Caspase-3 [159]. In another study in vivo, 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rat ulcerative colitis and LPS-infected Caco-2 cells were employed to evaluate the anti-inflammatory effect of GS. As a result, the iridoid glycoside was found to regulate abnormal NF-κB, cyclooxygenase-2, inducible nitric oxide synthase (iNOS), myosin light chain kinase (MLCK) protein expression and tight junction protein (occludin and zonula occludens-1) expression; as well as activating 5’-AMP-activated protein kinase (AMPK) phosphorylation. It was concluded that GS (i.g.; 25, 50 mg/kg) could ameliorate inflammation and modulate barrier dysfunction via the activation of the AMPK pathway [1].
As for acute lung injury (ALI), GS also showed good protective effect performance. In LPS-induced ALI mice in vivo, the natural product (i.p.; 20, 40, 80 mg/kg) inhibited the pathological changes in lung tissue, including alveolar wall changes, alveolar hemorrhage and neutrophil infiltration; reduced inflammatory cells and total protein concentration in the bronchoalveolar lavage fluid; and finally regulated inflammatory mediators, such as tumor necrosis factor-α (TNF-α), IL-6 and IL-10 [160].

5.3. Anti-Diabetic Effect

In China, as early as in the Tang Dynasty, G. jasminoides fruits were used in the clinic for treatment of “Xiaoke” (Type 2 diabetes), which was recorded in “Yaoxinglun”, a famous book on herbal medicines. In the early 1980s, Japanese researchers led by Kimura first revealed that GS derived from G. jasminoides fruits exhibited hypoglycemic actions in high sugar diet-fed rats in vivo at the dose of 100 and 300 mg/kg (i.g.) [161]. From then on, many studies have been carried out to examine this mechanism of action. In an in vitro study of HepG2 cells, GS (10, 100 μM) was found to suppress hepatic glucose production through activating AMPK, acetylcoenzyme A synthetase (ACC) and forkhead box class O1 (FoxO1) phosphorylation in addition to inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activities. The effects mentioned were related with the AMPK FoxO1 pathway to some extent, indicating the function of inhibiting hepatic gluconeogenesis in Type 2 diabetes [162]. Renal pathology is a common complication in diabetic patients. The levels of serum creatinine, blood urea nitrogen and urinary albumin are usually used to evaluate renal function. These indexes increased in streptozotocin-induced diabetic rats, which indicated renal dysfunction. Significant glomerular basement membrane thickening was also observed by histological examination. In the model rats pretreated with GS (i.g.; 50, 100 mg/kg), the abnormal structural and functional changes of kidney were all attenuated. The in vivo effects were concluded associated with an inhibition of NF-κB-mediated inflammatory response [163].
GS (10 μM) was shown to activate glucagon-like peptide 1 receptor (GLP-1R) and to improve glucose-stimulated insulin secretion (GSIS) in INS-1 pancreatic β cells in vitro [164]. The effect was found to be counteracted by preincubation with an inhibitor of phosphatidylinositol 3-phosphate kinase (PI3K), which suggested that a PI3K-dependent mechanism was perhaps involved and mediated with an increase of glucose transporter 2 (GLUT2) protein levels [165]. GS (10 μM) also exhibited the prevention in vitro against INS-1 cell damage induced by high-glucose through increasing heme oxygenase-1 (HO-1) and Bcl-2 protein levels; decreasing Bax protein level; as well as preventing caspase-3 cleavage. The findings indicated that AMPK played a fundamental role in the prevention of cell damage, which was confirmed by the effects of preincubation with an AMPK inhibitor and an AMPK activator [166]. Furthermore, GS of the same concentration as above could accelerate thioredoxin-interacting protein (Txnip) degradation in INS-1 pancreatic β-cells in vitro with high glucose (25 mM) treatment [167].

5.4. Neuroprotection

Synaptic and mitochondrial dysfunctions are commonly seen in the early stage of Alzheimer’s disease (AD). Amyloid-β (Aβ1–42) is able to induce axonal mitochondrial abnormalities and synaptic damage in cultured hippocampal neurons and model mice with AD. GS treatment (12.5, 25, 50 mg/kg in vivo, 2.5, 5, 10 μM in vitro) demonstrated the protection against the above dysfunction through attenuating axonal mitochondrial fragmentation, trafficking impairments and reactive oxygen species (ROS) elevation; protecting synaptic loss, abnormal spine density and morphology; and ameliorating the decrease in synapse-related proteins. The findings indicated GS as a potential drug to cease and prevent the early progression of AD [168].
A large body of evidence has shown that streptozotocin (STZ) is able to induce sporadic AD. However, intracerebral-ventricular (ICV) injection of GS (50 μM) was shown in vivo to prevent spatial learning deficit and tau phosphorylation in order to facilitate GSK3β (pS-9) expression and inhibit GSK3β (pY-216) expression, which were all induced by STZ. In terms of STZ-induced neural pathology, the active component could avert paired helical filament-like structures, vesicles accumulation in synaptic terminals, endoplasmic reticulum abnormalities and early stages of apoptosis [169]. In addition, GS could reduce Aβ production in addition to attenuating the corresponding neurotoxicity in neurons (10 μM) in vitro and amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice in vivo (i.g.; 40 mg/kg). As for the protective mechanism, the iridoid glycoside could induce the phosphorylation of Janus kinase 2 (JAK2) in addition to the signal transducers and activators of transcription 3 (STAT3). Furthermore, this glycoside can regulate the expression level of α- and β-secretase, which may be mediated with leptin signaling [170]. Furthermore, Aβ accumulation and cholinergic defects are considered to be related with learning and memory impairments. In cultured primary hippocampal neurons of middle-aged Alzheimer’s model mice in vivo, GS (i.p.; 12.5, 25, 50 mg/kg) inhibited the toxic effect of cholinergic deficits through increasing choline acetyltransferase (ChAT) activity and decreasing acetylcholinesterase (AChE) activity [4].

5.5. Immunomodulation

It is well known that rheumatoid arthritis (RA) is a chronic systemic disease and its pathogenesis is related to the imbalance of cellular and humoral immunity. In RA rats in vivo, GS (i.g.; 33, 66, 132 mg/kg) was observed to improve the cell proliferation of mesenteric lymph node lymphocytes (MLNLs); to decrease IL-6 and IL-17; to increase IL-4 and TGF-β1; and to attenuate histopathological changes. The rapidly accelerated fibrosarcoma/mitogen activated protein kinase kinase/extracellular signal-regulated kinase1/2(Raf/MEK/ERK 1/2) signaling pathway in MLNLs is considered to be involved in the mechanism of this bioactivity [171]. Allergic asthma, which is related to immune responses, is considered as a chronic inflammatory disease to the respiratory system with the cardinal pathophysiological symptoms, such as airway hyperresponsiveness, bronchoalveolar lavage eosinophilia, mucus hypersecretion;as well as increased levels of T-helper-2-associated cytokines, chemokines and serum ovalbumin (OVA)-specific immunoglobulin E (IgE). These changes were all found in OVA-challenged BALB/c mice. The pathological changes in vivo were attenuated by intraperitoneal injections of GS (80 mg/kg) and the effects were comparable to dexamethasone, a well-known anti-asthma drug [172].

5.6. Anti-Tumor

Irradiation at a low dosage is a reliable strategy to treat tumors although it can destroy the hematopoietic organs, including spleen, thymus and bone marrow, at high doses. Hsu et al. found that GS (i.p.; 500 mg/kg) was able to reduce undesirable damages of sub-lethal radiation to the hematologic tissue in vivo, which was beneficial to preventing tumors in the hematologic system [173]. Pretreatment of GS (0.2 or 1.0 μM) could also inhibit H2O2 and myeloperoxidase formation caused by 12-O-tetradecanoylphorbol-13-acetate (TPA) in addition to inhibiting TPA-induced skin tumor in female CD-1 mice in vivo [174].

5.7. Effects on Cardiocerebrovascular Diseases

Brain microvascular endothelial cell (BMEC) with oxygen–glucose deprivation (OGD) was a common model of cerebral ischemia in vitro. After the OGD challenge, the mRNA and protein expression of P2Y14 were upregulated. However, GS (33.2 μg/mL) in vivo was able to alleviate the abnormal tendency by suppressing the phosphorylation of RAF-1, mitogen activated protein kinase kinase1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2); as well as declining the productions of IL-8, IL-1β and monocyte chemotactic protein 1 (MCP-1). The findings proved the potential of GS in treating cerebral ischemia in clinics [175]. Furthermore, GS (i.g.; 100 mg/kg) was proved to protect against atherosclerosis in vivo through inhibiting the development of atherosclerotic lesions; increasing Wnt1; decreasing dickkopf-related protein-1(DKK1) and NF-κB expression; reducing serum total cholesterol and low-density lipoprotein levels; and elevating the ratio of Wnt1/DKK1. Therefore, it was concluded that the protection of GS against atherosclerotic lesions were associated with enhancing Wnt1 and inhibiting DKK1 expression [176]. Another study on atherosclerosis was carried out in apolipoprotein E knockout (APOE-/-) mice. The findings indicated that GS (i.g.; 100 mg/kg) could promote the number and function of T-regulatory cells; in addition to decreasing plaque areas in the aorta, total cholesterol and low-density lipoprotein cholesterol in the serum, which contributed to stop the progression of atherosclerotic lesions in vivo [177].
As an agonist of GLP-1 receptor [164,178], GS also exerted inhibitory effects in cardiac hypertrophy. In mice with constriction of the transverse aorta, a functional decline in the heart was observed with a decrease in ejection fraction and fractional shortening, while the left ventricularinternal diastolic diameter increased significantly. All these morphological changes could be attenuated by GS treatment. In addition, the iridoid glycoside (i.g.; 25, 50 mg/kg) in vivo activated AMPKα and inhibited mTOR, ERK and ER stress in hypertrophic heart and in H9c2 cardiomyocytes. The protection and activation was mediated with GLP-1 receptor through the experiments of GLP-1 knockdown and blockade [179].

5.8. Other Effects

Apart from the actions mentioned above, GS also exhibited other effects, including anti-allergic, anti-depressive, anti-hyperuricemic, anti-oxidative and anti-thrombotic effects, which are shown in Table 3 [180,181,182,183,184,185,186,187].

6. Pharmacokinetics

With the rapid development in pharmacokinetics and further studies examining TCMs, an increasing amount of attention has been paid to natural products, especially bioactive ones, including GS.

6.1. Absorption

It is well known that the bioavailability of the drug can vary with different administration methods and GS is not an exception. To compare the bioavailabilities of GS, some Sprague Dawley (SD) rats were administered with this natural compound intragastrically (i.g.; 50 mg/kg), intramuscularly (i.m.; 8 mg/kg) and intranasally (i.n.; 8 mg/kg). The results demonstrated that the order of absolute bioavailability is i.m. (72.69%) > i.n. (49.54%) > i.g. (9.74%) [188]. GS was also found to penetrate the skin both in vivo and in vitro, allowing it to be quickly distributed in the subcutaneous tissue and blood after use of Shangyi Aerosol in mice [189]. To study the absorption mechanism of GS in Huanglian Jiedu Decoction, in vivo experiments and in vitro investigations, including intestinal perfusion and Caco-2 models, have been conducted. The results indicated that the GS absorption could be promoted by other co-existing compounds in the Chinese formula. In addition, GS was proved to be mainly absorbed by passive diffusion and to be a potential substance of P-glycoprotein in intestinal perfusion and Caco-2 models [151].

6.2. Distribution

In regard to tissue distribution after oral administration, the AUC0→4h values of GS were calculated as the order of kidney > spleen > liver > heart > lung > brain [150].

6.3. Metabolism

In a metabolic profile experiment, normal male SD rats were orally administrated with GS at the dosage of 350 mg/kg. As a result, 33 metabolites were found and identified. Among them, there were 17, 31, six, 12, three, six, 12 and six metabolites detected in the plasma, urine, heart, liver, spleen, lung, kidney and brain, respectively. It was concluded that one fundamental metabolic pathway involved the hydrolysis of the hydroxyl groups on C-1, while the other was related with demethylation, methylation, cysteine conjugation, glycosylation and glucuronide conjugation [190]. In another study on the male rats with adjuvant arthritis, GS and the four metabolites, genipin (G1), the mono-glucuronide conjugate of genipin (G2), a cysteine conjugate ring-opened genipin (G3), an oxidation of G3 (G4) were detected and identified: GS, G1 and G2 in plasma; GS and G1 in mesenteric lymph node; only GS in liver and synovium; GS, G1, G3 and G4 in spleen; in addition to GS, G1, G2 and G3 in urine [191].
From the results of a pharmacokinetics study of GS, Cmax was assayed as 0.68 ± 0.29 μg/mL at 0.44 ± 0.13 h and area under curve (AUC) was 1.46 ± 0.37 μg·h/mL [149]. To study the influence of gender on the pharmacokinetics of this natural product from Eucommia ulmoides Oliv. barks, some female and male rats were treated intragastrically with the extract of the plant. The pharmacokinetic parameters AUC0→t, AUC0→∞, Cmax, MRT0→∞ and T1/2 were quite different between the two sexes. It was observed that absorption was increased while the distribution and elimination were decreased in male rats compared with female rats, which showed gender influence on the metabolism of GS [192].
Apart from the pharmacokinetic study of GS alone in healthy rats, analogous studies of GS from some extracts or prescriptions in the model rats have been carried out. After the rats in the healthy group as well as Type 1 and Type 2 diabetic groups were orally administered with G. jasminoides extract, a longer Tmax, increased Cmax, MRT0→∞, AUC and decreased CL were observed in both diabetic groups while the values of T1/2 were similar among the three groups [193]. After i.v. infection of Reduning in the rats, the plasma concentration of GS reached its maximum around the administration time, before decreasing rapidly. The iridoid glycoside was eliminated quickly with a lower T1/2 (0.75 ± 0.04 h) [194].

6.4. Excretion

The excretion kinetics of GS was investigated with its concentration in urine. As for the volunteers in a clinic trial, the cumulative excretion amount of GS reached 70% as the prototype within 10 h after i.v. Naoxuening Injection. It was concluded that the majority of excretion of GS in human was via urine [195].

7. Toxicology

Although GS exerts many diverse biological activities, there are some studies examining its toxicity, which should be focused on by researchers. Hepatotoxicity was considered as the most fundamental issue of GS safety. An acute toxic study in rats revealed that GS of 574 mg/kg or above would result in hepatotoxicity associated with oxidative stress 24–48 h after oral administration. However, GS of 24.3 mg/kg or less would not cause hepatotoxicity even in the study of consecutive 90 days by oral administration [11]. As for the administration routes of GS, intranasal treatment was resulted in less hepatotoxicity than intravenous, intragastrical or intramuscular treatments [196]. The rats treated with GS had obvious hepatotoxicity, which did not show any significant differences between the SD rats and the Wistar rats of different ages. On the other hand, there was no obvious hepatotoxicity induced in the ICR mice [197].
Apart from the toxicity in normal rats, GS showed hepatotoxicity and nephrotoxicity in the rats with jaundice induced by ANIT. Alanine aminotransferase (ALT), aspartic transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), blood urea nitrogen (BUN) and creatinine (CREA) activities in serum were increased after the model rats were treated with GS of 1.2 g/kg (i.g.). In addition, serious pathological damages in the liver and kidney of these rats were observed [12].

8. Conclusions and Future Perspectives

With the idea of “back to Nature”, the traditional phytomedicines and natural products have drawn attention from the field of medicine. As a traditional phytomedicine in East Asia, G. jasminoides fruits have been employed to “purge fire to relieve vexation, clear heart and drain dampness in addition to cooling the blood to remove toxins” in clinics for thousands of years. Since GS was first isolated in this herbal plant, a considerable number of scientists and researchers have started to focus on this active iridoid glycoside.
To our knowledge, the content of GS varies in the different plants and even in different parts of the same plant. To successfully perform pharmacological, toxicological and pharmacokinetic studies, it is necessary to prepare a considerable amount of this iridoid glycoside. Therefore, extraction–isolation–purification is the common and inevitable procedure to obtain the active compound. The following are the necessary aspects that researchers would have to consider in the further studies: (1) High efficiency is important in order to obtain a relatively high content and relatively low cost. Therefore, many plant origins and their parts will be tested to find the optimal ones for GS preparation; (2) It is important to save resources and making full use of them to avoid waste is preferable. For example, we should try to search for some other valuable extracts or natural compounds as byproducts when preparing GS from one plant or otherwise; (3) It is important to be environmentally friendly. During the preparation procedure of GS, we should choose less toxic or non-toxic solvents to reduce pollution as far as possible, which requires screening of preparation methods.
In some studies of different bioactivities, GS was proved as a GLP-1 receptor agonist to stimulate insulin secretion in pancreatic β-cells [2], exhibit antinociception [178] and protect against cardiac hypertrophy [179]. Apart from the abovementioned effects, GLP-1 was also found: (1) to decelerate gastric emptying by suppressing the gastrointestinal peristalsis and gastricacidsecretion [198]; (2) to increase intracellular cyclic adenosine monophosphate (cAMP) content, to accelerate calcium influx, to decrease the pyruvic acid content of the myocardium and to inhibit cardiomyocyte apoptosis [199,200,201]; and (3) to reduce the damage caused by stroke [202]. Nevertheless, few articles of GS have examined these physiological functions. Is GS able to show effects on the gastrointestinal system, cardiovascular system and nervous system through such mechanisms? It is worth investigating for the pharmacological researchers and the results may extend the range of GS bioactivities.
On the other hand, there has been concern about the potential toxicity of GS. It has even been used to induce liver damage in mouse models [203]. Despite needing to remain cautious regarding toxicity during the drug research and development stage, it is important to consider the contributing factors to this toxicity. Dosage may be one obvious issue. In the studies on GS toxicity, the experimental animals were often administered orally with this natural compound at several hundred mg/kg, which was several times the dosage used for disease treatment. Furthermore, it was reported that low-dose GS would not induce acute toxicity (28 mg/kg) [203] or chronic toxicity (24.3 mg/kg) [11]. Meanwhile, we also found that present pharmacological experiments were performed on model animals while the toxicological experiments were carried out on normal animals. Sometimes, the effective dosage in one pharmacological study was found to overlap the toxic dosage in another toxicological study. However, as we have known, the responses stimulated by the same dosage on model animals and normal ones are obviously different. Essentially, toxic experiments in the future should be also carried out in model animals, which could accurately reflect the actual situation of disease treatments. For each indication, it is better to try several dosages to determine either the effective dosage or the toxic dosage. Thus, the therapeutic window of the disease could be confirmed and the active compound could be employed safely. The next problem to resolve would be finding out which compounds are toxic in vivo after GS administration. As an iridoid glycoside with low bioavailability, GS converts into some metabolites in vivo, among which genipin, the aglycone of GS, is the primary one and has been proposed as the toxic compound. Nevertheless, this theory lacks enough support, especially from pharmacokinetic study on model animals at toxic dosages of GS. We also speculated that there may be significant differences between the pharmacokinetic profiles at high (toxic) dosage and low (therapeutic) dosages, which probably provides some clues of the toxic metabolites. Therefore, it is important to carry out the comprehensive absorption–distribution–metabolism–excretion–toxicity studies on both models and normal animals at different doses of GS with various administrations, with which we could explain the reason of inducing toxicity explicitly. On the other hand, the systematic structure–activity relationship (SAR) studies of GS derivatives should be included in the future with actual screening trials and virtual computer designs, which will guide the subsequent structural modification. With the findings, the effects of GS may be improved through increasing the bioavailability, reducing the toxicity and changing the solubility.
Taken together, as a bioactive natural product, GS may be developed as a candidate drug or a lead compound. However, a considerable amount of studies are still required. In this review, we have summarized the research on GS in various research fields in the recent years covering its phytochemistry, pharmacology, pharmacokinetics and toxicology. In spite of these valuable findings, some problems still remain unresolved, which have been proposed here and demand prompt solutions. There will be many interesting directions of this iridoid glycoside for either fundamental research or study of applications. Therefore, this paper will provide valuable background information to the researchers who are either interested in thorough investigation of the bioactivity of GS or to develop effective therapies based on this natural product.

Acknowledgments

This study work was financially supported by Traditional Chinese Medicine Standardization Project of State Administration of Traditional Chinese Medicine (ZYBZH-C-JS-31), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD-2014), Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (TAPP-PPZY2015A070), and the Key Research Project of Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization (ZDXM-1-3).

Author Contributions

Mingqiu Shan, Wei Xiao, Qinan Wu and Anwei Ding designed the paper. Hui Yan and Sheng Guo collected literature on the phytochemistry. Li Zhang and Mingqiu Shan collected literature on the pharmacology. Sheng Yu and Zhenzhong Wang collected literature on the pharmacokinetics and toxicology. Mingqiu Shan wrote the paper. Sam Fong Yau Li provided some suggestions and modifications on the language in the paper.

Conflicts of Interest

All the authors declare no conflict of interest.

References

  1. Xu, B.; Li, Y.L.; Xu, M.; Yu, C.C.; Lian, M.Q.; Tang, Z.Y.; Li, C.X.; Lin, Y. Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function. Acta Pharmacol. Sin. 2017, 38, 688–698. [Google Scholar] [CrossRef] [PubMed]
  2. Zhang, Y.; Ding, Y.Q.; Zhong, X.Q.; Guo, Q.; Wang, H.; Gao, J.Y.; Bai, T.; Ren, L.L.; Guo, Y.Y.; Jiao, X.Y.; et al. Geniposide acutely stimulates insulin secretion in pancreatic beta-cells by regulating GLP-1 receptor/cAMP signaling and ion channels. Mol. Cell. Endocrinol. 2016, 430, 89–96. [Google Scholar] [CrossRef] [PubMed]
  3. Liu, J.H.; Yin, F.; Zheng, X.X.; Jing, J.J.; Hu, Y.H. Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway. Neurochem. Int. 2007, 51, 361–369. [Google Scholar] [CrossRef] [PubMed]
  4. Zhao, C.H.; Zhang, H.J.; Li, H.; Lv, C.; Liu, X.L.; Li, Z.; Xin, W.F.; Wang, Y.Y.; Zhang, W.S. Geniposide ameliorates cognitive deficits by attenuating the cholinergic defect and amyloidosis in middle-aged Alzheimer model mice. Neuropharmacology 2017, 116, 18–29. [Google Scholar] [CrossRef] [PubMed]
  5. Wang, L.L.; Wu, G.X.; Wu, F.H.; Jiang, N.; Lin, Y.N. Geniposide attenuates ANIT-induced cholestasis through regulation of transporters and enzymes involved in bile acids homeostasis in rats. J. Ethnopharmacol. 2017, 196, 178–185. [Google Scholar] [CrossRef] [PubMed]
  6. Chinese Pharmacopeia Commission. Pharmacopoeia of the People’s Republic of China; Chemical Industry Press: Beijing, China, 2000; Volume 1, p. 201. [Google Scholar]
  7. Chinese Pharmacopeia Commission. Pharmacopoeia of the People’s Republic of China; Chemical Industry Press: Beijing, China, 2005; Volume 1, p. 173. [Google Scholar]
  8. Chinese Pharmacopeia Commission. Pharmacopoeia of the People’s Republic of China; Chinese Medical Science Press: Beijing, China, 2010; Volume 1, pp. 231–232. [Google Scholar]
  9. Chinese Pharmacopeia Commission. Pharmacopoeia of the People’s Republic of China; Chinese Medical Science Press: Beijing, China, 2015; Volume 1, p. 248. [Google Scholar]
  10. Chinese Pharmacopeia Commission. Pharmacopoeia of the People’s Republic of China; Chinese Medical Science Press: Beijing, China, 2015; Volume 1, pp. 459–460, 644–645, 770–771, 1165–1166 and 1526–1528. [Google Scholar]
  11. Ding, Y.; Zhang, T.; Tao, J.S.; Zhang, L.Y.; Shi, J.R.; Ji, G. Potential hepatotoxicity of geniposide, the major iridoid glycoside in dried ripe fruits of Gardenia jasminoides (Zhi-zi). Nat. Prod. Res. 2013, 27, 929–933. [Google Scholar] [CrossRef] [PubMed]
  12. Cheng, S.H.; Zhang, Y.Y.; Li, H.F.; Wei, J.P. Acute hepatotoxicity and nephrotoxicity study of geniposide on jaundice rats. Chin. J. Exp. Tradit. Med. Formuae 2015, 21, 174–178. [Google Scholar]
  13. Inouye, H.; Saito, S.; Taguchi, H.; Endo, T. New Iridoid glucosides Gardenoside and geniposide from Gardenia jasminoides. Tetrahedron Lett. 1969, 28, 2347–2350. [Google Scholar] [CrossRef]
  14. Lee, E.J.; Hong, J.K.; Whang, W.K. Simultaneous determination of bioactive marker compounds from Gardeniae fructus by high performance liquid chromatography. Arch. Pharm. Res. 2014, 37, 992–1000. [Google Scholar] [CrossRef] [PubMed]
  15. Han, L.; Xu, H.; Liu, X.H.; Fu, X.S.; Li, J.S.; Cai, B.C. Simultaneous determination of five index components in Rehmanniae Radix by HPCE-DAD. Chin. Pharm. J. 2012, 47, 1937–1942. [Google Scholar]
  16. Zhou, J.; Qi, H.Y. Simultaneous determination of eight components in Radix Scrophulariae by HPLC-MS/MS. Mod. Chin. Med. 2017, 19, 670–674. [Google Scholar]
  17. Sun, J.; Lu, Y.; Xiang, W.Y.; Cao, X.; Gong, Z.P.; Wang, A.M. Simultaneous Determination of Six Components in Eucommia ulmoides by UPLC. Nat. Prod. Res. Dev. 2016, 28, 874–879. [Google Scholar]
  18. Meng, D.L.; Ji, S.; Zhang, Y.C.; Li, N.; Li, X. Isolation and identification of terpenoids and saccharides from root of Achyranthese bidentata Bl. J. Shenyang Pharm. Univ. 2009, 26, 348–353. [Google Scholar]
  19. Zhang, Y.L.; Gan, M.L.; Li, S.; Wang, S.J.; Zhu, C.G.; Yang, Y.C.; Hu, J.F.; Chen, N.H.; Shi, J.G. Study on chemical constituents of Adina polycephala Benth. branches and stems. China J. Chin. Mater. Med. 2010, 35, 1261–1270. [Google Scholar]
  20. Da Silva, V.C.; Bolzania, V.D.; Young, M.C.M.; Lopes, M.N. A new antifungal phenolic glycoside derivative, iridoids and lignans from Alibertia sessilis (Vell.) K. Schum. (Rubiaceae). J. Braz. Chem. Soc. 2007, 18, 1405–1409. [Google Scholar] [CrossRef]
  21. Meng, J.C.; Lu, H.; Li, H.; Yang, L.; Tan, R.X. A new antibacterial sesquiterpene glycoside and other bioactive compounds from Biebersteinia heterostemon. Spectrosc. Lett. 1999, 32, 1005–1012. [Google Scholar] [CrossRef]
  22. Herrera-Ruiz, M.; Lopez-Rodriguez, R.; Trejo-Tapia, G.; Dominguez-Mendoza, B.E.; Gonzalez-Cortazar, M.; Tortoriello, J.; Zamilpa, A. A new furofuran lignan diglycoside and other secondary metabolites from the antidepressant extract of Castilleja tenuiflora Benth. Molecules 2015, 20, 13127–13143. [Google Scholar] [CrossRef] [PubMed]
  23. Liu, X.M.; Jiang, Y.; Sun, Y.Q.; Xu, X.W.; Tu, P.F. Study on chemical constituents of Cistanche deserticola. Chin. Pharm. J. 2011, 46, 1053–1058. [Google Scholar]
  24. He, Q.; Zhu, E.Y.; Wang, Z.T.; Chou, G.X.; Xu, L.S.; Hu, Z.B. Study on chemical constituents of Codonopsis pilosula. Chin. Pharm. J. 2006, 41, 10–12. [Google Scholar]
  25. Rosendal, S.; Kjaer, A.; Juhlniel, B. Geniposide and monotropein in Cornus-suecica. Phytochemistry 1973, 12, 2065–2066. [Google Scholar]
  26. Jiang, Y.; Choi, H.G.; Li, Y.; Park, Y.M.; Lee, J.H.; Kim, D.H.; Lee, J.H.; Son, J.K.; Na, M.; Lee, S.H. Chemical constituents of Cynanchum wilfordii and the chemotaxonomy of two species of the family Asclepiadacease, C. wilfordii and C. auriculatum. Arch. Pharm. Res. 2011, 34, 2021–2027. [Google Scholar] [CrossRef] [PubMed]
  27. Zhang, Y.L.; Fu, H.Y.; Zhang, Y.Y.; Song, Q.Y.; Xu, W.H.; Kuang, H.X. Chemical components from Dryopteris fragrans and their cytotoxicity. Chin. Tradit. Herb. Drugs 2008, 39, 648–651. [Google Scholar]
  28. Wang, S.Y.; Ding, L.F.; Wu, X.D.; Wang, H.Y.; Zhao, Q.S.; Song, L.D. Chemical constituents of Eucommia ulmoides. J. Chin. Med. Mat. 2014, 37, 807–811. [Google Scholar]
  29. Zuo, Y.M.; Zhang, Z.L.; Wang, Y.Y.; Chen, L.Y.; Liu, R.H.; Li, Y.Y. Study on chemical constituents of iridoids from Eucommiae folium. J. Chin. Med. Mater. 2014, 37, 252–254. [Google Scholar]
  30. Machida, K.; Takehara, E.; Kobayashi, H.; Kikuchi, M. Studies on the constituents of Gardenia Species. III. (1) new iridoid glycosides from the leaves of Gardenia jasminoides cv. fortuneana HARA. Chem. Pharm. Bull. 2003, 51, 1417–1419. [Google Scholar] [CrossRef] [PubMed]
  31. Endo, T.; Taguchi, H. Constituents of Gardenia jasminoides geniposide and genipin-gentiobioside. Chem. Pharm. Bull. 1973, 21, 2684–2688. [Google Scholar] [CrossRef]
  32. Miura, T.; Nishiyama, Y.; Ichimaru, M.; Moriyasu, M.; Kato, A. Hypoglycemic activity and structure-activity relationship of iridoidal glycosides. Biol. Pharm. Bull. 1996, 19, 160–161. [Google Scholar] [CrossRef] [PubMed]
  33. Liu, S.J.; Zhang, X.T.; Wang, W.M.; Qin, M.J.; Zhang, L.H. Studies on chemical constituents of Gardenia jasminoides var. radicans. Chin. Tradit. Herb. Drugs 2012, 43, 238–241. [Google Scholar]
  34. Zhang, H.; Feng, N.; Xu, Y.T.; Li, T.X.; Gao, X.M.; Zhu, Y.; Song, Y.S.; Wang, Y.N.; Wu, H.H. Chemical constituents from the flowers of wild Gardenia jasminoides J. Ellis. Chem. Biodivers. 2017, 14. [Google Scholar] [CrossRef] [PubMed]
  35. Yu, Y.; Xie, Z.L.; Gao, H.; Ma, W.W.; Dai, Y.; Wang, Y.; Zhong, Y.; Yao, X.S. Bioactive iridoid glucosides from the fruit of Gardenia jasminoides. J. Nat. Prod. 2009, 72, 1459–1464. [Google Scholar] [CrossRef] [PubMed]
  36. Li, Y.; Wang, X.L.; Song, J.L.; Qi, H.Y. Chemical constituents from leaves of Gardeniae fructus. Chin. J. Exp. Tradit. Med. Formuae 2016, 22, 68–70. [Google Scholar]
  37. Shi, X.J.; Yu, H.N.; Zhan, Z.J.; Shan, W.G. Studies on the glycosides constituents from the rhizome of Gardenia jasminoides. J. Zhejiang Univ. Technol. 2010, 38, 142–144. [Google Scholar]
  38. Wang, G.L.; Zhao, S.J.; Chen, D.C. Studies on chemical constituents of fruits of Gardenia sootepensis Hutch. China J. Chin. Mater. Med. 1999, 24, 38–40. [Google Scholar]
  39. Calis, I.; Kirmizibekmez, H.; Tasdemir, D.; Ireland, C.M. Iridoid glycosides from Globularia davisiana. Chem. Pharm. Bull. 2002, 50, 678–680. [Google Scholar] [CrossRef] [PubMed]
  40. Ono, M.; Ueno, M.; Masuoka, C.; Ikeda, T.; Nohara, T. Iridoid glucosides from the fruit of Genipa americana. Chem. Pharm. Bull. 2005, 53, 1342–1344. [Google Scholar] [CrossRef] [PubMed]
  41. Ma, H.; Li, F.L.; Wang, F.; Guo, Q.; Cao, G.S.; Yang, P.M. Chemical constituents from Oldenlandia diffusa. J. Chin. Med. Mater. 2016, 39, 98–102. [Google Scholar]
  42. Noiarsa, P.; Ruchirawat, S.; Otsuka, H.; Kanchanapoom, T. Chemical constituents from Oldenlandia corymbosa L. of Thai origin. J. Nat. Med. 2008, 62, 249–250. [Google Scholar] [CrossRef] [PubMed]
  43. Pan, W.D.; Li, Y.J.; Mai, L.T.; Ohtani, K.; Kasai, R.; Tanaka, O. Studies on chemical constituents of the roots of Lantana camara. Acta Pharmaceut. Sin. 1992, 27, 515–521. [Google Scholar]
  44. Hennebelle, T.; Sahpaz, S.; Joseph, H.; Bailleul, F. Phenolics and iridoids of Lippia alba. Nat. Prod. Commun. 2006, 1, 727–730. [Google Scholar]
  45. Oku, H.; Ogawa, Y.; Iwaoka, E.; Ishiguro, K. Allergy-preventive effects of chlorogenic acid and iridoid derivatives from flower buds of Lonicera japonica. Biol. Pharm. Bull. 2011, 34, 1330–1333. [Google Scholar] [CrossRef] [PubMed]
  46. Zhao, X.M.; Li, N.; Du, C.X. Chemical constituents of lowering LDL-C in effective part of Oroxylum indicum. J. Chin. Med. Mater. 2016, 39, 555–558. [Google Scholar]
  47. Quang, D.N.; Hashimoto, T.; Tanaka, M.; Dung, N.X.; Asakawa, Y. Iridoid glucosides from roots of Vietnamese Paederia scandens. Phytochemistry 2002, 60, 505–514. [Google Scholar] [CrossRef]
  48. Hamerski, L.; Furlan, M.; Silva, D.H.; Cavalheiro, A.J.; Eberlin, M.N.; Tomazela, D.M.; da Silva Bolzani, V. Iridoid glucosides from Randia spinosa (Rubiaceae). Phytochemistry 2003, 63, 397–400. [Google Scholar] [CrossRef]
  49. Fu, G.M.; Shi, S.P.; Ip, F.C.F.; Pang, H.H.; Ip, N.Y. A new carotenoid glycoside from Rehmannia glutinosa. Nat. Prod. Res. 2011, 25, 1213–1218. [Google Scholar] [CrossRef] [PubMed]
  50. Jensen, S.R. Iridoids in Rothmannia globosa. Phytochemistry 1983, 22, 1761–1765. [Google Scholar] [CrossRef]
  51. Ji, X.Y.; Liu, H.; Liu, B. Chemical Constituents from Scrophularia ningpoensis. Nat. Prod. Res. Dev. 2014, 26, 1775–1779. [Google Scholar]
  52. Yang, X.Z.; Tang, C.P.; Ke, C.Q.; Ye, Y. Chemical constituents of Stemona japonica. Nat. Prod. Res. Dev. 2008, 20, 399–402. [Google Scholar]
  53. Xie, B.X.; Tang, W.Z.; Wang, L.H.; Wang, X.J. Study on chemical constituents of Strychnos nux-vomica. J. Chin. Med. Mater. 2016, 39, 86–89. [Google Scholar]
  54. Huang, X.Z.; Cheng, C.M.; Yin, Y.; Guo, J.M.; Liang, H.; Dai, Y. Studies on the chemical constituents from the roots of Tinospora sagittata var. yunnanensis (II). J. Chin. Med. Mater. 2010, 33, 1574–1576. [Google Scholar]
  55. Mohamed, S.M.M.; Elokely, K.M.; Bachkeet, E.Y.; Bayoumi, S.A.L.; Carnevale, V.; Klein, M.L.; Cutler, S.J.; Ross, S.A. New glycosides and trypanocidal Metabolites from Vangueria edulis. Nat. Prod. Commun. 2015, 10, 1897–1900. [Google Scholar] [PubMed]
  56. Yamasaki, T.; Kawabata, T.; Masuoka, C.; Kinjo, J.; Ikeda, T.; Nohara, T.; Ono, M. Two new lignan glucosides from the fruit of Vitex cannabifolia. J. Nat. Med. 2008, 62, 47–51. [Google Scholar] [CrossRef] [PubMed]
  57. Kirmizibekmez, H.; Bassarello, C.; Piacente, S.; Calis, I. Phenylethyl glycosides from Globularia alypum growing in Turkey. Helv. Chim. Acta 2008, 91, 1525–1532. [Google Scholar] [CrossRef]
  58. Kirmizibekmez, H.; Bassarello, C.; Piacente, S.; Akaydin, G.; Calis, I. Flavonoid, phenylethanoid and iridoid glycosides from Globularia aphyllanthes. Z. Naturforsch. B 2009, 64, 252–256. [Google Scholar] [CrossRef]
  59. Kirmizibekmez, H.; Caliş, I.; Akbay, P.; Sticher, O. Iridoid and bisiridoid glycosides from Globularia cordifolia. Z. Naturforsch. C 2003, 58, 337–341. [Google Scholar] [CrossRef] [PubMed]
  60. Kirmizibekmez, H.; Akbay, P.; Sticher, O.; Caliş, I. Iridoids from Globularia dumulosa. Z. Naturforsch. C 2003, 58, 181–186. [Google Scholar] [CrossRef] [PubMed]
  61. Calis, I.; Kirmizibekmez, H.; Sticher, O. Iridoid glycosides from Globularia trichosantha. J. Nat. Prod. 2001, 64, 60–64. [Google Scholar] [CrossRef] [PubMed]
  62. Cui, L.; Li, Z.; Sun, Y.N.; Zhang, N. Protein tyrosine phosphatase 1B inhibitory activity of iridoid glucosides isolated from Plantago asiatica. J. Yanbian Univ. (Nat. Sci.) 2011, 37, 180–183. [Google Scholar]
  63. Jensen, S.R.; Olsen, C.E.; Rahn, K.; Rasmussen, J.H. Iridoid glucosides in Plantago alpina and P-altissima. Phytochemistry 1996, 42, 1633–1636. [Google Scholar] [CrossRef]
  64. Taskova, R.; Handjieva, N.; Evstatieva, L.; Popov, S. Iridoid glucosides from Plantago cornuti, Plantago major and Veronica cymbalaria. Phytochemistry 1999, 52, 1443–1445. [Google Scholar] [CrossRef]
  65. Kaewkrud, W.; Matsunami, K.; Otsuka, H.; Ruchirawat, S.; Kanchanapoom, T. Chemical constituents of the Thai medicinal plant, Dioecrescis erythroclada (Kurz) Tirveng. J. Nat. Med. 2007, 61, 476–477. [Google Scholar] [CrossRef]
  66. Bolzani, V.D.; Trevisan, L.M.V.; Izumisawa, C.M.; Young, M.C.M. Antifungal iridoids from the stems of Tocoyena Formosa. J. Braz. Chem. Soc. 1996, 7, 157–160. [Google Scholar] [CrossRef]
  67. Sainty, D.; Bailleul, F.; Delaveau, P.; Jacquemin, H. Iridoids of Borreria verticillata. Planta Med. 1981, 42, 260–264. [Google Scholar] [CrossRef] [PubMed]
  68. Lee, J.H.; Ku, C.H.; Baek, N.I.; Kim, S.H.; Park, H.W.; Kim, D.K. Phytochemical constituents from Diodia teres. Arch. Pharmacol. Res. 2004, 27, 40–43. [Google Scholar] [CrossRef]
  69. Takamura, C.; Hirata, T.; Yamaguchi, Y.; Ono, M.; Miyashita, H.; Ikeda, T.; Nohara, T. Studies on the chemical constituents of green leaves of Eucommia ulmoides Oliv. J. Nat. Med. 2007, 61, 220–221. [Google Scholar] [CrossRef]
  70. Mitova, M.I.; Handjieva, N.V.; Anchev, M.E.; Popov, S.S. Iridoid glucosides from four Balkan endemics of the Galium incurvum group (Rubiaceae). Z. Naturforsch. C 1996, 51, 286–290. [Google Scholar]
  71. Mitova, M.; Handjieva, N.; Anchev, M.; Popov, S. Iridoid glucosides from Galium humifusum Bieb. Z. Naturforsch. C 1999, 54, 488–491. [Google Scholar] [CrossRef]
  72. Tzakou, O.; Mylonas, P.; Vagias, C.; Petrakis, P.V. Iridoid glucosides with insecticidal activity from Galium melanantherum. Z. Naturforsch. C 2007, 62, 597–602. [Google Scholar] [CrossRef] [PubMed]
  73. De Rosa, S.; Iodice, C.; Mitova, M.; Handjieva, N.; Popov, S.; Anchev, M. Triterpene saponins and iridoid glucosides from Galium rivale. Phytochemistry 2000, 54, 751–756. [Google Scholar] [CrossRef]
  74. Demirezer, L.O.; Gurbuz, F.; Guvenalp, Z.; Stroch, K.; Zeeck, A. Iridoids, flavonoids and monoterpene glycosides from Galium verum subsp verum. Turk. J. Chem. 2006, 30, 525–534. [Google Scholar]
  75. Otsuka, H.; Yoshimura, K.; Yamasaki, K.; Cantoria, M.C. Isolation of 10-O-acyl iridoid glucosides from a Philippine medicinal plant, Oldenlandia corymbosa L. (Rubiaceae). Chem. Pharm. Bull. 1991, 39, 2049–2052. [Google Scholar] [CrossRef]
  76. Yuan, Q.M.; Yang, H.W.; Zhao, J.F.; Li, L. One new iridoid glycoside from Hedyotis tenelliflora. Chin. Herb. Med. 2011, 3, 87–89. [Google Scholar]
  77. Li, B.; Zhang, D.M.; Luo, Y.M.; Chen, X.G. Three new and antitumor anthraquinone glycosides from Lasianthus acuminatissimus MERR. Chem. Pharm. Bull. 2006, 54, 297–300. [Google Scholar] [CrossRef] [PubMed]
  78. Akihisa, T.; Seino, K.; Kaneko, E.; Watanabe, K.; Tochizawa, S.; Fukatsu, M.; Banno, N.; Metori, K.; Kimura, Y. Melanogenesis inhibitory activities of iridoid-, hemiterpene-, and fatty acid-glycosides from the fruits of Morinda citrifolia (Noni). J. Oleo Sci. 2010, 59, 49–57. [Google Scholar] [CrossRef] [PubMed]
  79. Yang, X.L.; Jiang, M.Y.; Hsieh, K.L.; Liu, J.K. Chemical constituents from the seeds of Morinda citrifolia. Chin. J. Nat. Med. 2009, 7, 119–122. [Google Scholar] [CrossRef]
  80. Kim, D.H.; Lee, H.J.; Oh, Y.J.; Kim, M.J.; Kim, S.H.; Jeong, T.S.; Baek, N.I. Iridoid glycosides isolated from Oldenlandia diffusa inhibit LDL-oxidation. Arch. Pharmacol. Res. 2005, 28, 1156–1160. [Google Scholar] [CrossRef]
  81. Mahibalan, S.; Rao, P.C.; Khan, R.; Basha, A.; Siddareddy, R.; Masubuti, H.; Fujimoto, Y.; Begum, A.S. Cytotoxic constituents of Oldenlandia umbellata and isolation of a new symmetrical coumarin dimer. Med. Chem. Res. 2016, 25, 466–472. [Google Scholar] [CrossRef]
  82. Ling, S.K.; Komorita, A.; Tanaka, T.; Fujioka, T.; Mihashi, K.; Kouno, I. Sulfur-containing bis-iridoid glucosides and iridoid glucosides from Saprosma scortechinii. J. Nat. Prod. 2002, 65, 656–660. [Google Scholar] [CrossRef] [PubMed]
  83. Kirmizibekmez, H.; Bardakci, H.; Masullo, M.; Kamburoglu, O.; Eryilmaz, G.; Akaydin, G.; Yesilada, E.; Piacente, S. Flavonol glycosides and iridoids from Asperula lilaciflora. Helv. Chim. Acta 2014, 97, 1571–1576. [Google Scholar] [CrossRef]
  84. Li, H.Q.; Li, C.; Xia, B.H.; Zhou, Y.M.; Lin, L.M.; Liao, D.F. A chemotaxonomic study of phytochemicals in Hedyotis corymbosa. Biochem. Syst. Ecol. 2015, 62, 173–177. [Google Scholar] [CrossRef]
  85. Van Long, L.H.; Nga, V.T.; Dam, N.P.; Hung, M.A.; Dung, T.D.; Quang, T.T.; Phung, N.K.P. Three new iridoid glueoside salts from Hedyotis tenelliflora growing in Vietnam. Nat. Prod. Commun. 2013, 8, 1507–1508. [Google Scholar] [PubMed]
  86. Takeda, Y.; Mizuno, K.; Inouchi, S.; Masuda, T.; Hirata, E.; Shinzato, T.; Aramoto, M.; Otsuka, H. An iridoid glucoside dimer and a non-glycosidic iridoid from the leaves of Lasianthus wallichii. Chem. Pharm. Bull. 2002, 50, 1395–1397. [Google Scholar] [CrossRef] [PubMed]
  87. Zhao, G.Q.; Yin, Z.F.; Liu, Y.C.; Li, H.B. Iridoid glycosides from buds of Jasminum officinale L. var. grandiflorum. Acta Pharmaceut Sin. 2011, 46, 1221–1224. [Google Scholar]
  88. Choi, J.; Lee, K.T.; Choi, M.Y.; Nam, J.H.; Jung, H.J.; Park, S.K.; Park, H.J. Antinociceptive anti-inflammatory effect of monotropein isolated from the root of Morinda officinalis. Biol. Pharm. Bull. 2005, 28, 1915–1918. [Google Scholar] [CrossRef] [PubMed]
  89. Inouye, H.; Inouye, S.; Shimokawa, N.; Okigawa, M. The iridoid glucoside from Paederia scandens (Lour.) Merrill var. Mairei (Leveille) Hara. Tetrahedron Lett. 1968, 6, 683–688. [Google Scholar] [CrossRef]
  90. Wang, M.; Liang, J.Y.; Liu, X.T.; Qiu, W. Chemical constituents from Serissa serissoides. Chin. J. Nat. Med. 2006, 4, 198–201. [Google Scholar]
  91. Stermitz, F.R.; Krull, R.E. Iridoid glycosides of Cornus canadensis: A comparison with some other Cornus species. Biochem. Syst. Ecol. 1998, 26, 845–849. [Google Scholar] [CrossRef]
  92. Yang, F.; Su, Y.F.; Zhao, Z.Q.; Que, M.; Li, T.X.; Gao, X.M. Anthraquinones and Iridoids from Morinda officinalis. Chem. Nat. Compd. 2016, 52, 989–991. [Google Scholar] [CrossRef]
  93. Huang, F.; Cui, H.H.; Yu, Z.C.; Shen, Z.B. Chemical constituents of Dicliptera chinensis. Chin. J. Exp. Tradit. Med. Formulae 2012, 18, 90–91. [Google Scholar]
  94. Chen, Q.C.; Zhang, W.Y.; Youn, U.; Kim, H.; Lee, I.; Jung, H.J.; Na, M.; Min, B.S.; Bae, K. Iridoid glycosides from Gardeniae Fructus for treatment of ankle sprain. Phytochemistry 2009, 70, 779–784. [Google Scholar] [CrossRef] [PubMed]
  95. Luciano, J.H.S.; Lima, M.A.S.; Silveira, E.R.; Vasconcelos, I.M.; Fernandes, G.S.; de Souza, E.B. Antifungal iridoids, triterpenes and phenol compounds from Alibertia myrciifolia Sprunge ex. Schum. Quim. Nova 2010, 33, 292–294. [Google Scholar] [CrossRef]
  96. Tzakou, O.; Lempesis, K.; Loukis, A. Secondary metabolites from Asperula lutea subsp. rigidula. Nat. Prod. Commun. 2011, 6, 237–238. [Google Scholar] [PubMed]
  97. Venditti, A.; Serrilli, A.M.; Bianco, A. Iridoids from Bellardia trixago (L.) All. Nat. Prod. Res. 2013, 27, 1413–1416. [Google Scholar] [CrossRef] [PubMed]
  98. Nahrstedt, A.; Rockenbach, J.; Wray, V. Phenylpropanoid glycosides, a furanone glucoside and geniposidic acid from members of the Rubiaceae. Phytochemistry 1995, 39, 375–378. [Google Scholar] [CrossRef]
  99. Carrillo-Ocampo, D.; Bazaldua-Gomez, S.; Bonilla-Barbosa, J.R.; Aburto-Amar, R.; Rodriguez-Lopez, V. Anti-inflammatory activity of iridoids and verbascoside isolated from Castilleja tenuiflora. Molecules 2013, 18, 12109–12118. [Google Scholar] [CrossRef] [PubMed]
  100. Pennacchio, M.; Syah, Y.M.; Ghisalberti, E.L.; Alexander, E. Cardioactive compounds from Eremophila species. J. Ethnopharmacol. 1996, 53, 21–27. [Google Scholar] [CrossRef]
  101. Dai, X.P.; Huang, Q.; Zhou, B.T.; Gong, Z.C.; Liu, Z.Q.; Shi, S.Y. Preparative isolation and purification of seven main antioxidants from Eucommia ulmoides Oliv. (Du-zhong) leaves using HSCCC guided by DPPH-HPLC experiment. Food Chem. 2013, 139, 563–570. [Google Scholar] [CrossRef] [PubMed]
  102. Ersoz, T.; Berkman, M.Z.; Tasdemir, D.; Ireland, C.M.; Calis, I. An iridoid glucoside from Euphrasia pectinata. J. Nat. Prod. 2000, 63, 1449–1450. [Google Scholar] [CrossRef] [PubMed]
  103. Li, H.B.; Yu, Y.; Wang, Z.Z.; Dai, Y.; Gao, H.; Xiao, W.; Yao, X.S. Iridoid and bis-iridoid glucosides from the fruit of Gardenia jasminoides. Fitoterapia 2013, 88, 7–11. [Google Scholar] [CrossRef] [PubMed]
  104. Mohamed, N.M.; Makboul, A.; Farag, S.F.; Tarawneh, A.H.; Khan, S.I.; Brooks, T.A.; Wang, Y.H.; Ross, S.A. Iridoid and phenylpropanoid glycosides from the roots of Lantana montevidensis. Med. Chem. Res. 2017, 26, 1117–1126. [Google Scholar] [CrossRef]
  105. Cuong, N.M.; Huong, T.T.; Son, N.T.; Cuong, T.D.; Van, D.T.; Khanh, P.N.; Ha, V.T.; Tram, N.C.; Long, P.Q.; Kim, Y.H. Morinlongosides A-C, two new naphthalene glycoside and a new iridoid glycoside from the roots of Morinda longissima. Chem. Pharm. Bull. 2016, 64, 1230–1234. [Google Scholar] [CrossRef] [PubMed]
  106. Jia, Z.J.; Liu, Z.M. Phenylpropanoid and iridoid glycosides from Pedicularislongiflora. Phytochemistry 1992, 31, 3125–3127. [Google Scholar]
  107. Jia, Z.J.; Gao, J.J.; Liu, Z.M. Iridoid and phenylpropanoid glycosides from Pedicularis plicata Maxim. Indian J. Chem. B 1994, 33, 460–464. [Google Scholar]
  108. Su, B.L.; Yang, L.; Jia, Z.J. Neolignan, phenylpropanoid and iridoid glycosides from Pedicularis verticillata. Phytochemistry 1997, 45, 1271–1273. [Google Scholar] [CrossRef]
  109. Yan, P.F.; Liu, G.Y.; Zhao, S.M.; Song, L.L.; Tan, L.N.; Jin, Y.R.; Li, X.W. Studies on chemical constituents of Plantago depressa Willd. Chin. Pharm. J. 2009, 44, 19–21. [Google Scholar]
  110. Liu, Y.F.; Liang, D.; Luo, H.; Hao, Z.Y.; Wang, Y.; Zhang, C.L.; Chen, R.Y.; Yu, D.Q. Chemical constituents from root tubers of Rehmannia glutinosa. Chin. Tradit. Herb. Drugs 2014, 45, 16–22. [Google Scholar]
  111. Zeng, Y.B.; Mei, W.L.; Wang, H.; Li, X.N.; Dai, H.F. Scyphiphin D, a new iridoid glucoside dimer from Scyphiphora hydrophyllacea. J. Asian Nat. Prod. Res. 2010, 12, 1010–1014. [Google Scholar] [CrossRef] [PubMed]
  112. Tao, S.H.; Wu, J.; Qi, S.H.; Zhang, S.; Li, M.Y.; Li, Q.X. Scyphiphorins A and B, two new iridoid glycosides from the stem bark of a Chinese mangrove Scyphiphora hydrophyllacea. Helv. Chim. Acta 2007, 90, 1718–1722. [Google Scholar] [CrossRef]
  113. Tatli, I.I.; Khan, I.A.; Akdemir, Z.S. Acylated iridoid glycosides from the flowers of Verbascum lasianthum Boiss. ex Bentham. Z. Naturforsch. B 2006, 61, 1183–1187. [Google Scholar] [CrossRef]
  114. Su, B.N.; Yang, L.; Gao, K.; Jia, Z.J. Aquaticol, a bis-sesquiterpene and iridoid glucosides from Veronica anagallis-aquatica. Planta Med. 2000, 66, 281–283. [Google Scholar] [CrossRef] [PubMed]
  115. Taskova, R.; Handjieva, N.; Peev, D.; Popov, S. Iridoid glucosides from three Veronica species. Phytochemistry 1998, 49, 1323–1327. [Google Scholar] [CrossRef]
  116. Handjieva, N.; Spassov, S.; Bodurova, G.; Saadi, H.; Popov, S. Majoroside, an iridoid glucoside from Platago major. Phytochemistry 1991, 30, 1317–1318. [Google Scholar] [CrossRef]
  117. De Araujo, F.C.V.; Marques, F.G.; da Silva, C.C.; Santin, S.M.D.; Nakamura, C.V.; Zamuner, M.L.M.; de Souza, M.C. Terpenes isolated of Coussarea platyphylla Müll. Arg. (Rubiaceae). Quim. Nova 2009, 32, 1760–1763. [Google Scholar] [CrossRef]
  118. Yang, X.L.; Zhang, P.; Wu, J.Z. Chemical constituents from the root of Damnacanthus officinarum Huang. Biochem. Syst. Ecol. 2014, 52, 49–52. [Google Scholar] [CrossRef]
  119. Liu, L.; Chen, Y.P.; Wan, Z.; Li, A.L.; Li, R.Y.; Tu, P.F. Studies on chemical constituents of Pyrola calliatha. China J. Chin. Mater. Med. 2007, 32, 1762–1765. [Google Scholar]
  120. Yang, X.; Peng, Q.; Liu, Q.; Hu, J.; Tang, Z.; Cui, L.; Lin, Z.; Xu, B.; Lu, K.; Yang, F.; et al. Antioxidant activity against H2O2-induced cytotoxicity of the ethanol extract and compounds from Pyrola decorate leaves. Pharm. Biol. 2017, 55, 1843–1848. [Google Scholar] [CrossRef] [PubMed]
  121. Bergeron, C.; Marston, A.; Antus, S.; Gauthier, R.; Hostettmann, K. Flavonoids from Pyrola elliptica. Phytochemistry 1998, 49, 233–236. [Google Scholar] [CrossRef]
  122. Kim, J.S.; Shim, S.H.; Xu, Y.N.; Kang, S.S.; Son, K.H.; Chang, H.W.; Kim, H.P.; Bae, K.H. Phenolic glycosides from Pyrola japonica. Chem. Pharm. Bull. 2004, 52, 714–717. [Google Scholar] [CrossRef] [PubMed]
  123. Fu, X.P.; Jia, N.E.; Ai, L.T.; Ba, H. Chemical constituents of Pyrola xinjiangensis. Lishizhen Med. Mater. Med. Res. 2007, 18, 1117–1118. [Google Scholar]
  124. Hu, H.Q.; Han, H.D.; Lin, Y.; Chen, L.H.; Wang, X.L. Chemical constituents of Paederia pertomentosa. China J. Chin. Mater. Med. 2013, 38, 2657–2660. [Google Scholar]
  125. He, D.H.; Chen, J.S.; Wang, X.L.; Ding, K.Y. A new iridoid glycoside from Paederia scandens. Chin. Chem. Lett. 2010, 21, 437–439. [Google Scholar] [CrossRef]
  126. Singh, D.N.; Verma, N. Iridoid glucosides and anthraquinone from the aerial parts of Saprosma fragrans. J. Indian Chem. Soc. 2012, 89, 429–431. [Google Scholar]
  127. Jiang, W.; Kuang, L.S.; Hou, A.J.; Qian, M.; Li, J.Z. Iridoid glycosides from Hedyotis corymbosa. Helv. Chim. Acta 2007, 90, 1296–1301. [Google Scholar] [CrossRef]
  128. Tao, S.H.; Qi, S.H.; Zhang, S.; Xiao, Z.H.; Li, Q.X. Scyphiphorins C and D, two new iridoid glycosides from the Chinese mangrove Scyphiphora hydrophyllacea. Heterocycles 2009, 78, 1557–1562. [Google Scholar] [CrossRef]
  129. Hennebelle, T.; Sahpaz, S.; Gressier, B.; Joseph, H.; Bailleul, F. Antioxidant and neurosedative properties of polyphenols and iridoids from Lippia alba. Phytother. Res. 2008, 22, 256–258. [Google Scholar] [CrossRef] [PubMed]
  130. Fu, X.M.; Chou, G.X.; Wang, Z.T. Iridoid glycosides from Gardenia jasminoides ELLIS. Helv. Chim. Acta 2008, 91, 646–653. [Google Scholar] [CrossRef]
  131. Zhao, C.C.; Shao, J.H.; Zhang, Y.W.; Cao, D.D.; Li, X. Chemical constituents from whole plant of Galiun verum L. J. Shenyang Pharm. Univ. 2009, 26, 904–906. [Google Scholar]
  132. Nie, T.T.; Zhao, H.X.; Bai, H. Chemical constituents of Pittosporum glabratum. Chin. J. Nat. Med. 2011, 9, 180–184. [Google Scholar]
  133. Velazquez-Fiz, M.P.; Diaz-Lanza, A.M.; Fernandez-Matellano, L. Iridoids from Plantago lagopus. Pharm. Biol. 2000, 38, 268–270. [Google Scholar] [CrossRef]
  134. Machida, K.; Onodera, R.; Furuta, K.; Kikuchi, M. Studies of the constituents of Gardenia species. I. Monoterpenoids from Gardeniae Fructus. Chem. Pharm. Bull. 1998, 46, 1295–1300. [Google Scholar] [CrossRef]
  135. Zhao, J.F.; Yuan, Q.M.; Yang, X.D.; Zhang, H.B.; Li, L. Two new iridoid glycosides from Hedyotis tenelliflora BLUME. Helv. Chim. Acta 2005, 88, 2532–2536. [Google Scholar] [CrossRef]
  136. Raju, B.L.; Lin, S.J.; Hou, W.C.; Lai, Z.Y.; Liu, P.C.; Hsu, F.L. Antioxidant iridoid glucosides from Wendlandia formosana. Nat. Prod. Res. 2004, 18, 357–364. [Google Scholar] [CrossRef] [PubMed]
  137. Nishihama, Y.; Masuda, K.; Yamaki, M.; Takagi, S.; Sakina, K. Three new iridoid glucosides from Hedyotis diffusa. Planta Med. 1981, 43, 28–33. [Google Scholar] [CrossRef] [PubMed]
  138. Wu, H.M.; Tao, X.L.; Chen, Q.; Lao, X.F. Iridoids from Hedyotis-diffusa. J. Nat. Prod. 1991, 54, 254–256. [Google Scholar] [CrossRef]
  139. Xu, G.H.; Kim, Y.H.; Chi, S.W.; Choo, S.J.; Ryoo, I.J.; Ahn, J.S.; Yoo, I.D. Evaluation of human neutrophil elastase inhibitory effect of iridoid glycosides from Hedyotis diffusa. Bioorg. Med. Chem. Lett. 2010, 20, 513–515. [Google Scholar] [CrossRef] [PubMed]
  140. Akihisa, T.; Watanabe, K.; Yamamoto, A.; Zhang, J.; Matsumoto, M.; Fukatsu, M. Melanogenesis Inhibitory Activity of Monoterpene Glycosides from Gardeniae Fructus. Chem. Biodivers. 2012, 9, 1490–1499. [Google Scholar] [CrossRef] [PubMed]
  141. Handjieva, N.; Taskova, R.; Popov, S. 10-Hydroxymajoroside, an iridoid glucoside from Plantago cornuti Gouan L. Z. Naturforsch. C 1993, 48, 827–828. [Google Scholar]
  142. Takeda, T.; Narukawa, Y.; Hada, N. Studies on the constituents of Leonotis nepetaefolia. Chem. Pharm. Bull. 1999, 47, 284–286. [Google Scholar] [CrossRef]
  143. Shaker, K.H.; Elgamal, M.H.A.; Seifert, K. Iridoids from Avicennia marina. Z. Naturforsch. C 2001, 56, 965–968. [Google Scholar] [CrossRef] [PubMed]
  144. Qu, J.; Chen, X.; Niu, C.S.; Yu, S.S. Chemical constituents from Vaccinium bracteatum. China J. Chin. Mater. Med. 2014, 39, 684–688. [Google Scholar]
  145. Inouye, H.; Ueda, S.; Takeda, Y. Studies on monoterpene glucosides and related natural products. XVIII. Formation sequences of iridoid glucosides in highly oxidized levels. Chem. Pharm. Bull. 1972, 20, 1305–1311. [Google Scholar] [CrossRef]
  146. Chinese Pharmacopeia Commission. Pharmacopoeia of the People’s Republic of China; Chinese Medical Science Press: Beijing, China, 2015; Volume 1, pp. 68–69. [Google Scholar]
  147. Weng, Z.B.; Yan, C.P.; Wu, Y.; Cai, B.C.; Li, W.D.; Chen, Z.P. Determination of ten components in Eucommia ulmoides Oliver by high-performance liquid chromatography with dual detectors. Anal. Lett. 2014, 47, 1978–1986. [Google Scholar] [CrossRef]
  148. Yan, S.K.; Luo, G.A.; Wang, Y.M.; Cheng, Y.Y. Simultaneous determination of nine components in Qingkailing injection by HPLC/ELSD/DAD and its application to the quality control. J. Pharmaceut. Biomed. 2006, 40, 889–895. [Google Scholar] [CrossRef] [PubMed]
  149. Jin, M.J.; Kim, I.S.; Kim, D.H.; Yoo, H.H. Liquid chromatography-tandem mass spectrometric determination of geniposide in rat Plasma and its pharmacokinetic application. Bull. Korean Chem. Soc. 2013, 34, 2760–2764. [Google Scholar] [CrossRef]
  150. Wang, F.G.; Cao, J.; Hao, J.F.; Liu, K. Pharmacokinetics, bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats. Biopharm. Drug Dispos. 2014, 35, 97–103. [Google Scholar] [CrossRef] [PubMed]
  151. Yu, D.; Zhang, Y.; Guo, L.W.; Zhang, Q.C.; Zhu, H.X. Study on the absorption mechanism of geniposide in the Chinese Formula Huang-Lian-Jie-Du-Tang in rats. AAPS PharmSciTech 2017, 18, 1382–1392. [Google Scholar] [CrossRef] [PubMed]
  152. Cheung, H.Y.; Lai, W.P.; Cheung, M.S.; Leung, F.M.; Hood, D.J.; Fong, W.F. Rapid and simultaneous analysis of some bioactive components in Eucommia ulmoides by capillary electrophoresis. J. Chromatogr. A 2003, 989, 303–310. [Google Scholar] [CrossRef]
  153. Zhong, Y.C.; Yang, L.W.; Qiu, Y.Q.; Wang, S.M.; Liang, S.W. Rapid determination of geniposide in Gardenia jasminoides Ellis in different preparations methods with NIRS. Spectrosc. Spectr. Aanl. 2017, 37, 1771–1777. [Google Scholar]
  154. Chen, P.; Chen, Y.; Wang, Y.; Cai, S.; Deng, L.; Liu, J.; Zhang, H. Comparative evaluation of hepatoprotective activities of geniposide, crocins and crocetin by CCl4-induced liver injury in mice. Biomol. Ther. 2016, 24, 156–162. [Google Scholar] [CrossRef] [PubMed]
  155. Wang, J.; Miao, M.; Qu, L.; Cui, Y.; Zhang, Y. Protective effects of geniposide against Tripterygium glycosides (TG)-induced liver injury and its mechanisms. J. Toxicol. Sci. 2016, 41, 165–173. [Google Scholar] [CrossRef] [PubMed]
  156. Wang, J.M.; Zhang, Y.Y.; Liu, R.X.; Li, X.B.; Cui, Y.; Qu, L.B. Geniposide protects against acute alcohol-induced liver injury in mice via upregulating the expression of the main antioxidant enzymes. Can. J. Physiol. Pharmacol. 2015, 93, 261–267. [Google Scholar] [CrossRef] [PubMed]
  157. Park, J.H.; Yoon, J.; Lee, K.Y.; Park, B. Effects of geniposide on hepatocytes undergoing epithelial-mesenchymal transition in hepatic fibrosis by targeting TGF beta/Smad and ERK-MAPK signaling pathways. Biochimie 2015, 113, 26–34. [Google Scholar] [CrossRef] [PubMed]
  158. Tan, Z.; Liu, A.M.; Luo, M.; Yin, X.; Song, D.J.; Dai, M.Y.; Li, P.X.; Chu, Z.B.; Zou, Z.Q.; Ma, M.; et al. Geniposide inhibits alpha-naphthylisothiocyanate-induced intrahepatic cholestasis: The downregulation of STAT3 and NF kappa B signaling plays an important role. Am. J. Chin. Med. 2016, 44, 721–736. [Google Scholar] [CrossRef] [PubMed]
  159. Song, X.J.; Guo, M.Y.; Wang, T.C.; Wang, W.; Cao, Y.G.; Zhang, N.S. Geniposide inhibited lipopolysaccharide-induced apoptosis by modulating TLR4 and apoptosis-related factors in mouse mammary glands. Life Sci. 2014, 119, 9–17. [Google Scholar] [CrossRef] [PubMed]
  160. Yang, X.F.; Cai, Q.R.; He, J.P.; Chu, X.; Wei, M.M.; Feng, X.R.; Xie, X.X.; Huo, M.X.; Liu, J.; Wei, J.Y.; et al. Geniposide, an iridoid glucoside derived from Gardenia jasminoides, protects against lipopolysaccharide-induced acute lung injury in mice. Planta Med. 2012, 78, 557–564. [Google Scholar]
  161. Kimura, Y.; Okuda, H.; Arichi, S. Effect of geniposide isolated from Gardenia jasminoides on metabolic alterations in high sugar diet-fed rats. Chem. Pharm. Bull. 1982, 30, 4444–4447. [Google Scholar] [CrossRef] [PubMed]
  162. Guo, L.X.; Zheng, X.X.; Liu, J.H.; Yin, Z.Y. Geniposide suppresses hepatic glucose production via AMPK in HepG2 cells. Biol. Pharm. Bull. 2016, 39, 484–491. [Google Scholar] [CrossRef] [PubMed]
  163. Hu, X.L.; Zhang, X.M.; Jin, G.X.; Shi, Z.M.; Sun, W.H.; Chen, F.L. Geniposide reduces development of streptozotocin-induced diabetic nephropathy via regulating nuclear factor-kappa B signaling pathways. Fund. Clin. Pharmacol. 2017, 31, 54–63. [Google Scholar] [CrossRef] [PubMed]
  164. Guo, L.X.; Xia, Z.N.; Gao, X.; Yin, F.; Liu, J.H. Glucagonlike peptide 1 receptor plays a critical role in geniposide-regulated insulin secretion in INS-1 cells. Acta Pharmacol. Sin. 2012, 33, 237–241. [Google Scholar] [CrossRef] [PubMed]
  165. Guo, L.X.; Liu, J.H.; Yin, F. Regulation of insulin secretion by geniposide: Possible involvement of phosphatidylinositol 3-phosphate kinase. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 1287–1294. [Google Scholar] [PubMed]
  166. Liu, C.Y.; Hao, Y.A.; Yin, F.; Zhang, Y.L.; Liu, J.H. Geniposide protects pancreatic cells from high glucose-mediated injury by activation of AMP-activated protein kinase. Cell Biol. Int. 2017, 41, 544–554. [Google Scholar] [CrossRef] [PubMed]
  167. Liu, C.Y.; Hao, Y.N.; Yin, F.; Zhang, Y.L.; Liu, J.H. Geniposide accelerates proteasome degradation of Txnip to inhibit insulin secretion in pancreatic beta-cells. J. Endocrinol. Investig. 2017, 40, 505–512. [Google Scholar] [CrossRef] [PubMed]
  168. Zhang, H.J.; Zhao, C.H.; Lv, C.; Liu, X.L.; Du, S.J.; Li, Z.; Wang, Y.Y.; Zhang, W.S. Geniposide alleviates amyloid-induced synaptic injury by protecting axonal mitochondrial trafficking. Front. Cell. Neurosci. 2017, 10. [Google Scholar] [CrossRef] [PubMed]
  169. Gao, C.; Liu, Y.Z.; Jiang, Y.H.; Ding, J.M.; Li, L. Geniposide ameliorates learning memory deficits, reduces Tau phosphorylation and decreases apoptosis via GSK3β pathway in streptozotocin-induced alzheimer rat model. Brain Pathol. 2014, 24, 261–269. [Google Scholar] [CrossRef] [PubMed]
  170. Liu, Z.X.; Zhang, Y.L.; Liu, J.H.; Yin, F. Geniposide attenuates the level of Aβ1–42 via enhancing leptin signaling in cellular and APP/PS1 transgenic mice. Arch. Pharm. Res. 2017, 40, 571–578. [Google Scholar] [CrossRef] [PubMed]
  171. Wang, R.; Wu, H.; Chen, J.; Li, S.P.; Dai, L.; Zhang, Z.R.; Wang, W.Y. Antiinflammation effects and mechanisms study of geniposide on rats with collagen-induced arthritis. Phytother. Res. 2017, 31, 631–637. [Google Scholar] [CrossRef] [PubMed]
  172. Deng, Y.H.; Guan, M.F.; Xie, X.X.; Yang, X.F.; Xiang, H.; Li, H.Y.; Zou, L.C.; Wei, J.Y.; Wang, D.C.; Deng, X.M. Geniposide inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. Int. Immunopharmacol. 2013, 17, 561–567. [Google Scholar] [CrossRef] [PubMed]
  173. Hsu, H.Y.; Yang, J.J.; Lin, S.Y.; Lin, C.C. Comparisons of geniposidic acid and geniposide on antitumor and radioprotection after sublethal irradiation. Cancer Lett. 1997, 113, 31–37. [Google Scholar] [CrossRef]
  174. Lee, M.J.; Hsu, J.D.; Wang, C.J. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-caused tumor promotion in benzo[a]pyrene-initiated CD-1 mouse skin by geniposide. Anticancer Res. 1995, 15, 411–416. [Google Scholar] [PubMed]
  175. Li, F.H.; Li, W.H.; Li, X.G.; Li, F.; Zhang, L.P.; Wang, B.C.; Huang, G.R.; Guo, X.J.; Wan, L.Q.; Liu, Y.Q.; et al. Geniposide attenuates inflammatory response by suppressing P2Y(14) receptor and downstream ERK1/2 signaling pathway in oxygen and glucose deprivation-induced brain microvascular endothelial cells. J. Ethnopharmacol. 2016, 185, 77–86. [Google Scholar] [CrossRef] [PubMed]
  176. Wang, B.; Liao, P.P.; Liu, L.H.; Fang, X.; Li, W.; Guan, S.M. Baicalin and geniposide inhibit the development of atherosclerosis by increasing Wnt1 and inhibiting dickkopf-related protein-1 expression. J. Geriatr. Cardiol. 2016, 13, 846–854. [Google Scholar] [PubMed]
  177. Liao, P.P.; Liu, L.H.; Wang, B.; Li, W.; Fang, X.; Guan, S.M. Baicalin and geniposide attenuate atherosclerosis involving lipids regulation and immunoregulation in ApoE-/- mice. Eur. J. Pharmacol. 2014, 740, 488–495. [Google Scholar] [CrossRef] [PubMed]
  178. Gong, N.; Fan, H.; Ma, A.N.; Xiao, Q.; Wang, Y.X. Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors. Neuropharmacology 2014, 84, 31–45. [Google Scholar] [CrossRef] [PubMed]
  179. Ma, Z.G.; Dai, J.; Zhang, W.B.; Yuan, Y.; Liao, H.H.; Zhang, N.; Bian, Z.Y.; Tang, Q.Z. Protection against cardiac hypertrophy by geniposide involves the GLP-1 receptor/AMPKα signaling pathway. Br. J. Pharmacol. 2016, 173, 1502–1516. [Google Scholar] [CrossRef] [PubMed]
  180. Sung, Y.Y.; Lee, A.Y.; Kim, H.K. The Gardenia jasminoides extract and its constituent, geniposide, elicit anti-allergic effects on atopic dermatitis by inhibiting histamine in vitro and in vivo. J. Ethnopharmacol. 2014, 156, 33–40. [Google Scholar] [CrossRef] [PubMed]
  181. Wang, J.M.; Duan, P.L.; Cui, Y.; Li, Q.; Shi, Y.R. Geniposide alleviates depression-like behavior via enhancing BDNF expression in hippocampus of streptozotocin-evoked mice. Metab. Brain Dis. 2016, 31, 1113–1122. [Google Scholar] [CrossRef] [PubMed]
  182. Lin, Y.J.; Lai, C.C.; Lai, C.H.; Sue, S.C.; Lin, C.W.; Hung, C.H.; Lin, T.H.; Hsu, W.Y.; Huang, S.M.; Hung, Y.L.; et al. Inhibition of enterovirus 71 infections and viral IRES activity by Fructus gardeniae and geniposide. Eur. J. Med. Chem. 2013, 62, 206–213. [Google Scholar] [CrossRef] [PubMed]
  183. Lan, W.J.; Wang, H.Y.; Lan, W.; Wang, K.Y.; Wang, R.M. Evidence that geniposide abrogates norepinephrine-induced hypopigmentation by the activation of GLP-1R-dependent c-kit receptor signaling in melanocyte. J. Ethnophamacol. 2008, 118, 154–158. [Google Scholar]
  184. Meng, Z.Q.; Tang, Z.H.; Yan, Y.X.; Ding, G.; Xiao, W.; Yang, Z.L. Study on anti-hyperuricemia effect of geniposide. World Sci. Technol. Mod. Tradit. Chin. Med. Mater. Med. 2014, 16, 1565–1568. [Google Scholar]
  185. Ha, H.; Ho, J.Y.; Shin, S.; Kim, H.; Koo, S.; Kim, I.H.; Kim, C. Effects of eucommiae cortex on osteoblast-like cell proliferation and osteoclast inhibition. Arch. Pharmacal. Res. 2003, 26, 929–936. [Google Scholar] [CrossRef]
  186. Ding, S.T.; Liu, H.T.; Li, W.M.; Li, X.Y.; Yu, C. Protective effects of geniposide on human umbilical vein endothelial cell injury induced by H2O2 in vitro. Chin. Pharmacol. Bull. 2009, 25, 725–729. [Google Scholar]
  187. Suzuki, Y.; Kondo, K.; Ikeda, Y.; Umemura, K. Antithrombotic effect of geniposide and genipin in the mouse thrombosis model. Planta Med. 2001, 67, 807–810. [Google Scholar] [CrossRef] [PubMed]
  188. Yang, M.; Chen, X.Y.; Zhang, H.Y.; Wang, J.M.; Lu, Q.; Song, W. Pharmacokinetics of geniposide through 4 routes of administration. Chin. J. New Drugs 2010, 19, 746–750. [Google Scholar]
  189. Zhan, H.L.; Wang, Y.G.; Zhu, Z.Y.; Hua, L.; Zhao, Y.; Xu, R.X.; Lei, F.; Du, L.J. Transdermal Behavior of Geniposide in Shangyi Aerosol in vivo and in vitro. World Sci. Technol. Mod. Tradit. Chin. Med. Mater. Med. 2010, 12, 413–417. [Google Scholar]
  190. Li, Y.; Cai, W.; Cai, Q.; Che, Y.Y.; Zhao, B.S.; Zhang, J.Y. Comprehensive characterization of the in vitro and in vivo metabolites of geniposide in rats using ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer. Xenobiotica 2016, 46, 357–368. [Google Scholar] [CrossRef] [PubMed]
  191. Chen, J.; Wu, H.; Dai, M.M.; Li, H.; Chen, J.Y.; Hu, S.L. Identification and distribution of four metabolites of geniposide in rats with adjuvant arthritis. Fitoterapia 2014, 97, 111–121. [Google Scholar] [CrossRef] [PubMed]
  192. Hu, F.D.; An, J.; Li, W.; Zhang, Z.J.; Chen, W.X.; Wang, C.H.; Wang, Z.T. UPLC-MS/MS determination and gender-related pharmacokinetic study of five active ingredients in rat plasma after oral administration of Eucommia cortex extract. J. Ethnopharmacol. 2015, 169, 145–155. [Google Scholar] [CrossRef] [PubMed]
  193. Zhang, X.J.; Wang, L.; Zheng, Z.; Pi, Z.F.; Liu, Z.Q.; Song, F.R. Online microdialysis-ultra performance liquid chromatography-mass spectrometry method for comparative pharmacokinetic investigation on iridoids from Gardenia jasminoides Ellis in rats with different progressions of type 2 diabetic complications. J. Pharm. Biomed. Anal. 2017, 140, 146–154. [Google Scholar] [CrossRef] [PubMed]
  194. Wang, Y.J.; Wen, J.; Zheng, W.H.; Zhao, L.S.; Fu, X.H.; Wang, Z.Z.; Xiong, Z.L.; Li, F.M.; Xiao, W. Simultaneous determination of neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid and geniposide in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study after administration of Reduning injection. Biomed. Chromatogr. 2015, 29, 68–74. [Google Scholar] [CrossRef] [PubMed]
  195. Wu, X.J.; Zhao, L.M. Serum pharmacochemistry and pharmarcokinetic study of Naoxuening Injection. Trdit. Chin. Drug Res. Clin. Pharmacol. 2008, 19, 376–379. [Google Scholar]
  196. Wang, Z.Y.; Zhang, H.Y.; Yang, M.; Gao, L.T.; Lu, Q.; Song, W.; Liu, H.; Wang, J.M. Preliminary studies on liver toxicity of geniposide with four different pathways of administration. Prog. Mod. Biomed. 2013, 13, 824–827. [Google Scholar]
  197. Li, D.F.; Cheng, L.; Wu, H.W.; Zong, G.Z.; Zhang, Y.; Yang, H.J. Comparative study of hepatoxicity induced by geniposide in SD rat, Wistar rat and ICR mouse. Chin. J. Exp. Tradit. Med. Formulae 2007, 13, 31–33. [Google Scholar]
  198. Meier, J.J.; Gallwitz, B.; Salmen, S.; Goetze, O.; Holst, J.J.; Schmidt, W.E.; Nauck, M.A. Normalization of glucose concentrations and deceleration of gastric emptying after solid mealsduring intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 2003, 88, 2719–2725. [Google Scholar] [CrossRef] [PubMed]
  199. Okerson, T.; Chilton, R.J. The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc. Ther. 2012, 30, 146–155. [Google Scholar] [CrossRef] [PubMed]
  200. Saraiva, F.K.; Sposito, A.C. Cardiovascular effects of glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovasc. Diabetol. 2014, 13. [Google Scholar] [CrossRef] [PubMed]
  201. Seufert, J.; Gallwitz, B. The extra-pancreatic effects of GLP-1 receptor agonists: A focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes. Metab. 2014, 16, 673–688. [Google Scholar] [CrossRef] [PubMed]
  202. Darsalia, V.; Larsson, M.; Nathanson, D.; Klein, T.; Nyström, T.; Patrone, C. Glucagon-like receptor 1 agonists and DPP-4 inhibitors: Potential therapies for the treatment of stroke. J. Cereb. Blood Flow Metab. 2015, 35, 718–723. [Google Scholar] [CrossRef] [PubMed]
  203. Liu, Q.; Lu, B.P.; Jia, R. Preliminary study on the establishment of mouse model of liver injury by perfusing stomach with geniposide. China J. Chin. Med. 2013, 28, 994–996. [Google Scholar]
Figure 1. Chemical structure of geniposide.
Figure 1. Chemical structure of geniposide.
Molecules 22 01689 g001
Figure 2. Chemical structures of some representative geniposide derivatives.
Figure 2. Chemical structures of some representative geniposide derivatives.
Molecules 22 01689 g002aMolecules 22 01689 g002b
Table 1. Plants containing geniposide.
Table 1. Plants containing geniposide.
No.PlantFamilyPartReferences
1Achyranthes bidentata BlumeAmarathaceaeroots[18]
2Adina polycephala Benth.Rubiaceaebranches and stems[19]
3Alibertia sessilis (Vell.) K. Schum.Rubiaceaestems[20]
4Biebersteinia heterostemon Maxim.Geraniaceaewhole plants[21]
5Castilleja tenuiflora Benth.Orobanchaceaewhole plants[22]
6Cistanche deserticola Y. C. MaOrobanchaceaestems[23]
7Codonopsis pilosula (Franch.) Nannf.Campanulaceaeroots[24]
8Cornus suecica L.Cornaceaewhole plants[25]
9Cynanchum wilfordii (Maxim.) Hemsl.Asclepiadaceaeroots[26]
10Dryopteris fragrans (L.) SchottDryopteridaceaewhole plants[27]
11Eucommia ulmoides Oliv.Eucommiaceaebarks[28]
leaves[29]
12Gardenia jasminoides cv. fortuneana HaraRubiaceaeleaves[30]
13Gardenia jasminoides forma grandiflora (Lour.) MakinoRubiaceaefruits[31]
leaves[32]
14Gardenia jasminoides var. radicans (Thunb.) MakinoRubiaceaefruits[33]
15Gardenia jasminoides EllisRubiaceaeflowers[34]
fruits[35]
leaves[36]
tubers[37]
16Gardenia sootepensis Hutchins.Rubiaceaefruits[38]
17Globularia davisiana O. SchwarzGlobulariaceaeaerial parts[39]
18Genipa americana L.Rubiaceaefruits[40]
19Hedyotis diffusa Willd.Rubiaceaewhole plants[41]
20Hedyotis corymbosa (Linn.) Lam.Rubiaceaewhole plants[42]
21Lantana camara L.Verbenaceaeroots[43]
22Lippia alba (Mill.) N.E. BrownVerbenaceae [44]
23Lonicera japonica Thunb.Caprifoliaceaeflower buds[45]
24Oroxylum indicum (L.) KurzBignoniaceaeseeds[46]
25Paederia scandens (Lour.) MerrillRubiaceaeroots[47]
26Randia spinosa (Thunb.) Tirveng.Rubiaceaestems[48]
27Rehmannia glutinosa Libosch.Scrophulariaceaeroots[49]
28Rothmanniaglobosa (Hochst.) KeayRubiaceaefruits[50]
29Scrophularia ningpoensis Hemsl.Scrophulariaceaeroots[51]
30Stemona japonica (Bl.) Miq.Stemonaceaeroots[52]
31Strychnos nux-vomica L.Loganiaceaeseeds[53]
32Tinospora sagittata var. yunnanensis (S. Y. Hu) H. S. LoMenispermaceaeroots[54]
33Vangueria edulis VahlRubiaceaeflowers and leaves[55]
34Vitex cannabifolia Sieb. et Zucc.Verbenaceaefruits[56]
Table 2. Natural derivatives of geniposide.
Table 2. Natural derivatives of geniposide.
No.CompoundsSources
1AlpinosideGlobularia alypum L. leaves [57], Globularia aphyllanthes Crantz aerial parts [58], Globularia cordifolia L. underground parts [59], Globularia davisiana O. Schwarz aerial parts [39], Globularia dumulosa O. Schwarz aerial parts [60], Globularia trichosantha Fisch. & C. A. Meyer whole plants [61], Plantago asiatica L. seeds [62], Plantago alpina L. aerial parts [63] and Veronica cymbalaria Bodard. aerial parts [64]
2ApodanthosideDioecrescis erythroclada (Kurz) Tirveng leaves and branches [65], Tocoyena Formosa (Cham. & Schltdl.) K. Schum. stems [66] and Vangueria edulis Vahl flowers and leaves [55]
3Asperulosidic acidBorreria verticillata (L.) G. Mey. root barks [67], Diodia teres Walter whole plants [68], Eucommia ulmoides Oliv. leaves [69], Galium aegeum (Stoj. & Kitan.) Ancev aerial parts [70], Galium humifusum Bieb. aerial parts [71], Galium macedonicum Krendl. aerial parts [70], Galium melanantherum Boiss aerial parts [72], Galium mirum Rech. Fil. aerial parts [70], Galium rhodopeum Velen. aerial parts [70], Galium rivale (Sibth. and Sm.) Griseb. aerial parts [73], Galium verum subsp. verum L. aerial parts [74], Globularia aphyllanthes Crantz aerial parts [58], Globularia trichosantha Fisch. & C. A. Meyer whole plants [61], Hedyotis corymbosa (Linn.) Lam. whole plants [42] and aerial plants [75], Hedyotis tenelliflora Blume whole plants [76], Lasianthus acuminatissimus Merr. roots [77], Morinda citrifolia L. fruits [78] and seeds [79], Oldenlandia diffusa Roxb. aerial parts [80], Oldenlandia umbellata L.aerial parts [81], Paederia scandens (Lour.) Merrill roots [47] and Saprosma scortechinii Bl. King & Gamble stems [82]
4DaphyllosideAsperula lilaciflora Boissaerial parts [83], Borreria verticillata (L.) G. Mey. root barks [67], Globularia aphyllanthes Crantz aerial parts [58], Galium aegeum (Stoj. & Kitan.) Ancev aerial parts [70], Galium humifusum Bieb.aerial parts [71], Galium macedonicum Krendl. aerial parts [70], Galium mirum Rech. Fil. aerial parts [70], Galium verum subsp. verum L. aerial parts [74], Hedyotis corymbosa (Linn.) Lam.whole plants [84], Hedyotis diffusa Willd. whole plants [41], Hedyotis tenelliflora Blume leaves [85] and Lasianthus wallichii (Wight & Arn.) Wight leaves [86]
5DeacetylalpinosideGlobularia dumulosa O. Schwarz aerial parts [60], Globularia trichosantha Fisch. & C. A. Meyer whole plants [61]
6Deacetylasperulosidic acidAsperula lilaciflora Boiss aerial parts [83], Borreria verticillata (L.) G. Mey. root barks [67], Eucommia ulmoides Oliv. leaves [69], Jasminum officinale L. var. grandiflorum buds [87], Galium aegeum (Stoj. & Kitan.) Ancev aerial parts [70], Galium humifusum Bieb. aerial parts [71], Galium macedonicum Krendl. aerial parts [70], Galium melanantherum Boiss aerial parts [72], Galium mirum Rech. Fil. aerial parts [70], Galium rhodopeum Velen. aerial parts [70], Galium rivale (Sibth. and Sm.) Griseb. aerial parts [73], Galium verum subsp. verum L. aerial parts [74], Hedyotis corymbosa (Linn.) Lam. whole plants [84], Lasianthus acuminatissimus Merr. roots [77], Morinda citrifolia L. fruits [78] and seeds [79], Morinda officinalis How roots [88], Oldenlandia diffusa Roxb. aerial parts [80], Paederia scandens (Lour.) Merrill var. Mairei (Leveille) Hara whole plants [89], Saprosma scortechinii Bl. King & Gamble leaves and stems [82] and Serissa serissoides (DC.) Druce whole plants [90]
7GaliosideCornus canadensis L.leaves [91], Gardenia jasminoides cv. fortuneana Hara leaves [30], Hedyotis diffusa Willd. whole plants [41], Morinda officinalis How roots [92], Randia spinosa (Thunb.) Tirveng. stems [48] and Tocoyena Formosa (Cham. & Schltdl.) K. Schum. stems [66]
8GardenosideDicliptera chinensis (L.) Juss. whole plants [93], Dioecrescis erythroclada (Kurz) Tirveng leaves and branches [65], Gardenia jasminoides Ellis flowers [34], fruits [94] and leaves [36], Gardenia jasminoides cv. fortuneana Hara leaves [30], Genipa americana L. fruits [40], Hedyotis diffusa Willd. whole plants [37] and Randia spinosa (Thunb.) Tirveng. stems [48]
9Geniposidic aicdAdina polycephala Benth. branches and stems [19], Alibertia myrciifolia Spruce ex K. Schum. aerial parts [95], Alibertia sessilis (Vell.) K. Schum. stems [20], Asperula lutea subsp. rigidula aerial parts [96], Bellardia trixago (L.) All. whole plants [97], Canthium gilfillanii leaves [98], Castilleja tenuiflora Benth. aerial parts [99], Diodia teres Walter whole plants [68], Eremophila longifolia F. Muell. leaves [100], Eucommia ulmoides Oliv. leaves [69,101], Euphrasia pectinata Ten. aerial parts [102], Galium aegeum (Stoj. & Kitan.) Ancev aerial parts [70], Galium humifusum Bieb. aerial parts [71], Galium melanantherum Boiss aerial parts [72], Galium mirum Rech. Fil. aerial parts [70], Galium rhodopeum Velen. aerial parts [70], Galium rivale (Sibth. and Sm.) Griseb. aerial parts [73], Gardenia sootepensis Hutchins. fruits [38], Gardenia jasminoides fruits [103], Genipa americana L. fruits [40], Globularia trichosantha Fisch. & C. A. Meyer whole plants [61], Lantana montevidensis (Spreng.) Briq. roots [104], Morinda longissima Y. Z. Ruan roots [105], Oldenlandia diffusa Roxb. aerial parts [80], Pedicularis longiflora Rudolph whole plants [106], Pedicularis plicata Maxim whole plants [107], Pedicularis verticillata L. whole plants [108], Plantago alpina L. aerial parts [63], Plantago depressa Willd whole plants [109], Rehmannia glutinosa Libosch. roots [49,110], Scyphiphora hydrophyllacea Gaertn. F. aerial parts [111] and stem barks [112], Vangueria edulis Vahl flowers and leaves [55], Verbascum lasianthum Boiss. ex Bentham flowers [113], Veronica anagallis-aquatica L. whole plants [114], Veronica bellidioides L. aerial parts [115] and Veronica kellererii aerial parts [115]
10Genipin 1,10-di-O-β-d-glucopyranosideGardenia jasminoides Ellis flowers [34] and fruits [94] and Genipa americana L. fruits [40]
11Genipin gentiobiosideGardenia jasminoides Ellis flowers [34] and fruits [94,103], Gardenia jasminoides forma grandiflora (Lour.) Makino fruits [31] and leaves [32], Genipa americana L. fruits [40] and Rehmannia glutinosa Libosch roots [110]
12Genipin isomaltosideGardenia jasminoides Ellis flowers and fruits [94]
13Jasmigeniposide AGardenia jasminoides Ellis fruits [103]
14Jasmigeniposide BGardenia jasminoides Ellis fruits [103]
15MajorosidePlantago asiatica L.seeds [62], Plantago cornuti Gouan L. aerial plants [64], Plantago depressa Willd whole plants [109] and Platago major L. aerial parts [116]
16MonotropeinCornus canadensis L. leaves [91], Cornus suecica L.whole plants [25], Coussarea platyphylla Müll. Arg. [117], Damnacanthus officinarum Huang roots [118], Galium aegeum (Stoj. & Kitan.) Ancev aerial parts [70], Galium humifusum Bieb.aerial parts [71], Galium macedonicum Krendl. aerial parts [70], Galium melanantherum Boiss aerial parts [72], Galium mirum Rech. Fil. aerial parts [70], Galium rhodopeum Velen. aerial parts [70], Galium rivale (Sibth. and Sm.) Griseb.aerial parts [73], Galium verum subsp. verum L. aerial parts [74], Morinda officinalis How roots [88], Pyrola calliatha H. Andres whole plants [119], Pyrola decorate leaves [120], Pyrola elliptica roots [121], Pyrola japonica whole plants [122], Pyrola xinjiangensis Y. L. Chou whole plants [123] and Saprosma scortechinii Bl. King & Gamble leaves [82]
17Paederosidic acidPaederia pertomentosa Merr. ex Li aerial parts [124], Paederia scandens (Lour.) Merrill roots [47] and stems [125], Paederia scandens (Lour.) Merrill var. Mairei (Leveille) Hara whole plants [89], Saprosma fragrans Beddome aerial parts [126], Saprosma scortechinii Bl. King & Gamble leaves and stems [82] and Serissa serissoides (DC.) Druce whole plants [90]
18Paederosidic acid methyl esterPaederia scandens (Lour.) Merrill roots [47] and stems [125]
19ScandosideAsperula lutea subsp. rigidula aerial parts [96], Cornus canadensis L. leaves [91], Galium aegeum (Stoj. & Kitan.) Ancev aerial parts [70], Galium humifusum Bieb. aerial parts [71], Galium macedonicum Krendl. aerial parts [70], Galium melanantherum Boiss aerial parts [72], Galium mirum Rech. Fil. aerial parts [70], Galium rhodopeum Velen. aerial parts [70], Galium rivale (Sibth. and Sm.) Griseb. aerial parts [73], Globularia aphyllanthes Crantz aerial parts [58], Globularia trichosantha Fisch. & C. A. Meyer whole plants [61], Oldenlandia diffusa Roxb. aerial parts [80], Oldenlandia umbellata L. aerial parts [81], Paederia scandens (Lour.) Merrill var. Mairei (Leveille) Hara whole plants [89] and Saprosma scortechinii Bl. King & Gamble stems [82]
20Scyphiphorin AHedyotis corymbosa (Linn.) Lam. whole plants [127] and Scyphiphora hydrophyllacea Gaertn. F. stem barks [112]
21Scyphiphorin BScyphiphora hydrophyllacea Gaertn. F. stem barks [112]
22Scyphiphorin CScyphiphora hydrophyllacea Gaertn. F. stem barks [128]
23Scyphiphorin DScyphiphora hydrophyllacea Gaertn. F. stem barks [128]
24ThevesideLantana montevidensis (Spreng.) Briq. roots [104] and Lippia alba leaves [129]
254′-O-β-d-Glucopyranosyl-geniposideGenipa americana L. fruits [40]
264′′-O-(E)-p-Coumaroylgenipin gentiobiosideGardenia jasminoides Ellis fruits [130]
276α-HydroxygeniposideAdina polycephala Benth. branches and stems [19], Alibertia sessilis (Vell.) K. Schum. stems [20], Galium aegeum (Stoj. & Kitan.) Ancev aerial parts [70], Galium macedonicum Krendl. aerial parts [70], Galium melanantherum Boiss aerial parts [72], Galium verum L. whole plants [131], Galium verum subsp. verum L. aerial parts [74], Gardenia jasminoides Ellis flowers [34], fruits [94] and tubers [37], Gardenia jasminoides cv. fortuneana Hara leaves [30], Gardenia jasminoides forma grandiflora (Lour.) Makino leaves [32], Gardenia sootepensis Hutchins. fruits [38], Hedyotis corymbosa (Linn.) Lam.whole plants [84], Hedyotis diffusa Willd. whole plants [41], Hedyotis tenelliflora Blume leaves [85], Oldenlandia umbellata L. aerial parts [81], Paederia pertomentosa Merr. ex Li aerial parts [124], Paederia scandens (Lour.) Merrill stems [125], Pittosporum glabratum Lindl. roots [132], Plantago lagopus L. aerial parts [133] and Randia spinosa (Thunb.) Tirveng. stems [48]
286α-MethoxygeniposideGardenia jasminoides Ellis fruits [94], Hedyotis tenelliflora Blume leaves [85]
296α-n-ButoxygeniposideGardenia jasminoides Ellis forma grandiflora (Lour.) Makino fruits [134]
306α-Methoxygeniposidic acidHedyotis tenelliflora Blume leaves [85]
316β-EthoxygeniposideGardenia jasminoides Ellis flowers [34]
326β-HydroxygeniposideAdina polycephala Benth. branches and stems [19], Alibertia sessilis (Vell.) K. Schum.stems [20], Biebersteinia heterostemon Maxim.whole plants [21], Borreria verticillata root barks [67], Cornus canadensis L. leaves [91], Gardenia jasminoides cv. fortuneana Hara leaves [30], Gardenia jasminoides Ellis flowers [34] and fruits [94], Gardenia jasminoides forma grandiflora (Lour.) Makino leaves [32], Gardenia sootepensis Hutchins. fruits [38], Hedyotis corymbosa (Linn.) Lam. whole plants [42,79] and aerial plants [74], Hedyotis diffusa Willd. whole plants [41], Hedyotis tenelliflora Blume leaves [85] and roots [135], Morinda citrifolia L. fruits [78], Oldenlandia diffusa Roxb. aerial parts [80], Oldenlandia umbellata L. aerial parts [81], Randia spinosa (Thunb.) Tirveng. stems [48], Vangueria edulis Vahl flowers and leaves [55] and Wendlandia formosana Cowan leaves [136]
336β-MethoxygeniposideHedyotis tenelliflora Blume leaves [85] and Wendlandia formosana Cowan leaves [136]
346β-n-ButoxygeniposideGardenia jasminoides Ellis flowers [34] and Gardenia jasminoides Ellis forma grandiflora (Lour.) Makino fruits [134]
356β-O-β-d-Glucosylpaederosidic acidPaederia scandens (Lour.) Merrill stems [125]
366β-O-(E)-p-methoxy-cinnamoylgeniposideHedyotis diffusa Willd.aerial parts [137,138] and whole plants [139]
376β-O-(E)-FeruloylgeniposideHedyotis diffusa Willd.aerial parts [137,138] and whole plants [139]
386β-O-(E)-p-Coumaroyl-geniposideHedyotis diffusa Willd.aerial parts [137,138] and whole plants [139]
396β-O-(Z)-FeruloylgeniposideHedyotis diffusa Willd.aerial parts [138]
406β-O-(Z)-p-Methoxycinnamoyl-geniposideHedyotis diffusa Willd.aerial parts [138] and whole plants [139]
416β-O-(Z)-p-Coumaroyl-geniposideHedyotis diffusa Willd.aerial parts [138] and whole plants [139]
426-epi-Paederosidic acidSaprosma scortechinii Bl. King & Gamble stems [82]
436-O-AcetylscandosideGalium aegeum (Stoj. & Kitan.) Ancev aerial parts [70]
446′-O-(E)-p-CoumaroylgeniposideGardenia jasminoides Ellis fruits [35,140]
456′-O-(E)-p-coumaroyl-geniposidic acidGardenia jasminoides Ellis fruits [35]
466′-O-AcetylgeniposideGardenia jasminoides Ellis fruits [35,140]
476′-O-(E)-SinapoylgeniposideGardenia jasminoides Ellis fruits [35,130,140]
486’-O-(E)-caffeoyl-6α-hydroxygeniposideGardenia jasminoides Ellis fruits [130]
496′′-O-(E)-Sinapoylgenipin gentiobiosideGardenia jasminoides Ellis fruits [35,101]
506′′-O-(E)-p-Coumaroylgenipin gentiobiosideGardenia jasminoides Ellis fruits [35,103,130]
516′′-O-(E)-Cinnamoylgenipin gentiobiosideGardenia jasminoides Ellis fruits [35]
526′′-O-(E)-Feruloylgenipin gentiobiosideGardenia jasminoides Ellis fruits [103]
536′′-O-(Z)-p-Coumaroylgenipin gentiobiosideGardenia jasminoides Ellis forma grandiflora (Lour.) Makino fruits [134]
548α-ButylgaliosideGardenia jasminoides Ellis flowers [34]
558-epi-ApodantherosideGardenia jasminoides cv. fortuneana Hara leaves [30]
569-epi-6α-Methoxygeniposidic acidMorinda citrifolia L. fruits [78]
5710-AcetoxymajorosidePlantago cornuti Gouan L. aerial plants [64], Platago major L. aerial parts [64]
5810-AcetylscandosideSaprosma scortechinii Bl. King & Gamble stems [82]
5910-Deoxygeniposidic acidScyphiphora hydrophyllacea Gaertn. F. stem barks [128]
6010-HydroxymajorosidePlantago asiatica L. seeds [62], Plantago cornuti Gouan L. aerial parts [141], Plantago depressa Willd whole plants [109], Platago major L. aerial parts [64]
6110-MethoxyapodanthosideVangueria edulis Vahl flowers and leaves [55]
6210-O-(4′′-O-Methylsuccinoyl)-geniposdeGardenia jasminoides Ellis fruits [140]
6310-O-AcetylgeniposideGardenia jasminoides Ellis fruits [35,140]
6410-O-Acetylgeniposidic acidPlantago alpina L. aerial parts [63] and Scyphiphora hydrophyllacea Gaertn. F. stem barks [128]
6510-O-AcetylscandosideEucommia ulmoides Oliv. Leaves [69]
6610-O-Benzoyl-6α-hydroxygeniposideHedyotis corymbosa (Linn.) Lam. whole plants [84,127] and aerial plants [75]
6710-O-Benzoyl-6β-hydroxygeniposideHedyotis corymbosa (Linn.) Lam. whole plants [42,84,127] and aerial plants [75] and Oldenlandia diffusa Roxb. aerial parts [80]
6810-O-BenzoylgeniposideHedyotis corymbosa (Linn.) Lam. whole plants [127]
6910-O-Benzoyldeacetyl-asperulosidic acidSaprosma scortechinii Bl. King & Gamble stems [82]
7010-O-Benzoyl-6′-O-arabinosyl-6β-hydroxygeniposideOldenlandia diffusa Roxb. aerial parts [80]
7110-O-Caffeoyl-6β-hydroxygeniposideWendlandia formosana Cowan leaves [136]
7210-O-CaffeoyldaphyllosideWendlandia formosana Cowan leaves [136]
7310-O-(E)-3,4-Dimethoxycinnamoyl-geniposidic acidLeonotis nepetaefolia (L.) R. Br. stems [142]
7410-O-(E)-Caffeoylgeniposidic acidAvicennia marina (Forssk.) Vierh. whole plants [143]
7510-O-(E)-Caffeoyl-6α-hydroxygeniposideGardenia jasminoides Ellis tubers [37]
7610-O-(E)-Cinnamoylgeniposidic acidAvicennia marina (Forssk.) Vierh.whole plants [143]
7710-O-(E)-p-Coumaroyl-6β-hydroxygeniposideHedyotis corymbosa (Linn.) Lam. whole plants [42,127] and aerial plants [75]
7810-O-(E)-p-Coumaroyl-geniposidic acidAvicennia marina (Forssk.) Vierh. whole plants [143]
7910-O-p-Hydroxybenzoyl-6β-hydroxygeniposideHedyotis corymbosa (Linn.) Lam. whole plants [42,127] and aerial plants [75]
8010-O-p-Hydroxybenzoyl-geniposidicacidLeonotis nepetaefolia (L.) R. Br. stems [142]
8110-O-p-Hydroxybenzoyl-geniposideHedyotis corymbosa (Linn.) Lam. whole plants [127]
8210-O-SuccinoylgeniposideGardenia jasminoides Ellis fruits [35]
8310-O-Vanilloyl geniposidic acidAlibertia myrciifolia Spruce ex K. Schum. aerial parts [95]
8410-O-(Z)-p-CoumaroylmonotropeinVaccinium bracteatum Thunb. branches and leaves [144]
Table 3. Other pharmacological effects of geniposide.
Table 3. Other pharmacological effects of geniposide.
FunctionInducerModelEfficacy EvaluationReference
Anti-allergy
(in vitro)
Compound 48/80MC/9 cellsInhibited histamine release[180]
Anti-depression
(in vivo)
STZMice (i.g.; 50, 100 mg/kg)Attenuated increased immobility time in FST,
elevated BDNF levels,
upregulated the mRNA expression of BDNF and TrkB
[181]
Anti-enterovirus
(in vitro)
EV 71Rd cells (1, 2, 3 mg/mL)Inhibited both EV71 replication and viral IRES activity[182]
Anti-hypopigmentation
(in vitro)
NorepinephrineHuman epidermal melanocyte
(1, 10,100 μM)
Upregulated c-kit production,
abrogated the repression of tyrosinase activity and melanin production
[183]
Anti-hyperuricemia
(in vivo)
Potassium oxonateMice
(i.g.; 50, 100, 200 mg/kg)
Reduced SUA level,
Elevated UUA level
[184]
Anti-osteoporosis
(in vitro)
-Osteoblast-like cells (MG-63, Saos-2), osteoclast (10−1–10−5 mg/mL)Increased proliferation of osteoblast-like cells and proline incorporation activity, Inhibited osteoclast activity[185]
Anti-oxidation
(in vitro)
H2O2HUVEC
(12.5, 25, 50 μg/mL)
Increased the viability of injured cells,
increased the activities of SOD, GSH-Px, NOS and NO production,
decreased intracellular ROS level,
reduced apoptosis rate,
restored the potential of cell proliferation
[186]
Anti-thrombosis
(in vivo)
Photochemical reactionMale ICR mice (i.v.; 20, 40 mg/kg)Prolonged the time required for thrombotic occlusion[187]
CollagenBlood (7.7, 26, 77 μM)Inhibited platelet aggregation and PLA2 activity.
BDNF = brain-derived neurotrophic factor; EV = enterovirus; FST = forced swimming test; GSH-Px = glutathione peroxidase; HUVEC = human umbilical vein endothelial cell; IRES = internal ribosome entry site; NOS = nitric oxide synthase; PLA2 = phospholipase A2; SUA = serum uric acid; TrkB = tropomyosin-related kinase B; and UUA = urinary uric acid. - indicates no inducer.
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