Geniposide

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Geniposide
Geniposide structure
Names
IUPAC name
Methyl (1S,4aS,7aS)-1-(β-D-glucopyranosyloxy)-7-(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate
Systematic IUPAC name
Methyl (1S,4aS,7aS)-7-(hydroxymethyl)-1-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate
Other names
Jasminoidin;[1] methyl 1-(hexopyranosyloxy)-7-(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.208.687 Edit this at Wikidata
EC Number
  • 683-175-1
KEGG
MeSH geniposide
UNII
  • InChI=1S/C17H24O10/c1-24-15(23)9-6-25-16(11-7(4-18)2-3-8(9)11)27-17-14(22)13(21)12(20)10(5-19)26-17/h2,6,8,10-14,16-22H,3-5H2,1H3/t8-,10-,11-,12-,13+,14-,16+,17+/m1/s1
    Key: IBFYXTRXDNAPMM-BVTMAQQCSA-N checkY
  • COC(=O)C1=COC(C2C1CC=C2CO)OC3C(C(C(C(O3)CO)O)O)O
Properties
C17H24O10
Molar mass 388.369 g·mol−1
Melting point 245.23 °C (473.41 °F; 518.38 K)
Boiling point 641.4±55.0 °C at 760 mmHg
log P -1.854
Acidity (pKa) 12.80±0.70
Hazards
GHS labelling:
GHS06: Toxic
Danger
H301
P264, P270, P301+P310, P321, P330, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Geniposide, the

iridoid glycoside that is found in a wide variety of medicinal herbs, such as Gardenia jasminoides (fruits) .[2]
Geniposide shows several pharmacological effects (in vitro and in vivo) including neuroprotective, antidiabetic, hepatoprotective, anti-inflammatory, analgesic, antidepressant-like, cardioprotective, antioxidant, immune-regulatory, antithrombotic and antitumoral activity.[3] These pharmacology benefits arise through the modulating action of geniposide on several proteins and genes that are associated with inflammatory and oxidative stress processes.[4]

Physiological activity

Neuroprotective

A growing body of evidence shows that the neuroprotective benefit of geniposide probably arises from its agonist action on the

synapses, reducing oxidative stress and the chronic inflammatory response.,[5][6]
These effects could be promising in the treatment of Alzheimer's and Parkinson's diseases.

Antidepressant-Like

Studies on depressive rats (induced by chronic unpredictable mild stress) have shown that the antidepressant effect of geniposide is similar to

5-hydroxytryptamine (5-HT) in the hippocampus.[7][8]
Geniposide was able to reverse the high levels of cortisol and hypothalamic corticotropin-releasing hormone gene expression, which lead to an increase of 5-HT in the hippocampus and 5-Hydroxyindoleacetic acid (5-HIAA) in striatum.[7]

Antioxidant

Geniposide shows a reasonable capacity of induction of endogenous antioxidative proteins, which offer protection against cell injury by oxidative stress. A study with hippocampal neurons revealed that geniposide could enhance cytoprotection, though the activation of the enzyme

Phosphoinositide 3-kinases (PI3K) and the induction of the nuclear translocation of erythroid 2–related factor 2 (NFE2L2).[9]
The PI3K/Nrf2 pathway signaling triggers several responses, such as the expression of antioxidative enzymes
NAD(P)H dehydrogenase quinone 1 (NQO1), reducing accumulation of reactive oxygen species (ROS).[10]

Anti-inflammatory

Several studies have shown geniposide's potential to treat inflammatory diseases, such as arthritis, due to its effect in the production on cytokine and pro-inflammatory mediators. In rats with arthritis, oral administration of geniposide (30, 60, and 120 mg/kg) shows a decrease in T helper 17 cell cytokines such as

TGF-beta 1).[2][11]
Another study revealed that geniposide's effect was probably enhanced by immunoregulation in immunologic tissues, such as gut-associated lymphoid tissue (GALT). When regulating, the mesenteric lymph node triggers the amelioration of the JNK-mitogen-activated protein kinases (MAPKs) and p38 mitogen-activated protein kinases (p38MAPKs) signaling cascades. The same pathway was observed in peripheral blood lymphocytes.[12]

Antidiabetic activity

Geniposide has been reported as having a hypoglycemic effect, which could be mediated by hepatic glucose-metabolizing enzymes, such as hepatic

glucose-6-phosphatase (G6Pase).[13]
GP and G6Pase are induced by chronic hyperglycemia. High levels of blood sugar increased their expression and activity, which lead to an increase in hepatic glucose production and unbalance the glucose metabolism.[14] A study with the high-fat diet (HFD) - streptozotocin (STZ) diabetic mouse model using geniposides doses of 200 and 400 (mg/kg) has shown a significant decrease in body weight, blood glucose, insulin and triglycerides (TG) levels. An increase in the activity of GP and G6Pas was also observed in this diabetic mouse model, but when the same geniposide doses were administered, activity decreased significantly.[13]

Pharmacokinetics

Absorption

Studies show that oral (50 mg/kg), intravenous (50 mg/kg) and intramuscular (8 mg/kg) administration of Geniposide follow a one-compartment model and nasal administration (8 mg/kg) a two-compartment model. The absolute bioavailability is higher in intramuscular administration (F = 72,69%) followed by nasal administration (F = 49,54%).[15]

Distribution

In rats, after an oral administration of geniposide (200 mg/kg) the highest tissue concentration was observed in the kidney (1.12 ± 0.37 μg/ml) with a tmax of 2h. The tissue distribution, measured in terms of AUC0→4h values, follows kidney > spleen> liver > heart > lung> brain.[16]

Metabolism

Using ultrahigh-performance liquid chromatography 17 metabolites were identified in plasma and 31 in urine. In vivo, geniposide can follow two distinct metabolic pathways. The main metabolic pathway involves the hydrolysis of the

hydroxyl groups followed by a series of reactions, such as taurine, sulfate and glucuronide conjugation.[3][17]

Excretion

In humans, the majority of excretion of Geniposide is urinary.[3]

Toxicity

Hepatoxicity is a safety issue of geniposide. Several studies in rats have shown an increase in serum

aspartate aminotransferase activities (oral administration of 320 mg/kg body weight).[18]
A 2012 study linked geniposide hepatoxicity with oxidative stress, due to a decrease of total superoxide dismutase activity and an increase of malondialdehyde concentration in rats’ livers. These results were associated only with a high dose of geniposide (greater than 574 mg/kg).[19] A repeated dosing study has shown that geniposide is safe at a dosage of 24.3 mg/kg or less.[19]

Acute nephrotoxicity was observed after an oral administration of geniposide (dose of 1.2 g/kg) on

urea nitrogen and creatinine were detected.[20]

Long-term oral intake of Chinese herbal liquid containing geniposide may play a role in the pathogenesis of idiopathic mesenteric phlebosclerosis.[21]

References

  1. ^ CID 387043706 from PubChem
  2. ^
    PMID 31118959
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  3. ^
    PMID 28994736
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  4. PMID 31089416
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  5. S2CID 32753663
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  6. S2CID 38096561
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  7. ^
    S2CID 45890530
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  8. PMID 8706631
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  9. PMID 21048309
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  10. PMID 31257486
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  11. S2CID 41542274
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  12. PMID 24583144
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  13. ^
    PMID 19122671
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  14. PMID 9502760
    .
  15. ^ Yang M, Chen XY, Zhang HY, et al. (January 2010). "Pharmacokinetics of geniposide through 4 routes of administration". Chinese Journal of New Drugs. 19 (9): 746–749+754.
  16. S2CID 44774570
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  17. S2CID 32443681
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  18. PMID 2210524
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  19. ^
    S2CID 2310392
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  20. doi:10.13422/j.cnki.syfjx.2015040174
    .
  21. PMID 34168411
    .
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