Protective Role of St. John’s Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies
Abstract
:1. Introduction
2. Inflammatory Signaling and Diabetes
3. Anti-Inflammatory Drugs against Diabetes
4. SJW and Its Components
5. Mechanisms of the Anti-Inflammatory Activities of SJW and Its Components
5.1. Inhibition of Cytokine-Induced Activation of STAT, NF-kB and MAPK Signaling
5.2. Inhibition of Phospholipid-Derived Inflammatory Mediators by SJW and HPF
5.3. Free Radical Scavenging and Antioxidant Activity of SJW and HPF
5.4. Activation of AMPK by SJW and Its Components
5.5. Anti-Inflammatory Effects of SJW and HPF Mediated by PXR Activation
5.6. Neuroprotective Effects of SJW and HPF Mediated by Anti-Inflammatory Mechanisms
5.7. Beneficial Effects of SJW and HPF in Various Experimental Models of Acute and Chronic Inflammation
6. Effects of SJW Extract, HPF and HYP in β Cells and Isolated Pancreatic Islets
7. Effects of SJW Extract and HPF in Adipocytes
8. Effects of SJW Extract: In Vivo Studies
9. Effects of SJW on Diabetic Complications
10. Discussion
11. Concluding Remarks and Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
T1D | type 1 diabetes mellitus |
T2D | type 2 diabetes mellitus |
IFN | interferon |
IL | interleukin |
TNF | tumor necrosis factor |
MCP-1 | monocyte chemoattractant protein-1 |
M1-macrophages | classically activated M1 macrophages |
SJW | St. John’s wort |
HPF | hyperforin |
HYP | hypericin |
STAT | signal transducer and activator of transcription |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
JAK | receptor-associated Janus kinases |
IkB | inhibitor molecules |
IKK | protein kinase complex |
iNOS | inducible nitric oxide synthase |
MAPKs | mitogen-activated protein kinases |
ERK | extracellular signal-related kinase |
JNK | c-jun N-terminal kinase |
ROS | reactive oxygen species |
RNS | reactive nitrogen species |
ER | endoplasmic reticulum |
CHOP | C/EBP homologous protein |
DP5 | death protein 5 |
NSAIDs | non-steroidal anti-inflammatory drugs |
AMPK | adenosine monophosphate-activated protein kinase |
SOCS3 | suppressor of cytokine signaling 3 |
DCHA-hyperforin | hyperforin dicyclohexylammonium salt |
5-LO | 5-lipoxygenase |
COX | cyclooxygenase |
PGE2 | prostaglandin E2 |
fMLP | N-formyl-methionyl-leucyl-phenylalanine |
LPS | lipopolysaccharide |
PMN | polymorphonuclear neutrophils |
PXR | pregnane X receptor |
RXR | retinoid X receptor |
HFD | high-fat-diet |
AD | Alzheimer’s disease |
SOD | superoxide dismutase |
Aβ | amyloid-β-peptide |
AAP | amyloid precursor protein |
AST | aspartate aminotransferase |
ALT | alanine aminotransferase |
ICAM | intercellular cell adhesion molecule |
BCL-2 | B-cell lymphoma protein 2 |
BAX | B-cell lymphoma protein 2 (Bcl-2)-associated X |
CXCL | C‑X‑C motif chemokine ligand |
CIITA | immune-transcriptional co-activator |
Puma | p53-upregulated mediator of apoptosis |
Bim | B-cell lymphoma 2 interacting mediator of cell death |
Chop | C/EBP homologous protein |
PDX-1 | pancreatic duodenal homeobox-1 |
FFA | free fatty acids |
IAPP | islet amyloid polypeptide |
FATP1 | transporter of free fatty acids |
HYP | hypericin |
HFHS | high-fat/high-sucrose |
NAFLD | non-alchoholic liver fatty disease |
pAMPK | phosphorylated adenosine monophosphate-activated protein kinase |
PKACs | protein kinase A catalytic |
CRP | C reactive protein |
TG | triglycerides |
LDL | low-density lipoprotein |
PKA | protein kinase cAMP-dependent |
TGF-β | transforming growth factor beta |
TRPC6 | transient receptor potential channel |
GABA | gamma-aminobutyric acid |
NMDA | N-methyl-d-aspartate |
PPAR-γ | peroxisome proliferator-activated receptor-gamma |
STZ-NA | streptozotocin-nicotinamide |
AGE | advanced glycation end products |
TLR | Toll-like receptor |
CYPs | cytochromes P450s |
P-gp | P-glycoprotein |
cAMP | cyclic adenosine monophosphate |
PTP1B | protein tyrosine phosphatase 1B |
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Napoli E 2018 [82] | Bruni R 2009 [83] | Seyis F 2020 [84] | ||
---|---|---|---|---|
mg/g Dry Weight | mg/g Dry Weight | mg/g Dry Matter | High Yielding Plant Part | |
Naphtodianthrones | ||||
Pseudohypericin | 5.14 | 0.1–12 | 0.05–6.75 | Dark glands in leaf and petal margin; stamens |
Hypericin | 3.69 | 0.1–7 | 0.01–2.77 | |
Acylphloroglucinols | ||||
Hyperforin | 41.0 | 0.3–150 | 2.15–28.1 | Flowering tops; sepals; translucent glands in leaves |
Adhyperforin | 4.68 | |||
Flavonoids | ||||
Catechins | 0.02 | 1.41–8.7 | Floral dehiscent leaves: sepals, stamens, petals. Likely accumulation in vacuoles | |
Quercetin-3-O-galactoside | 4.34 | |||
Quercetin-3-O-glucoside | 1.87 | |||
Quercetin-3-O-rhamnoside | 2.13 | |||
Quercetin | 0.30 | 0.05–6.04 | ||
Isoquercitrin | 0.15–6.99 | |||
Hyperoside | 1–25 | 1.70–22.3 | ||
Rutin | 0–35 | 0 | ||
Phenylpropanes | ||||
Chlorogenic acid | 0.42–10.55 | Flowers and leaves | ||
Neochlorogenic acid | 0.37–4.25 | |||
Biflavones | ||||
Biapigenin | 4.56 | 0.3–10.2 | Trace-2.65 | Floral dehiscent leaves: sepals, stamens, petals. |
Amentoflavone | 0.18 | 0–1.8 |
Dosages | Models | Effects | Hypothesized Mechanisms | Refs. |
---|---|---|---|---|
SJW standard extract 100, 200 and 300 mg/kg b.w. daily oral administration for 14 days | STZ-NA diabetic rats | Dose-dependent reduction of fasting blood glucose levels | Antioxidant and free radical scavenging properties; stimulation by of muscarinic M3 receptor in β cells and increased insulin release; activation by HPF of TRPC6 cation channels and increased glucose-stimulated insulin secretion. | Husain GM 2009 [188] |
SJW standard extract 125 or 250 mg/kg b.w. daily i.p. administration for one week | STZ diabetic rats | Dose-dependent decrease in hyperglycemia; restoration of metabolic parameters and improvement of decreased body weights | Can ÖD 2011 [189] | |
SJW oral suspension in 0.3% carboxy-methyl cellulose 100 and 200 mg/kg b.w. daily for 15 days | High-fat-diet-fed rats Fructose-fed rats | Decrease in plasma glucose and insulin levels; improvement of lipid abnormalities; prevention of weight increase | Reduction of appetite and food intake mediated by serotonin increase. | Husain GM 2011 [190] |
SJW ethyl acetate extract 50, 100 and 200 mg/kg b.w. daily i.p. administration for 15 days | STZ diabetic rats | Decrease in blood glucose, serum triglycerides and total cholesterol; increase in plasma insulin and muscle and liver glycogen content | Increase of insulin secretion by the remaining β cells; enhanced muscle and liver glycogen content; decline in glucose-6-phosphatase activity and gluconeogenesis. | Arokiyaraj S 2011 [191] |
SJW extract containing mainly hypericin analogues 50 and 200 mg/kg b.w. daily by gastric gavage for three weeks | High-fat-diet-fed C57BL/6J mice | Improvement of hyperinsulinemia, hyperglycemia, insulin tolerance and dyslipidemia | Increase in insulin sensitivity and fatty acid oxidation through PTP1B inhibition. | Tian J 2015 [192] |
SJW standard extract 50, 100 and 200 mg/kg b.w. daily by gastric gavage for eight weeks | STZ-NA diabetic rats | Decrease in hyperglycemia and increase in insulinemia; protection against nephropathy | Same mechanisms as in [191] and [192]. | Abd El Motteleb 2017 [193] |
Hypericin 0.5–2 mg/kg b.w. daily i.p. administration for either 90 or 30 days | High-fat/high-sucrose-fed mice | Prevention in weight gain; decrease in fasting hyperglycemia; improvement of glucose and insulin intolerance. | Reduction of gluco- and lipo-toxicity; improvement in β-cell function; maintenance of β-cell mass; prevention of insulin resistance | Liang C 2019 [16] |
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Novelli, M.; Masiello, P.; Beffy, P.; Menegazzi, M. Protective Role of St. John’s Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies. Int. J. Mol. Sci. 2020, 21, 8108. https://doi.org/10.3390/ijms21218108
Novelli M, Masiello P, Beffy P, Menegazzi M. Protective Role of St. John’s Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies. International Journal of Molecular Sciences. 2020; 21(21):8108. https://doi.org/10.3390/ijms21218108
Chicago/Turabian StyleNovelli, Michela, Pellegrino Masiello, Pascale Beffy, and Marta Menegazzi. 2020. "Protective Role of St. John’s Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies" International Journal of Molecular Sciences 21, no. 21: 8108. https://doi.org/10.3390/ijms21218108