Synephrine and Its Derivative Compound A: Common and Specific Biological Effects
Abstract
:1. Introduction
2. Source, Chemical and Pharmacological Features of Synephrine
3. Mechanism of Synephrine Effects
4. Chemical and Pharmacological Features of CpdA and Its Target Receptors
5. Overlapping Targets and Activities of Synephrine, SEGRA, and Glucocorticoids in Pathological Conditions
5.1. Anti-Inflammatory Effects
Possible Molecular Mechanisms | Effects | Model Description | Substance |
---|---|---|---|
Anti-inflammatory effects | |||
In vitro | |||
Downregulated p38 MAPK and NF-κB signaling pathway; Inhibited expression of pro-inflammatory cytokines: IL-8, IL-6, TNF-α [9] | LPS-stimulated RAW264.7 cells | Synephrine | |
Inhibited IL-4-induced expression of eotaxin-1 via suppression of STAT6 [26] | NIH/3T3 mouse fibroblasts | ||
Attenuated expression of TNF-α, iNOS, and IL-1, but increased expression of anti-inflammatory IL-10; Induced macrophage differentiation towards M2 anti-inflammatory phenotype [85] | Immortalized murine macrophage cell line RAW 264.7 | CpdA | |
Inhibited NF-κB activity and IKK phosphorylation; Induced IκB-α accumulation; decreased IL-1β expression [86,87] | Synovial fibroblasts from patients with rheumatoid arthritis | ||
In vivo | |||
Reduced TNF-α, IL-6 and increased IL-10 activity; Elevated SOD activity and suppressed ROS generation; Reduced MPO activity; Attenuated histological changes; Inhibited NF-κB phosphorylation and IkB degradation [75] | Inhibited pulmonary edema; Reduced histological changes | LPS-induced ALI, mice | Synephrine |
Reduced serum levels of proinflammatory cytokines [9] | Improved survival rate | LPS-induced systemic inflammatory response syndrome, a mouse model | |
Increased activity of SOD, CAT, and GSH; Reduced MDA content; Downregulation of TNF-α, IL-6, and IL-1β gene expression levels [7] | The mouse model of diabetes mellitus | ||
Suppressed NF-κB activity and nuclear translocation; Inhibited STAT6 activity and nuclear translocation; Reduced expression of Th2-cytokines: IL-4, IL-5, and IL-13 [88] | Reduced inflammatory cell infiltration in lungs, cytokine production, mucus, and Ig production; Reduced development of airway hyperresponsiveness | Ovalbumin-induced Th2-driven asthma model | CpdA |
Decreased NF-κB activity and downregulation of pro-inflammatory cytokines: IL-8, IL-6, and E-selectin [14] | Decreased swelling | Zymosan-induced inflamed paw | |
Inhibited pro-inflammatory cytokines: IL-1β, TNF-α, IL-6; Upregulation of anti-inflammatory cytokines: IL-4 and IL-10 [89] | Protected from the development of diabetes; Modulated peripheral immune response (switching from Th1/Th17 towards anti-inflammatory T-regulatory/Treg response) | Streptozotocin-induced model of type 1 diabetes | |
Anti-cancer effects | |||
In vitro | |||
Reduced expression of p-AKT, AKT, p-ERK, and ERK [90] | Suppressed proliferation | Esophageal squamous cell carcinoma | Synephrine |
Increased ROS formation; Increased activity of the antioxidant molecules glutathione and catalase [8] | Revealed no cytotoxic effect | Human colon adenocarcinoma (Caco-2) cells | |
Induced DNA damage and apoptosis; Hyperproduction of intracellular ROS [91,92] | Human hepatocellular carcinoma (HepG2) | ||
Increased expression of Bax and p53 at the mRNA and protein levels; Suppressed PI3K/AKT/mTOR signaling pathway [10] | Lung cancer cells (H460) | ||
Inhibited several transcription factors, including nuclear factor kappa B (NF-κB), AP-1, Ets-1, Elk-1; Induced caspase-dependent apoptosis [69] | Decreased growth | Highly malignant androgen-independent DU145 and PC3 cells | CpdA |
Strongly inhibited growth and viability [63] | CEM T-cell acute lymphoblastic leukemia; K562 chronic myeloid leukemia cells | ||
Inhibited NF-κB signaling [16] | Murine L929sa fibrosarcoma cells | ||
Increased GR-GR dimerization; Decreased number of MR-GR heterodimers [93] | Rat pheochromocytoma PC12 cells | ||
In vivo | |||
Reduced level of glucose metabolism genes, G6Pase, and PEPCK [90] | Reduced glucose production | Human ESCC xenografts in nude mice | Synephrine |
Induced apoptosis in cancer cells via the upregulation of pro-apoptotic members of the B-cell lymphoma (Bcl-2) family [93] | P2 rat pups | CpdA | |
Metabolic and anti-diabetic effects | |||
In vitro | |||
Reduced level of glucose metabolism genes, G6Pase, and PEPCK [94] | Reduced glucose production | Rat liver cells (H4IIE) | Synephrine |
Acted as partial GR antagonist [95] | Immortalized murine keratinocytes | CpdA | |
In vivo | |||
Suppressed gene expression levels of TNF-α, IL-6, IL-1β; Activated enzymes of the antioxidant system; Inhibited oxidative stress via suppressing the NF-κB and MAPK pathways [7] | Prevented alloxan-induced changes in body weight, organ parameters, serum uric acid, and serum creatinine, and improved lipid profile | Alloxan-induced diabetes mellitus in mice | Synephrine |
Increased metabolic rate via agonistic activity on β-3 adrenoreceptors; Exhibited hypoglycemic and insulin-stimulating properties; Stimulated translocation of the glucose-4 transporter protein [96] | Decreased blood glucose levels; Increased insulin levels; Decreased insulin resistance | Gliclazide-treated rats and rabbits | |
Did not induce gluconeogenesis enzymes in the liver [87] | Did not increase in blood glucose levels; Did not induce hyperinsulinemia | Collagen-induced arthritis in mice | CpdA |
Inhibited endogenous GR signaling due to CpdA antagonistic effect on GR activity [95] | Revealed anti-inflammatory and atrophogenic effects | Model of contact dermatitis in mice |
5.2. Anti-Cancer Effects
5.3. The Effects on Diabetes Mellitus and Obesity
5.4. The Effect on the Cardiovascular System
6. Conclusions
Funding
Conflicts of Interest
Abbreviations
5-HT | 5-hydroxytryptamine receptors |
AR | adrenoreceptor |
ALT | alanine transaminase |
AMPK | adenosine monophosphate-activated protein kinase |
AP-1 | activator protein-1 |
ARK | adrenergic kinase |
AST | aspartate transaminase |
ATF-2 | activating transcription factor 2 |
Bcl-2 | B cell lymphoma-2 |
cAMP | cyclic adenosine monophosphate |
cAMP/PKA | 3′,5′-cyclic adenosine monophosphate/protein kinase A |
CNS | central nervous system |
CpdA | compound A |
CREB | cAMP-responsive element-binding protein |
DDIT4 | DNA-damage-inducible transcript 4 |
DHT | dihydrotestosterone |
EPAC | exchange protein directly activated by cAMP |
ERK | extracellular signal-regulated kinase |
ESCC | esophageal squamous cell carcinoma |
G6Pase | glucose-6-phosphatase |
GCs | glucocorticoids |
GEF | guanine nucleotide exchange factor |
COX-2 | cyclooxygenase -2 |
GNAS | guanine nucleotide binding protein, alpha stimulating activity polypeptide |
GPCR | G protein-coupled receptors |
GRK | G protein-coupled receptors kinase |
GR | glucocorticoid receptor |
GRE | glucocorticoid-responsive elements |
GSH | glutathione |
HSL | hormone-sensitive lipase |
IκBα | nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha |
IL | interleukin |
LPS | lipopolysaccharide |
MAOs | monoamine oxidases |
MAPK | mitogen-activated protein kinase |
MMP2/9 | matrix metalloproteinases 2/9 |
MDA | malondialdehyde |
MR | mineralocorticoid receptor |
NF-κB | nuclear factor kappa B |
NMU2R | neuromedin U2 receptor |
PEPCK | phosphoenolpyruvate carboxykinase |
PKA | protein kinase A |
PRKACA | protein kinase cAMP-activated catalytic subunit alpha |
RAP | Ras-related protein or Ras proximate protein |
RhoA | Ras homolog family member A |
ROS | reactive oxygen species |
SEGRA | selective glucocorticoid receptor activators |
SOD | superoxide dismutase |
STAT 6 | signal transducer and transcription activator 6 |
SVF | stromal vascular fraction |
TA | transactivation |
TAAR1 | trace amine-associated receptor 1 |
TNF-α | tumor necrosis factor-α |
TR | transrepression |
UCP1 | uncoupling protein 1 |
VEGF | vascular endothelial growth factor |
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Dodonova, S.A.; Zhidkova, E.M.; Kryukov, A.A.; Valiev, T.T.; Kirsanov, K.I.; Kulikov, E.P.; Budunova, I.V.; Yakubovskaya, M.G.; Lesovaya, E.A. Synephrine and Its Derivative Compound A: Common and Specific Biological Effects. Int. J. Mol. Sci. 2023, 24, 17537. https://doi.org/10.3390/ijms242417537
Dodonova SA, Zhidkova EM, Kryukov AA, Valiev TT, Kirsanov KI, Kulikov EP, Budunova IV, Yakubovskaya MG, Lesovaya EA. Synephrine and Its Derivative Compound A: Common and Specific Biological Effects. International Journal of Molecular Sciences. 2023; 24(24):17537. https://doi.org/10.3390/ijms242417537
Chicago/Turabian StyleDodonova, Svetlana A., Ekaterina M. Zhidkova, Alexey A. Kryukov, Timur T. Valiev, Kirill I. Kirsanov, Evgeny P. Kulikov, Irina V. Budunova, Marianna G. Yakubovskaya, and Ekaterina A. Lesovaya. 2023. "Synephrine and Its Derivative Compound A: Common and Specific Biological Effects" International Journal of Molecular Sciences 24, no. 24: 17537. https://doi.org/10.3390/ijms242417537
APA StyleDodonova, S. A., Zhidkova, E. M., Kryukov, A. A., Valiev, T. T., Kirsanov, K. I., Kulikov, E. P., Budunova, I. V., Yakubovskaya, M. G., & Lesovaya, E. A. (2023). Synephrine and Its Derivative Compound A: Common and Specific Biological Effects. International Journal of Molecular Sciences, 24(24), 17537. https://doi.org/10.3390/ijms242417537