Table 1.
Overlapping targets and activities of synephrine and CpdA in pathological conditions.
| 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 | |