**Background**
Inflammation is a complex biological response to harmful stimuli, but chronic inflammation is linked to various diseases, including cardiovascular disorders and cancer. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways play pivotal roles in regulating the expression of pro-inflammatory cytokines. Dysregulation of these pathways often leads to the overproduction of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), contributing to tissue damage and disease progression. Consequently, identifying small molecules that can modulate these pathways is essential for developing new therapeutic strategies. In this context, we will introduce an isoquinoline alkaloid with potent biological properties – Reticuline.
**Definition**
Reticuline is a human endogenous metabolite and an isoquinoline alkaloid that targets JAK2, STAT3, and NF-κB to exert anti-inflammatory and cardiovascular effects.
**In Vitro and In Vivo Studies**
According to the Reticuline description, this compound demonstrates significant anti-inflammatory activity by inhibiting the mRNA expressions of TNF-α and IL-6 while reducing the phosphorylation levels of JAK2 and STAT3. In terms of Reticuline biological activity, in vitro studies using isolated rat aortic rings with intact endothelium showed that Reticuline (3 μM, 30 μM, 300 μM, 900 μM, and 1.5 mM) inhibits contractions induced by Phenylephrine (1 μM), KCl (80 mM), and KCl (30 mM) in a concentration-dependent manner, with IC50 values of 40±10, 240±40, and 300±40 μM, respectively. Furthermore, it antagonizes CaCl2-induced contractions and inhibits intracellular calcium-dependent transient contractions induced by Norepinephrine (1 μM), although it does not affect those induced by Caffeine (20 mM).
Reticuline in vivo studies in normotensive rats revealed that injections of 5, 10, and 20 mg/kg (i.v.) produced intense hypotension. This effect is attributed to peripheral vasodilation resulting from muscarinic stimulation and NOS activation in the vascular endothelium, voltage-dependent Ca2+ channel blockade, and the inhibition of Ca2+ release from norepinephrine-sensitive intracellular stores. Additionally, cytotoxicity assays indicated that Reticuline exhibits varying effects across cell lines, with an IC50 of 29.44 μM in HCT-15 cells and IC50 values > 30 μM in A549 and SK-OV-3 cells. In conclusion, Reticuline is a versatile alkaloid that serves as a valuable tool for researching inflammatory signaling and cardiovascular regulation.
Keywords
Reticuline, 485-19-8, JAK, STAT, NF-κB, Endogenous Metabolite, Janus kinase, Nuclear factor-κB, Nuclear factor-kappaB, anti-inflammation, alkaloid, JAK2, STAT3, Inhibitor, inhibitor
References
[1] Yang X, et al. Anti-Inflammatory Effects of Boldine and Reticuline Isolated from Litsea cubeba through JAK2/STAT3 and NF-κB Signaling Pathways. Planta Med. 2018 Jan;84(1):20-25.
[2] Katy Lísias Dias, et al. Cardiovascular effects induced by reticuline in normotensive rats. Planta Med. 2004 Apr;70(4):328-33.