Therapeutic Potential and Mechanisms of Rosmarinic Acid and the Extracts of Lamiaceae Plants for the Treatment of Fibrosis of Various Organs

Abstract

Fibrosis, which causes structural hardening and functional degeneration in various organs, is characterized by the excessive production and accumulation of connective tissue containing collagen, alpha-smooth muscle actin (α-SMA), etc. In traditional medicine, extracts of medicinal plants or herbal prescriptions have been used to treat various fibrotic diseases. The purpose of this narrative review is to discuss the antifibrotic effects of rosmarinic acid (RA) and plant extracts that contain RA, as observed in various experimental models. RA, as well as the extracts of Glechoma hederacea, Melissa officinalis, Elsholtzia ciliata, Lycopus lucidus, Ocimum basilicum, Prunella vulgaris, Salvia rosmarinus (Rosmarinus officinalis), Salvia miltiorrhiza, and Perilla frutescens, have been shown to attenuate fibrosis of the liver, kidneys, heart, lungs, and abdomen in experimental animal models. Their antifibrotic effects were associated with the attenuation of oxidative stress, inflammation, cell activation, epithelial-mesenchymal transition, and fibrogenic gene expression. RA treatment activated peroxisomal proliferator-activated receptor gamma (PPARγ), 5' AMP-activated protein kinase (AMPK), and nuclear factor erythroid 2-related factor 2 (NRF2) while suppressing the transforming growth factor beta (TGF-β) and Wnt signaling pathways. Interestingly, most plants that are reported to contain RA and exhibit antifibrotic activity belong to the family Lamiaceae. This suggests that RA is an active ingredient for the antifibrotic effect of Lamiaceae plants and that these plants are a useful source of RA. In conclusion, accumulating scientific evidence supports the effectiveness of RA and Lamiaceae plant extracts in alleviating fibrosis and maintaining the structural architecture and normal functions of various organs under pathological conditions.

Keywords: 5′ AMP-activated protein kinase; AMPK; Lamiaceae; NRF2; PPARγ; TGF-β1; Wnt; erythroid 2-related factor 2; fibrosis; peroxisomal proliferator-activated receptor γ; rosmarinic acid; transforming growth factor β1.

Figure 1

The chemical structure of rosmarinic acid (RA).

Figure 2

Common mediators of fibrosis. Surgery, ischemia, pressure, drugs, chemicals, heavy metals, allergens, diets, radiation, transplantation, etc. stimulate the production of intracellular reactive oxygen species (ROS) and cause oxidative damage, structural deformation, and functional abnormalities in various organs. These stresses stimulate the expression of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), Wnt, heat shock proteins (HSPs), etc. The canonical TGF-β signaling pathway is mediated by the small mothers against decapentaplegic (SMAD) and induces the expression of the target genes. As a result, the expression of connective tissue growth factor (CTGF) is induced and the signaling pathway that it mediates is activated. Additionally, the noncanonical TGF-β signaling pathway activates the Wnt signaling pathway by suppressing Dickkopf-1 (DKK1) through an extracellular signal-regulated kinase (ERK)-dependent mechanism. The activation of the canonical Wnt signaling pathway activates β-catenin and induces the expression of the target genes. The TGF-β, CTGF, and Wnt signaling pathways cooperatively induce cell activation, epithelial–mesenchymal transition (EMT), and the expression of fibrogenic genes, such as alpha-smooth muscle actin (α-SMA) and collagens to promote fibrogenesis. Sharp red arrows (→) indicate stimulation, and blunt blue arrows (⊥) indicate suppression.

Figure 3

Hypothetical mechanisms of the antifibrotic action of rosmarinic acid (RA). RA can remove ROS and suppress cell activation, EMT, and fibrogenic gene expression by inhibiting the stress-induced expression of TGF-β, CTGF, and Wnt and their signaling pathways. Peroxisomal proliferator-activated receptor (PPAR) γ is repressed in myofibroblastic cells, and RA restores the gene expression of PPAR γ through an epigenetic mechanism that reduces the methylation of histone H3 lysine 27 (H3K27). PPARγ activates 5′ AMP-activated protein kinase (AMPK), which inhibits cell activation, EMT, and fibrogenic gene expression. RA also activates the nuclear factor erythroid 2-related factor (NRF) 2 via multiple mechanisms to induce the transcriptional expression of phase II/antioxidant enzymes, and the increased expression of catalytic subunits of glutamate cysteine ligase (GCLc) promotes the synthesis of glutathione (GSH), thereby reducing ROS. Collectively, RA alleviates oxidative stress and maintains the structural and functional integrity of the organs through multiple mechanisms. Profibrotic and antifibrotic factors are shown in brown and green circles, respectively. Sharp red arrows (→) indicate stimulation, and blunt blue arrows (⊥) indicate suppression.

Figure 4

Inhibitory effects of rosmarinic acid (RA) and Lamiaceae plant extracts on fibrosis of various organs in animal models exposed to various fibrosis-inducing factors. Profibrotic and antifibrotic factors are shown in brown and green boxes, respectively. Sharp red arrows (→) indicate stimulation or progression, and blunt blue arrows (⊥) indicate inhibition or suppression.