Capillarisin

Neurochem Res. 2015 Jun;40(6):1095-101.

Capillarisin Suppresses Lipopolysaccharide-Induced Inflammatory Mediators in BV2 Microglial Cells by Suppressing TLR4-Mediated NF-κB and MAPKs Signaling Pathway.[Pubmed: 25894679]

Capillarisin, one of the major bioactive compounds derived from Artemisia capillaries Thunb, has been reported to have extensive pharmacological properties, such as ant-inflammatory and anti-nociceptive activities. However, the molecular mechanisms responsible for the anti-inflammatory activity of Capillarisin have not been elucidated in microglia.
METHODS AND RESULTS:
In the present study, we investigated the anti-inflammatory effects and molecular mechanisms of Capillarisin on LPS-stimulated BV2 microglial cells. The effects of Capillarisin on inflammatory mediators TNF-α, IL-6, IL-1β, NO and PGE2 were detected. The effects of Capillarisin on NF-κB and MAPK activation were detected by western blotting. The results showed that Capillarisin suppressed LPS-induced TNF-α, IL-6, IL-1β, NO and PGE2 production in a dose-dependent manner. Capillarisin also inhibited LPS-induced TLR4 expression, NF-κB and MAPKs activation in BV2 microglia.
CONCLUSIONS:
In conclusion, Capillarisin inhibited LPS-induced inflammation by blocking TLR4-mediated NF-κB and MAPKs activation in BV2 microglia.

Immunopharmacol Immunotoxicol. 2013 Feb;35(1):34-42.

Capillarisin inhibits iNOS, COX-2 expression, and proinflammatory cytokines in LPS-induced RAW 264.7 macrophages via the suppression of ERK, JNK, and NF-κB activation.[Pubmed: 23131135]

The aerial parts of Artemisia capillaris (Compositae) have been used in traditional Korean medicine as a cholagogic, antipyretic, anti-inflammatory, and diuretic purposes. In our previous study, ethanolic extracts of the plant demonstrated a marked anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (J. Korean Soc. Appl. Biol. Chem., 2010, 53, 275-282).
METHODS AND RESULTS:
In the present study, Capillarisin (CPS), a flavone, main constituent of A. capillaris, was examined for its anti-inflammatory activity in the cells. We found that Capillarisin highly suppressed LPS-induced nitric oxide (NO) without exerting cytotoxic effects on RAW 264.7 cells. Capillarisin inhibited the expression of LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and their mRNA in a dose-dependent manner. Also, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and prostaglandin E(2) (PGE(2)) secretion were decreased by Capillarisin in LPS-stimulated macrophages. As a result, Capillarisin inhibited proinflammatory cytokines, iNOS, and COX-2, which is attributed to the suppression of LPS-induced ERK, JNK, and nuclear factor-κB (NF-κB) activation.
CONCLUSIONS:
Therefore, we demonstrate here that Capillarisin potentially inhibits the biomarkers related to inflammation through the abrogation of ERK, JNK, and NF-κB p65 activation, and it may be a potential therapeutic candidate for the treatment of inflammatory diseases.

Life Sci . 2020 Oct 15;259:118279.

Capillarisin protects SH-SY5Y cells against bupivacaine-induced apoptosis via ROS-mediated PI3K/PKB pathway[Pubmed: 32798562]

Abstract Aims: Bupivacaine, a common local anesthetic, can induce neurotoxicity and neurological complications. Capillarisin, a bioactive ingredient of Artemisia capillaris root extracts, has been reported to protect SH-SY5Y cells against oxidative stress-mediated neuronal cell death. Nevertheless, the effects of Capillarisin on bupivacaine-induced neurotoxicity in SH-SY5Y cells remain unclear. Main methods: Cell viability, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production, and apoptosis were detected. Malondialdehyde (MDA) content, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) activities were measured for evaluation of oxidative stress. Western blot was performed to detect the changes of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB) pathway, and expression of cleaved poly ADP ribose polymerase (PARP), cleaved caspase-3, glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). Activities of mitochondrial respiratory chain complexes I-III and adenosine triphosphate (ATP) content were measured to evaluate mitochondrial damage. Key findings: Bupivacaine treatment dose-dependently reduced cell viability, increased LDH release, and induced ROS production and PI3K/PKB pathway inactivation in SH-SY5Y cells, which were overturned by Capillarisin treatment. Capillarisin inhibited bupivacaine-induced apoptosis in SH-SY5Y cells by decreasing cleaved PARP and cleaved caspase-3 expression. Capillarisin inhibited bupivacaine-induced oxidative stress, decrease of mitochondrial respiratory chain complex I, II, and III activities and ATP content, and increase of GRP78 and CHOP expression in SH-SY5Y cells. However, treatment with LY294002 abolished the effects of Capillarisin on bupivacaine-induced neurotoxicity in SH-SY5Y cells. Significance: Capillarisin protected SH-SY5Y cells against bupivacaine-induced apoptosis by inhibiting oxidative stress, mitochondrial injury, and endoplasmic reticulum stress via ROS-mediated of PI3K/PKB pathway. Keywords: Bupivacaine; Capillarisin; Neurotoxicity; PI3K/PKB pathway; Reactive oxygen species.

J Ethnopharmacol. 2014 Mar 28;152(3):478-86.

Anti-hyperalgesic and anti-allodynic activities of capillarisin via suppression of inflammatory signaling in animal model.[Pubmed: 24495472]

Artemisia capillaris has widespread traditional and pharmacological applications such as analgesic, anti-inflammatory, anti-pyretic, enhance immunity and anti-tumor activity properties. To evaluate the pharmacological activities of this plant, Capillarisin, one of the potent constituent of Artemisia capillaris was studied based on anti-hyperalgesic and anti-allodynic effects with detailed mechanism. It can be assumed that measurement of anti-nociceptive effects of Capillarisin is one of the parameter for the evaluation of this herb. Capillarisin has extensive pharmacological properties and has been considered to have promising ant-inflammatory and anti-nociceptive activities. The aim of the current study is to investigate the effect of Capillarisin and underlying molecular mechanisms of action in preventing acute and subchronic inflammatory pain.
METHODS AND RESULTS:
The inflammatory pain was induced after 40 min or 1h of administration of vehicle, 70% EtOH extract of Artemisia capillaris (100mg/kg) or Capillarisin (20 and 80 mg/kg) by intraplantar (i.p.l.) injections of CFA and carrageenan in ICR mice, respectively. Mechanical hyperalgesia and allodynia were evaluated in both acute and subchronic models. Further analysis was performed in CFA-induced mice exploring various molecular and signaling pathways such as NF-κB, AP-1, and ERK-CREB involved in the persistent pain sensations. In acute model, mechanical hyperalgesia and allodynia were evaluated after every 2h until 6h of CFA and after 4h of carrageenan injections. Whereas, in subchronic inflammatory pain model, mechanical hyperalgesia and paw edema were measured after 4h of CFA injection and every day after 4h of daily treatment until 5 days with interval of day four in order to assess the tolerance effect of Capillarisin. Further analysis was performed in CFA-induced mice exploring various molecular and signaling pathways such as NF-κB, AP-1 and ERK-CREB involved in the persistent of pain sensations. Pre-treatment of Capillarisin strongly inhibited NF-κB mediated genes (iNOS, COX-2), involved in pain. The plasma leading nitrite production was significantly reduced by Capillarisin. Moreover, i.p. administration of Capillarisin markedly suppressed the adenosine 5׳-triphosphate (ATP) in plasma and substance P in CFA-induced paw tissue.
CONCLUSIONS:
The present study indicates that Capillarisin possessed promising anti-hyperalgesic and anti-allodynic effects through the inhibition of various inflammatory pain signaling, suggesting that Capillarisin constitutes a significant component for the treatment of inflammatory pain.

Cancer Lett. 2014 Apr 1;345(1):140-8.

Capillarisin inhibits constitutive and inducible STAT3 activation through induction of SHP-1 and SHP-2 tyrosine phosphatases.[Pubmed: 24333736]

Signal transducers and activators of transcription (STAT)-3 is a latent cytosolic transcription factor that has been closely associated with survival, proliferation, chemoresistance, and metastasis of tumor cells. Whether the anti-proliferative, pro-apoptotic, and anti-metastatic effects of Capillarisin (CPS), derived from Artemisia capillaris (Compositae), are linked to its capability to inhibit STAT3 activation was investigated.
METHODS AND RESULTS:
We found that Capillarisin specifically inhibited both constitutive and inducible STAT3 activation at tyrosine residue 705 but not at serine residue 727 in human multiple myeloma cells. Besides the inhibition of STAT3 phosphorylation, Capillarisin also abrogated STAT3 constitutive activity and nuclear translocation. The suppression of STAT3 was mediated through the inhibition of activation of upstream JAK1, JAK2, and c-Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate treatment reversed the Capillarisin-induced down-regulation of JAK1/2 and STAT3, thereby suggesting the involvement of a PTP. Indeed, knockdown of the SHP-1 and SHP-2 genes by small interfering RNA suppressed the ability of Capillarisin to inhibit JAK1 and STAT3 activation, suggesting the critical role of both SHP-1 and SHP-2 in its possible mechanism of action. Capillarisin downregulated the expression of STAT3-regulated antiapoptotic and proliferative gene products; and this correlated with suppression of cell viability, the accumulation of cells in sub-G1 phase of cell cycle and induction of apoptosis. Moreover, Capillarisin potentiated bortezomib-induced apoptotic effects in MM cells, and this correlated with down-regulation of various gene products that mediate cell proliferation (Cyclin D1 and COX-2), cell survival (Bcl-2, Bcl-xl, IAP1, IAP2, and Survivin), invasion (MMP-9), and angiogenesis (VEGF).
CONCLUSIONS:
Thus, overall, our results suggest that Capillarisin is a novel blocker of STAT3 activation and thus may have a potential in negative regulation of growth, metastasis, and chemoresistance of tumor cells.

Drug Res (Stuttg). 2014 Nov 4.

Capillarisin Exhibits Anticancer Effects by Inducing Apoptosis, Cell Cycle Arrest and Mitochondrial Membrane Potential Loss in Osteosarcoma Cancer Cells (HOS).[Pubmed: 25368903]

The aim of the present study was to assess the anticancer activity of Capillarisin against human osteosarcoma (HOS) cancer cells in vitro.
METHODS AND RESULTS:
Cell viability after Capillarisin drug treatment and evaluated by MTT assay. The extent of cell death induced by Capillarisin was estimated by using lactate dehydrogenase (LDH) assay. The effect of Capillarisin on cell cycle phase distribution and mitochondrial membrane potential (ΛΨm) was demonstrated via flow cytometry using propidium iodide (PI) and rhodamine-123 (Rh-123) DNA-binding fluorescent dyes respectively. Fluorescence microscopy was employed to examine the morphological changes in osteosarcoma cancer cells and presence of apoptotic bodies following Capillarisin treatment. The results of this study revealed that Capillarisin induced dose-dependent growth inhibition of these cancer cells after 12-h of incubation. Further, Capillarisin induced significant release of LDH from these cell cultures and this LDH release was much more noticeable at higher concentrations of Capillarisin. Hoechst 33258 staining revealed characteristic morphological features of apoptosis triggered by Capillarisin treatment. Cell cycle analysis revealed that Capillarisin induced dose-dependent G0/G1-phase cell cycle arrest. Capillarisin also trigerred a progressive and dose-dependent reduction in the mitochondrial membrane potential.
CONCLUSIONS:
In conclusion, Capillarisin inhibits cancer cell growth of osteosarcoma cells by inducing apoptosis accompanied with G0/G1-phase cell cycle arrest and loss in mitochondrial membrane potential.