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Andrographolide is the most abundant diterpene lactone in Andrographis paniculata, which is widely used as a traditional medicine in Southeast Asia. Heme oxygenase 1 (HO-1) is an antioxidant enzyme encoded by a stress-responsive gene. HO-1 has been reported to inhibit the expression of adhesion molecules in vascular endothelial cells (EC). Intercellular adhesion molecule (ICAM-1) is an inflammatory biomarker that is involved in the adhesion of monocytes to EC. In this study, we investigated the effect of andrographolide on the expression of ICAM-1 induced by tumor necrosis factor alpha (TNF-alpha) in EA.hy926 cells and the possible mechanisms involved. Andrographolide (2.5-7.5 microM) inhibited the TNF-alpha-induced expression of ICAM-1 in a dose-dependent manner and resulted in a decrease in HL-60 cell adhesion to EA.hy926 cells (p < 0.05). In parallel, andrographolide significantly induced the expression of HO-1 in a concentration-dependent fashion (p < 0.05). Andrographolide increased the rate of nuclear translocation of nuclear factor erythroid 2-related 2 (Nrf2) and induced antioxidant response element-luciferase reporter activity. Transfection with HO-1-specific small interfering RNA knocked down HO-1 expression, and the inhibition of expression of ICAM-1 by andrographolide was significantly reversed. These results suggest that stimulation of Nrf2-dependent HO-1 expression is involved in the suppression of TNF-alpha-induced ICAM-1 expression exerted by andrographolide.

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Matrix metalloproteinase-9 (MMP-9) plays a crucial role in tumor metastasis. Previous studies showed that polyunsaturated fatty acids exhibit an anti-cancer effect in various human carcinoma cells, but the effect of docosahexaenoic acid (DHA) and linoleic acid (LA) on metastasis of breast cancer cells is not fully clarified. We studied the anti-metastasis potential of DHA and LA in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MCF-7 cells. We found that TPA (100 ng/ml) induced MMP-9 enzyme activity both dose- and time-dependently, and 200 μM DHA and LA significantly inhibited MMP-9 mRNA and protein expression, enzyme activity, cell migration, and invasion. Treatment with PD98059 (10 μM), wortmannin (10 μM), and GF109203X (0.5 μM) decreased TPA-induced MMP-9 protein expression and enzyme activity. TPA-induced activation of ERK1, Akt, and PKCδ was attenuated by DHA, whereas LA attenuated only ERK1 activation. GF109203X also suppressed ERK1 activation. EMSA showed that DHA, LA, PD98059, and wortmannin decreased TPA-induced NF-κB and AP-1 DNA-binding activity. Furthermore, DHA rather than LA dose-dependently increased HO-1 expression. HO-1 siRNA alleviated the inhibition by DHA of TPA-induced MMP-9 protein expression and enzyme activity in MCF-7 cells, and HO-1 knockdown reversed the DHA inhibition of cell migration. These results suggest that DHA and LA have both similar and divergent signaling pathways in the suppression of TPA-induced MCF-7 metastasis.

Andrographolide, the main bioactive component of the medicinal plant Andrographis paniculata, has been shown to possess potent anti-inflammatory activity. Endothelin 1 (ET-1), a potent vasoconstrictor peptide produced by vascular endothelial cells, displays proinflammatory property. Hypoxia-inducible factor 1α (HIF-1α), the regulatory member of the transcription factor heterodimer HIF-1α/β, is one of the most important molecules that responds to hypoxia. Changes in cellular HIF-1α protein level are the result of altered gene transcription and protein stability, with the latter being dependent on prolyl hydroxylases (PHDs). In this study, inhibition of pro-inflammatory ET-1 expression and changes of HIF-1α gene transcription and protein stability under hypoxia by andrographolide in EA.hy926 endothelial-like cells were investigated. Hypoxic conditions were created using the hypoxia-mimetic agent CoCl We found that hypoxia stimulated the production of reactive oxygen species (ROS), the expression of HIF-1α mRNA and protein, and the expression and secretion of ET-1. These effects, however, were attenuated by co-exposure to andrographolide, bilirubin, and RuCO. Silencing Nrf2 and heme oxygenase 1 (HO-1) reversed the inhibitory effects of andrographolide on hypxoia-induced HIF-1α mRNA and protein expression. Moreover, andrographolide increased the expression of prolyl hydroxylases (PHD) 2/3, which hydroxylate HIF-1α and promotes HIF-1α proteasome degradation, with an increase in HIF-1α hydroxylation was noted under hypoxia. Inhibition of p38 MAPK abrogated the hypoxia-induced increases in HIF-1α mRNA and protein expression as well as ET-1 mRNA expression and secretion. Taken together, these results suggest that andrographolide suppresses hypoxia-induced pro-inflammatory ET-1 expression by activating Nrf2/HO-1, inhibiting p38 MAPK signaling, and promoting PHD2/3 expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 918-930, 2017.

Cell migration plays an important role in angiogenesis and wound repair. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is essential for endothelial cell survival, proliferation, and migration. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, shows both anti-inflammatory and antioxidant activities in vitro and in vivo. This study investigated the molecular mechanism by which DHA down-regulates VEGF-induced cell migration. HUVECs were used as the study model, and the MTT assay, Western blot, wound-healing assay, and phosphatase activity assay were used to explore the effects of DHA on cell migration. GPR120 is the putative receptor for DHA action. The results showed that DHA, PD98059 (an ERK1/2 inhibitor), and GW9508 (a GPR120 agonist) inhibited VEGF-induced cell migration. In contrast, pretreatment with okadaic acid (OA, a PP2A inhibitor) and S-nitroso-N-acetyl-DL-penicillamine (an NO donor) reversed the inhibition of cell migration by DHA. VEGF-induced cell migration was accompanied by phosphorylation of ERK1/2 and eNOS. Treatment of HUVECs with DHA increased PP2A enzyme activity and decreased VEGF-induced phosphorylation of ERK1/2 and eNOS. However, pretreatment with OA significantly decreased DHA-induced PP2A enzyme activity and reversed the DHA inhibition of VEGF-induced ERK1/2 and eNOS phosphorylation. These results suggest that stimulation of PP2A activity and inhibition of the VEGF-induced ERK1/2/eNOS signaling pathway may be involved in the DHA suppression of VEGF-induced cell migration. Thus, the effect of DHA on angiogenesis and wound repair is at least partly by virtue of its attenuation of cell migration.

The energy density of lithium-ion batteries (LIBs) can be meaningfully increased by utilizing Si-on-graphite composites (Si@Gr) as anode materials, because of several advantages, including higher specific capacity and low cost. However, long cycling stability is a key challenge for commercializing these composites. In this study, to solve this issue, we have developed a multifunctional polymeric artificial solid−electrolyte interphase (A-SEI) protective layer on carbon-coated Si@Gr anode particles (making Si@Gr/C-SCS) to prolong the cycling stability in LIBs. The coating is made of sulfonated chitosan (SCS) that is crosslinked with glutaraldehyde promoting good ionic conduction together with sufficient mechanical strength of the A-SEI. The focused ion beam-scanning electron microscopy and high-resolution transmission electron microscopy images show that the SCS is uniformly coated on the composite particles with thickness in nanometer. The anodes are investigated in Li metal cells Si@Gr/C-SCS||Li metal) and lithium-ion full-cells (LiNi 0.6 Co 0.2 Mn 0.2 O 2 (NCM-622)||Si@Gr/C-SCS) to understand the material/electrode intrinsic degradation as well as the impact of the polymer coating on active lithium losses because of the continuous SEI (re)formation. The anode composites exhibit a high capacity reaching over 600 mAh g −1 , and even without electrolyte optimization, the Si@Gr/C-SCS illustrates a superior long cycle life performance of up to 1000 cycles (over 67% capacity retention). The excellent long-term cycling stability of the anodes was attributed to the SCS polymer coating acting as the A-SEI. The simple polymer coating process is highly interesting in guiding the preparation of long-cycle-life electrode materials of high-energy LIB cells.