N-acetyl serotonin (NAS) as a melatonin precursor has neuroprotective actions. Nonetheless, it is not clarified how NAS protects neuronal cells against oxidative stress. Recently, we have reported that N-palmitoyl serotonins possessed properties of antioxidants and neuroprotection. Based on those, we hypothesized that NAS, a N-acyl serotonin, may have similar actions in oxidative stress-induced neuronal cells, and examined the effects of NAS based on in vitro and in vivo tests. NAS dose-dependently inhibited oxidative stress-induced cell death in HT-22 cells. Moreover, NAS suppressed glutamate-induced apoptosis by suppressing expression of AIF, Bax, calpain, cytochrome c and cleaved caspase-3, whereas it enhanced expression of Bcl-2. Additionally, NAS improved phosphorylation of tropomyosin-related kinase receptor B (TrkB) and cAMP response element-binding protein (CREB) as well as expression of brain-derived neurotrophic factor (BDNF), whereas the inclusion of each inhibitor of JNK, p38 or Akt neutralized the neuroprotective effect of NAS, but not that of ERK. Meanwhile, NAS dose-dependently reduced the level of reactive oxygen species, and enhanced the level of glutathione in glutamate-treated HT-22 cells. Moreover, NAS significantly increased expression of heme oxygenase-1, NAD(P)H quinine oxidoreductase-1 and glutamate-cysteine ligase catalytic subunit as well as nuclear translocation of NF-E2-related factor-2. Separately, NAS at 30 mg/kg suppressed scopolamine-induced memory impairment and cell death in CA1 and CA3 regions in mice. In conclusion, NAS shows actions of antioxidant and anti-apoptosis by activating TrkB/CREB/BDNF pathway and expression of antioxidant enzymes in oxidative stress-induced neurotoxicity. Therefore, such effects of NAS may provide the information for the application of NAS against neurodegenerative diseases.
3,3′-Diindolylmethane (DIM), a metabolite of indole-3-carbinol present in Brassicaceae vegetables, possesses various health-promoting effects. Nonetheless, the effect of DIM on neurodegenerative diseases has not been elucidated clearly. In this study, we hypothesized DIM may protect neuronal cells against oxidative stress-induced apoptosis by promoting the formation of brain-derived neurotrophic factor (BDNF) and antioxidant enzymes through stabilizing the activation of the tropomyosin-related kinase receptor B (TrkB) cascade and we investigated the effect of DIM on oxidative stress-mediated neurodegenerative models. DIM protected neuronal cells against oxidative stress-induced apoptosis by regulating the expression of apoptosis-related proteins in glutamate-treated HT-22 cells. Additionally, DIM improved the expression of BDNF and antioxidant enzymes, such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, and NAD(P)H quinine oxidoreductase-1, by promoting the activation of the TrkB/protein kinase B (Akt) pathway in the cells. Consistent with in vitro studies, DIM attenuated memory impairment by protecting hippocampal neuronal cells against oxidative damage in scopolamine-treated mice. Conclusionally, DIM exerted neuroprotective and antioxidant actions through the activation of both BDNF production and antioxidant enzyme formation in accordance with the TrkB/Akt pathway in neuronal cells. Such an effect of DIM may provide information for the application of DIM in the prevention of and therapy for neurodegenerative diseases.
The purpose of this study is to evaluate the effect of N-arachidonoyl serotonin (NA-5HT) on inflammatory response or oxidative stress in RAW264.7 cells exposed to lipopolysaccharide (LPS). When RAW264.7 cells were pre-incubated with NA-5HT before LPS treatment, NA-5HT was found to suppress LPS-induced formation of nitric oxide (NO), tumor necrosis factor-a or interleukins as well as expression of inducible NO synthase and cyclooxygenase-2 at non-cytotoxic concentrations. Consistent with this, NA-5HT efficiently reversed LPS-induced phosphorylative activation of nuclear factor-κB pathway probably through the suppression of mitogen-activated protein kinases (MAPKs) pathway or phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Separately, NA-5HT enhanced the antioxidant capacity accompanied by nuclear translocation of nuclear factor-E2-related factor-2 (Nrf2) in RAW264.7 cells. Additionally, NA-5HT-induced nuclear translocation of Nrf2 was suppressed significantly by the inhibition of c-Jun N-terminal kinase1/2 or PI3K/Akt pathways, although NA-5HT phosphorylated signal molecules in MAPKs and PI3K/Akt pathways. Taken together, NA-5HT is proposed to exert anti-inflammatory and antioxidant actions in RAW264.7 cells.
Recently, N‐acyl serotonins have been reported to exert neuroprotective actions against oxidative stress by inducing antioxidant enzymes. However, the mechanisms for the neuroprotective action of N‐acyl serotonins are still not clarified. In this study, we focuse on the suppressive effect of N‐palmitoyl serotonin on glutamate‐induced apoptosis in HT‐22 cells, and then examine the molecular mechanism for anti‐apoptotic action of N‐palmitoyl serotonin. For this purpose, flow cytometry, immunoblotting analysis and antibody‐mediated neutralization is formed. When HT‐22 cells are preincubated with N‐palmitoyl serotonin prior to glutamate treatment, N‐palmitoyl serotonin dose‐dependently reduces apoptotic bodies, and recoveres mitochondrial potential in glutamate‐treated HT‐22 cells. Further, N‐palmitoyl serotonin concentration‐dependently increases the expression of B‐cell lymphoma 2 (Bcl‐2), an anti‐apoptotic factor, whereas it reduces the expression of Bcl‐2‐associated X protein, apoptosis‐inducing factor, Ca2+‐dependent non‐lysosomal cysteine protease, cytochrome c, and cleaves caspase‐3. Meanwhile, N‐palmitoyl serotonin enhanced phosphorylation of tropomyosin‐related kinase receptors (TrkB) and cAMP response element‐binding protein (CREB) as well as expression of brain‐derived neurotrophic factor (BDNF). Separately, the inclusion of anti‐BDNF antibody neutralizes the neuroprotective action of N‐palmitoyl serotonin against glutamate‐induced cell death. In addition, K252a, a TrkB inhibitor, also reverses neuroprotective effect of N‐palmitoyl serotonin, suggesting that the action of N‐palmitoyl serotonin may be expressed through the formation of BDNF. Based on these results, it is proposed that N‐palmitoyl serotonin promotes formation and secretion of BDNF, and then protects neuronal cells against oxidative stress‐induced apoptosis through activation of TrkB/CREB pathway. Practical Applications: The results may provide further information for the application of N‐acyl serotonins as a therapeutic or preventive agent for neurodegenerative diseases. N‐Palmitoyl 2 serotonin (Pal‐5HT) not only induces brain‐derived neurotrophic factor (BDNF) expression but also protects neuronal cells against oxidative stress.
In the present study, the anti-inflammatory and antisepticemic activities of a water extract of Liriope platyphylla (LP) were investigated. We first estimated the scavenging activity of DPPH and the hydroxyl radical and total phenolic contents of LP. Results indicated that LP, a rich source of phenolic compounds, showed a remarkable radical scavenging capacity. A MTT assay showed that LP treatment did not affect the toxicity against the RAW 264.7 macrophage cells, up to the concentration of 500[Formula: see text][Formula: see text]g/mL. Treatment of LP significantly attenuated the production of inflammatory mediators, such as nitric oxide (NO), interleukin-6 (IL-6), tumor-necrosis factor (TNF)-[Formula: see text] and prostaglandin (PG)E in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages cells. Moreover, LP contributed to the down-regulation of inducible NO synthase (iNOS) and TNF-[Formula: see text] mRNA expression, as well as cyclooxygenase-2 (COX-2) protein expression. A western blotting assay further showed that LP inhibited activation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-[Formula: see text]B. In an animal experiment using an LPS-induced septicemia model in C57BL/6 mice, oral administration of LP (40[Formula: see text]mg/kg body weight) markedly reduced the level of TNF-[Formula: see text] and IL-6 in serum and protected against LPS-induced lethal shock in mice. Taken together, the results of treatments of LP on inhibited LPS-induced inflammatory responses in both in vitro and in vivo models and indicate it may be a promising neutraceutical or medicinal agent to prevent or cure inflammation-related disease.
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