Biological & pharmaceutical bulletin
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A growing body of evidence suggests that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) from the peel of citrus fruits, enhances the damaged cognitive function in disease animal models. However, the neuroprotective mechanism has not been clearly elucidated. Since nobiletin has shown anti-inflammatory effects in several tissues, we investigated whether nobiletin suppresses excessive microglial activation implicated in neurotoxicity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cell culture models. ⋯ LPS-induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) were also significantly inhibited by nobiletin treatment. In addition, nobiletin markedly inhibited the LPS-induced pro-inflammatory transcription factor nuclear factor κB (NF-κB) signaling pathway by suppressing nuclear NF-κB translocation from the cytoplasm and subsequent expression of NF-κB in the nucleus. Taken together, these results may contribute to further exploration of the therapeutic potential and molecular mechanism of nobiletin in relation to neuroinflammation and neurodegenerative diseases.
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Berberine has a wide range of biochemical and pharmacologic effects, including antitumor activity, but the mechanisms involved in berberine-induced apoptosis remain unclear. The purpose of the present study was to investigate the changes in oxidative stress and endoplasmic reticulum (ER)-related molecules, which are closely associated with cell death-signaling transduction pathways, in human glioblastoma T98G cells treated with berberine. Berberine significantly decreased the cell viability of T98G cells in a dose-dependent manner. ⋯ Berberine also markedly enhanced apoptosis in T98G cells through the induction of a higher ratio of Bax/Bcl-2 proteins, disruption of the mitochondrial membrane potential, activation of caspase-9 and -3, and cleavage of the poly(ADP-ribose) polymerase (PARP). The inhibition of ER stress using salubrinal led to an increased the level of Bcl-2, whereas the level of Bax, cleavage of procaspase-9 and -3, and PARP were decreased when compared with cells treated with berberine alone, indicating that berberine-induced apoptosis is associated with mitochondrial dysfunction. These results demonstrate that berberine induces apoptosis via ER stress through the elevation of ROS and mitochondrial-dependent pathway in human glioblastoma T98G cells.
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The complex molecular cascades of ischemic tolerance in brain cells remain unclear. Recently, sphingolipid-related metabolite ceramide has been implicated as a second messenger in many biological functions, including neuronal survival and death. The present study, therefore, examined the roles of ceramide (Cer) in ischemic tolerance induced by preconditioning with sublethal oxygen-glucose deprivation (OGD) using primary cultured cortical neurons of rats. ⋯ Treatment with an inhibitor of de novo ceramide synthesis, fumonisin B(1), during the ischemic preconditioning period completely blocked preconditioning-induced ischemic tolerance. Moreover, application of a non-cytotoxic concentration of exogenous cell-permeable ceramide produced neuroprotection against lethal OGD. The results suggest that ceramides increased by sublethal OGD preconditioning play an important role in induction of ischemic tolerance.
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RhoA plays an important role in Ca(2+) sensitization of bronchial smooth muscle in antigen-induced airway hyperresponsiveness (AHR). Glucocorticoids are now the most effective anti-inflammatory treatment for asthma, and inhaled corticosteroids are the most effective long-term control therapy for persistent asthma. To determine the mechanism of the inhibitory action of glucocorticoids on AHR in allergic bronchial asthma, that of prednisolone on RhoA upregulation was investigated using cultured human bronchial smooth muscle cells (hBSMCs). ⋯ Prednisolone partly inhibited the IL-13-induced RhoA upregulation and RhoA promoter activity, although prednisolone had no effects on the activations of signal transducers and activators of transcription (STAT)6 and nuclear factor (NF)-kappaB. Increased expression and promoter activity of RhoA induced by TNF-alpha was completely inhibited by prednisolone, although the activation of NF-kappaB failed to be inhibited by prednisolone in hBSMCs. These findings suggest that prednisolone might inhibit NF-kappaB-induced transcription via interaction between glucocorticoid receptor (GR), resulting in an inhibition of RhoA upregulation induced by IL-13 and TNF-alpha.
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Elevated levels of beta-amyloid (Abeta) in the brains being a hallmark of Alzheimer's disease (AD) have been believed to play a critical role in the cognitive dysfunction that occurs in AD. Recent evidence suggests that Abeta induces neuronal apoptosis in the brain and in primary neuronal cultures. In this study, we investigated the effects of beta-asarone, the major ingredient of Acorus Tatarinowii Schott, on cognitive function and neuronal apoptosis in Abeta hippocampus injection rats and its mechanism of action. ⋯ Abeta-induced c-Jun N-terminal kinase (JNK) results in phosphorylation, subsequent down-regulation of Bcl-2 and Bcl-w expression, and caspase-3 activation. Beta-asarone attenuate Abeta (1-42)-induced neuronal apoptosis in hippocampus by reversal down-regulation of Bcl-2, Bcl-w, caspase-3 activation, and JNK phosphorylation. These results suggest that beta-asarone may be a potential candidate for development as a therapeutic agent to manage cognitive impairment associated with conditions such as Alzheimer's disease.