Biochemical pharmacology
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Biochemical pharmacology · Dec 2013
Morin reduces hepatic inflammation-associated lipid accumulation in high fructose-fed rats via inhibiting sphingosine kinase 1/sphingosine 1-phosphate signaling pathway.
SphK1/S1P signaling pathway is involved in the development of hepatic inflammation and injury. But its role in high fructose-induced NAFLD has not yet been reported. The aim of this study was to elucidate the crucial role of SphK1/S1P signaling pathway in high fructose-induced hepatic inflammation and lipid accumulation in rats. ⋯ Subsequently, the reduced NF-κB signaling activation by morin decreased inflammatory cytokine production, recovered insulin and leptin signaling impairment to reduce lipid accumulation and injury in the rat liver. These effects of morin were confirmed in Buffalo rat liver (BRL3A) cell model stimulated with 5mM fructose. Thus, the inhibition of hepatic SphK1/S1P signaling pathway may be a novel mechanism by which morin exerts hepatoprotection in high fructose-fed rats, possibly involving liver inflammation inhibition and lipid accumulation recovery.
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Biochemical pharmacology · Oct 2013
Functional role of alpha7 nicotinic receptor in chronic neuropathic and inflammatory pain: studies in transgenic mice.
A growing body of evidence indicates that α7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. In the present study, we investigated the role of the endogenous α7 nicotinic receptors (nAChRs) signaling in pain and inflammation using transgenic mice. For that we evaluated pain-related behaviors in the α7 mutant mice (KO) and its complementary α7 hypersensitive mice (KI) expressing the L250T α7 nAChRs and their respective WT mice in acute, chronic inflammatory and neuropathic mouse models. α7 KO and KI mice showed no significant changes in pain responses evoked by acute noxious thermal and mechanical stimuli as compared with WT littermates. ⋯ Finally, the ability of systemic nicotine to reverse already-developed mechanical allodynia produced by intraplantar CFA seen in WT mice was lost in the α7 KO animals. Overall, our results demonstrate that endogenous α7 nAChRs mechanisms play an important role in chronic inflammatory and neuropathic pain models. This provides an additional rationale for the utility of α7 nAChR agonists in the treatment of inflammatory and chronic pain.
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Biochemical pharmacology · Oct 2013
Nicotinic acetylcholine receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons.
Nicotine and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties. Both drugs acutely increase activity of ventral tegmental area (VTA) dopaminergic (DAergic) neurons, a phenomenon associated with reward behavior. Recent evidence indicates that nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels activated by ACh and nicotine, may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated. ⋯ Finally, pre-application of α-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses. Together our data indicate that α6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons. These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement, providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse.
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Biochemical pharmacology · Aug 2013
Morphine mediates a proinflammatory phenotype via μ-opioid receptor-PKCɛ-Akt-ERK1/2 signaling pathway in activated microglial cells.
Anti-nociceptive tolerance to opioids severely limits their clinical efficacy for the treatment of chronic pain syndromes. Glia has a central role in the development of morphine tolerance. Here, we characterized the receptor-proximal signaling events that link μ-opioid receptors to activation of Akt and ERKs in lipopolysaccharide (LPS)-stimulated murine microglial cells with the aim to define the molecular mechanism contributing to the ability of morphine to increase inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in activated microglial cells. ⋯ The results indicate that morphine increases the LPS-induced expression and activation of PKCɛ and stimulates Akt pathway upstream of ERK1/2 and iNOS. Furthermore, we found that morphine enhanced the release of IL-1β, TNF-α, IL-6, and of NO via μ-opioid receptor-PKCɛ signaling pathway in activated microglial cells, mediating a proinflammatory phenotype in mouse microglial cells. Together, these data suggest that the modulation of μ-opioid receptor signaling on microglia through PKCɛ selective inhibition may provide a means to attenuate glial activation and, as a consequence, to treat opioid development of tolerance and dependence.
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Biochemical pharmacology · May 2013
The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels.
One of the most potent insecticidal venom peptides described to date is Aps III from the venom of the trapdoor spider Apomastus schlingeri. Aps III is highly neurotoxic to lepidopteran crop pests, making it a promising candidate for bioinsecticide development. However, its disulfide-connectivity, three-dimensional structure, and mode of action have not been determined. ⋯ Channel block by rAps III is voltage-independent insofar as it occurs without significant alteration in the voltage-dependence of channel activation or steady-state inactivation. Thus, rAps III appears to be a pore blocker that plugs the outer vestibule of insect voltage-gated sodium channels. This mechanism of action contrasts strikingly with virtually all other sodium channel modulators isolated from spider venoms that act as gating modifiers by interacting with one or more of the four voltage-sensing domains of the channel.