Flagellin of Gram-negative pathogens such as PA contributes to the inflammatory responses of corneal epithelium in a TLR5-NF-kappaB signaling pathway-dependent manner.

Objective-Oxidative stress plays an important role in type 2 diabetes-related endothelial dysfunction. We hypothesized that resveratrol protects against oxidative stress-induced endothelial dysfunction in aortas of diabetic mice by inhibiting tumor necrosis factor ␣ (TNF␣)-induced activation of NAD(P)H oxidase and preserving phosphorylation of endothelial nitric oxide synthase (eNOS pidemiological studies indicate that the meditteranean diet that is rich in resveratrol, a plant polyphenol is associated with reduced risk of cardiovascular diseases, 1 which account for the majority of the mortality in type 2 diabetes. 2 Vascular dysfunction is the initial step in the occurrence of many disease states in the cardiovascular system concurrent with diabetes. 3 Obesity is an established risk factor for type 2 diabetes. Recent studies suggest that resveratrol, by activating silent mating type information regulation 2 homolog 1 (SIRT1), safely mimics the effects of dietary restriction in laboratory animals. 4 In diet-induced obese mice, resveratrol improves insulin sensitivity, lowers plasma glucose, and increases mitochondrial capacity. 5 Furthermore, resveratrol attenuates aortic dysfunction in aging and high fat-induced obesity animal models. 6 However, there is no study regarding the effects of resveratrol on insulin sensitivity and vascular dysfunction in type 2 diabetic mice.Oxidative stress is known to be the key mechanism in the pathogenesis of diabetes-related vascular dysfunction. Oxidative stress is attributable to excessive production of reactive oxygen species (ROS). The inactivation of nitric oxide (NO, a potent vasodilator synthesized by endothelial NO synthase [eNOS]) by ROS is recognized to be a crucial factor in reducing NO bioavailability and the development of endothelial dysfunction. 7 NAD(P)H oxidase is a key source of superoxide (O 2 ⅐Ϫ ) in the vasculature. 8 Previous work shows that anti-tumor necrosis factor-alpha (TNF␣) treatment inhibits NAD(P)H oxidase activation in coronary arterioles from type 2 diabetic mice. 9 TNF␣ is reported to downregulate eNOS expression in fat and muscle of obese rodents. 10 Several studies also reported that resveratrol

Primaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studied in vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity. P rimaquine (PQ) is the only FDA-approved drug for treatment of relapsing infections with malarial strains, including Plasmodium vivax and P. ovale (1-3). PQ belongs to the 8-aminoquinoline (8AQ) class of antimalarial compounds, among which several molecules, including PQ, have potent antihypnozoite activity (2, 4, 5). Low doses of PQ are also recommended for malaria transmission-blocking efforts due to PQ's gametocidal activity (6, 7). PQ's utility in malaria treatment and potential use in malarial transmission reduction and malaria eradication efforts require an understanding of the molecular species involved in its mechanism of action.Recent reports have shown that PQ requires metabolic activation by the cytochrome P450 (CYP) 2D isoenzymes for liver-stage antimalarial activity in both mouse studies (CYP 2D) and human studies (CYP 2D6) (8-11). Pybus et al. demonstrated that PQ was active only in mice capable of metabolizing CYP 2D6 substrates. Deletion of the mouse enzyme closest to human CYP 2D6 (mouse CYP 2D22 via deletion of the CYP 2D gene cluster) in mice completely blocked liver-stage antimalarial activity in vivo (10). The study by Bennett et al. demonstrated a direct link between CYP 2D6 metabolizer status and PQ efficacy for P. vivax treatment in several human subjects (8). PQ therapy is of significant importance for P. vivax radical cure, presumptive antirelapse therapy (PART), and malaria eradication efforts, and the requirement of CYP 2D6 metabolism for PQ efficacy is problematic because CYP 2D6 is highly polymorp...

Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca2+-activated K+ (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance.