Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.
Neuroinflammation plays an important role in the induction and maintenance of chronic pain. Orchestra of pattern-recognition receptor-induced pro-inflammatory and anti-inflammatory cytokines is critical for inflammation homeostasis. CD11b on macrophages could inhibit toll-like receptor (TLR) activation-induced inflammatory responses. However, the function of CD11b on microglia remains unknown. In the current study, we demonstrated that CD11b-deficient microglia cells produced more inflammatory cytokines, such as interleukin-6 and tumor necrosis factor alpha, while less anti-inflammatory cytokines. Signal transduction assay confirmed that nuclear factor-κB activation was increased in CD11b-deficient microglia cells, which resulted from decreased activation of Src. Inhibition of Src by PP1 increased inflammation in wild-type microglia cells significantly, but not in CD11b-deficient microglia cells. In vivo, CD11b-deficient mice were more susceptible to chronic constrictive injury-induced allodynia and hyperalgesia with significantly more inflammatory cytokines expression. All these results indicated that the regulatory function of CD11b-Src signal pathway on both inflammatory and anti-inflammatory cytokines in microglia cells is a potential target in neuropathic pain treatment.
Dexamethasone (Dex) is one of the most effective anti-inflammatory glucocorticoids, while the side effect, osteoporosis seriously limits its clinical use. Cell adhesion is involved in the onset of inflammation and osteoporosis, and RGD-peptides are well known as anti-adhesion peptides. To enhance the anti-inflammatory efficacy and limit the osteoporotic risk of Dex three novel conjugates of RGDV, RGDS and RGDF covalently modified Dex were presented here. On xylene-induced ear edema model the ear edema of the mice treated with the conjugates was significantly lower than that of the mice treated with Dex. Receiving 15day therapy the total volumetric bone mineral density, the peripheral quantitative CT and the femur weight of the mice treated with the conjugates were significantly higher than those of the mice treated with Dex. Therefore covalently modifying Dex with RGDV, RGDS and RGDF not only increased the anti-inflammation activity but also decreased the osteoporotic risk of Dex. Besides, the enhanced anti-inflammation activity was collated with the downregulated DNA expression of the conjugates.
The hot water extract of Rabdosia rubescens was traditionally used as an antithrombotic medicine. To explore its antithrombotic utility and mechanism, we carried out a series of in vitro and in vivo assays in this study. In vitro platelet aggregation assay showed that the half maximal inhibitory concentration values of aqueous extract of R. rubescens leaves (AERL) inhibiting platelet aggregation induced by thrombin, arachidonic acid, adenosine diphosphate, and platelet-activating factor ranged from 0.12 mg/mL to 1.43 mg/mL. The minimal effective oral dose of AERL inhibiting the rats from forming thrombus was 25 mg/kg. Both in vitro and in vivo actions were correlated with AERL concentration-dependently inhibiting sP-selectin release. In water, AERL formed nanoparticles, and their size depended on the concentration. Docking the five nucleotides, 21 phenolic acids, and four diterpenoids identified by high-performance liquid chromatography–photodiode array detector/(−)electrospray ionization-tandem mass spectrometry analysis into the active site of P-selectin, rosmarinic acid was predicted to be the antithrombotic ingredient of AERL. In flow cytometry analysis, 1 μM of rosmarinic acid effectively inhibited sP-selectin release in arachidonic acid-activated platelets. In a rat model, 5 mg/kg of oral rosmarinic acid effectively inhibited thrombosis.
Background: Vancomycin (VCM) is an antibiotic widely used to treat a range of serious bacterial infections; however, it is associated with nephrotoxicity. Vitamin C (VC) is a classical antioxidant that can alleviate various organ injuries and inflammatory responses by reducing inflammation and oxidative stress.This study aimed to examine the effect of VC on VCM-related nephrotoxicity in mice.Methods: Mice were randomized into four groups: control, VCM (400 mg/kg/day), VCM (400 mg/kg/day) + VC (200 mg/kg/day), and VC (200 mg/kg/day) groups. Both VCM and VC were administered via intraperitoneal injection for 7 d, after which kidney and blood samples were collected and evaluated. Creatinine (Cr), blood urea nitrogen (BUN), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and nuclear factor-κB (NF-κB) were measured.Results: In the VCM group, kidney index, renal injury score, cell apoptosis, serum Cr and BUN, and kidney Cr, BUN, MDA, IL-1β, IL-6, TNF-α, and NF-κB were higher compared to the control group (all P<0.05), while body weight and kidney SOD activity were lower (both P<0.05). By contrast, no differences were observed between the control and VC groups (VC and VCM + VC groups) for all these indicators. Conclusions:The antioxidant VC reduces VCM-related renal injury by reducing oxidative stress, cell apoptosis, and inflammation.
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