Adenosine signaling via A1 receptor (A1R) and A2A receptor (A2AR) has shown promise in revealing potential targets for neuroprotection in cerebral ischemia. We recently showed a novel mechanism by which A1R activation with N(6)-cyclopentyl adenosine (CPA) induced GluA1 and GluA2 AMPA receptor (AMPAR) endocytosis and adenosine-induced persistent synaptic depression (APSD) in rat hippocampus. This study further investigates the mechanism of A1R-mediated AMPAR internalization and hippocampal slice neuronal damage through activation of protein phosphatase 1 (PP1), 2A (PP2A), and 2B (PP2B) using electrophysiological, biochemical and imaging techniques. Following prolonged A1R activation, GluA2 internalization was selectively blocked by PP2A inhibitors (okadaic acid and fostriecin), whereas inhibitors of PP2A, PP1 (tautomycetin), and PP2B (FK506) all prevented GluA1 internalization. Additionally, GluA1 phosphorylation at Ser831 and Ser845 was reduced after prolonged A1R activation in hippocampal slices. PP2A inhibitors nullified A1R-mediated downregulation of pSer845-GluA1, while PP1 and PP2B inhibitors prevented pSer831-GluA1 downregulation. Each protein phosphatase inhibitor also blunted CPA-induced synaptic depression and APSD. We then tested whether A1R-mediated changes in AMPAR trafficking and APSD contribute to hypoxia-induced neuronal injury. Hypoxia (20 min) induced A1R-mediated internalization of both AMPAR subunits, and subsequent normoxic reperfusion (45 min) increased GluA1 but persistently reduced GluA2 surface expression. Neuronal damage after hypoxia-reperfusion injury was significantly blunted by pre-incubation with the above protein phosphatase inhibitors. Together, these data suggest that A1R-mediated protein phosphatase activation causes persistent synaptic depression by downregulating GluA2-containing AMPARs; this previously undefined role of A1R stimulation in hippocampal neuronal damage represents a novel therapeutic target in cerebral ischemic damage.
Wound healing has always been a great challenge throughout human history. Today, with a substantial rise in chronic diseases and surgical operations, there is more demand for wound dressings to facilitate the healing process. Modern dressings come in different forms and offer significant advantages over the traditionally used passive bandages by inhibiting microbial activity and providing a suitable moist environment for the wound. Despite their widespread clinical usage and successful results in wound treatment, even modern dressings cannot promote wound healing as expected since they are not responsive to the wound conditions. On the other hand, smart dressings can interact with the environment through their built‐in sensors and respond to wound needs. They can monitor the changes in wound healing stages and provide insightful information that could affect the treatment direction. The current manuscript reviews the evolution of wound dressings from ancient, traditional to modern dressings and presents the advanced class of smart dressings as the future trend in the field.
Recurrent primary biliary cholangitis (rPBC) is frequent following liver transplantation and associated with increased morbidity and mortality. It has been argued that rPBC behaves like an infectious disease because more potent immunosuppression with tacrolimus is associated with earlier and more severe recurrence. Prophylactic ursodeoxycholic acid is an established therapeutic option to prevent rPBC, whereas the role of second line therapies, such as obeticholic acid and bezafibrate in rPBC, remains largely unexplored. To address the hypothesis that a human betaretrovirus plays a role in the development of PBC, we have tested antiretroviral therapy in vitro and conducted randomised controlled trials showing improvements in hepatic biochemistry. Herein, we describe the utility of combination antiretroviral therapy to manage rPBC in two patients treated with open label tenofovir/emtricitabine‐based regimens in combination with either lopinavir or raltegravir. Both patients experienced sustained biochemical and histological improvement with treatment, but the antiretroviral therapy was associated with side effects.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.