Aspirin ameliorates pulmonary vascular remodeling in pulmonary hypertension by dampening endothelial-to-mesenchymal transition.

Pulmonary vascular remodeling (PVR) is the pathological basis of pulmonary hypertension (PH). Incomplete understanding of PVR etiology has hindered drug development for this devastating disease, which exhibits poor prognosis despite the currently available therapies. Endothelial-to-mesenchymal transition (EndMT), a process of cell transdifferentiation, has been recently implicated in cardiovascular diseases, including PH. But the questions of how EndMT occurs and how to pharmacologically target EndMT in vivo have yet to be further answered. Herein, by performing hematoxylin-eosin and immunofluorescence staining, transmission electron microscopy and Western blotting, we found that EndMT plays a key role in the pathogenesis of PH, and importantly that aspirin, a FDA-approved widely used drug, was capable of ameliorating PVR in a preclinical rat model of hypoxia-induced PH. Moreover, aspirin exerted its inhibitory effects on EndMT in vitro and in vivo by suppressing HIF-1α/TGF-ß1/Smads/Snail signaling pathway. Our data suggest that EndMT represents an intriguing drug target for the prevention and treatment of hypoxic PH and that aspirin may be repurposed to meet the urgent therapeutic needs of hypoxic PH patients.

Ginsenosides in vascular remodeling: Cellular and molecular mechanisms of their therapeutic action.

Evidence is mounting that abnormal vascular remodeling (VR) is a vital pathological event that precedes many cardiovascular diseases (CVD). This provides us with a new research perspective that VR can be a pivotal target for CVD treatment and prevention. However, the current drugs for treating CVD do not fundamentally reverse VR and repair vascular function. The reason may be that a complicated regulatory network is formed between the various signaling pathways involved in VR. Recently, ginsenoside, the main active substance of ginseng, has become increasingly the focus of many researchers for its multiple targets, multiple pathways, and few side effects. Several data have revealed that ginsenosides can improve VR caused by vasodilation dysfunction, abnormal vascular structure and blood pressure. This review is intended to discuss the therapeutic effects and mechanisms of ginsenosides in some diseases involved in VR. Besides, we herein also give a new and contradictory insight into intracellular and molecular signaling of ginsenosides in all kinds of vascular cells. Most importantly, we also discuss the feasibility of ginsenosides Rb1/Rg1/Rg3 in drug development by combining the pharmacodynamics and pharmacokinetics of ginsenosides, and provide a pharmacological basis for the development of ginsenosides in clinical applications.

Reasonable drug analysis of Listeria monocytogenes meningitis related to mantle cell lymphoma.

We report a case of Listeria meningitis related to mantle cell lymphoma. A clinical pharmacist adjusted repeatedly the patient's anti-infective therapeutic regimen by analyzing the pharmacologic and pharmacokinetic characteristics of antibacterial drugs (such as cefotaxime, meropenem, etc.) due to the patient's repeated fever during hospitalization. To the best of our knowledge, this is the first case of Listeria meningitis related to mantle cell lymphoma treated successfully with meropenem reported in China. This case aims to optimize the anti-infection treatment regimen of Listeria meningitis and to provide a reference for clinicians and clinical pharmacists to use drugs rationally.

Activation of c-Jun NH2-terminal kinase 3 is mediated by the GluR6.PSD-95.MLK3 signaling module following cerebral ischemia in rat hippocampus.

Kainate receptor glutamate receptor 6 (GluR6) binds to the postsynaptic density protein 95 (PSD-95), which in turn anchors mixed lineage kinase 3 (MLK3) via SH3 domain in rat brain tissue. MLK3 subsequently activates c-Jun NH(2)-terminal kinase (JNK) via MAP kinase kinases (MKKs). We investigated the association of PSD-95 with GluR6 and MLK3, MLK3 autophosphorylation, the interaction of MLK3 with JNK3, and JNK3 phosphorylation following cerebral ischemia in rat hippocampus. Our results indicate that the GluR6.PSD-95.MLK3 complex peaked at 6 h of reperfusion. Furthermore, MLK3 autophosphorylation and the interaction of MLK3 with JNK3 occurred with the alteration of GluR6.PSD-95.MLK3 signaling module. To further prove whether JNK3 activation in ischemic hippocampus is mediated by GluR6.PSD-95.MLK3 signaling pathway, the AMPA/KA receptor antagonist 6,7-dinitroquinoxaline-2, (1H, 4H)-dione (DNQX), the GluR6 antagonist 6,7,8,9-Tetrahydro-5-nitro-1H-benz[g]indole-2,3-dione-3-oxime (NS102), the AMPA receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo diazepine (GYKI52466), and the NMDA receptor antagonist ketamine were given to the rats 20 min prior to ischemia. Our findings indicate that both DNQX and NS102 significantly attenuated the association of PSD-95 with GluR6 and MLK3, MLK3 autophosphorylation, interaction of MLK3 with JNK3, and JNK3 phosphorylation, while GYKI52466 and ketamine had no effect. Moreover, administration of NS102 before cerebral ischemia significantly increased the number of the surviving hippocampal CA1 pyramidal cells at 5 days of reperfusion. Consequently, GluR6, one subunit of kainate receptor, plays a critical role in inducing JNK3 activation after ischemic injury.