RESUMEN
In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K-Cl co-transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal -EPO and- nano- erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1-5, and autistic-like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high-dose NEPO improved autism-associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano- erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.
Asunto(s)
Trastorno Autístico , Eritropoyetina , Hipocampo , Simportadores , Animales , Femenino , Humanos , Masculino , Embarazo , Ratas , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/metabolismo , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Simportadores/metabolismo , Simportadores/farmacología , Simportadores/uso terapéutico , Ácido Valproico/farmacología , Eritropoyetina/farmacología , Eritropoyetina/uso terapéuticoRESUMEN
Hepatitis B virus (HBV) infection has been considered a crucial risk factor for hepatocellular carcinoma. Current treatment can only lessen the viral load but not result in complete remission. An efficient hepatocyte model for HBV infection would offer a true-to-life viral life cycle that would be crucial for the screening of therapeutic agents. Most available anti-HBV agents target lifecycle stages post viral entry but not before viral entry. This protocol details the generation of a competent hepatocyte model capable of screening for therapeutic agents targeting pre-viral entry and post viral entry lifecycle stages. This includes the targeting of sodium taurocholate cotransporting polypeptide (NTCP) binding, cccDNA formation, transcription, and viral assembly based on imHC or HepaRG as host cells. Here, the HBV entry inhibition assay used curcumin to inhibit HBV binding and transporting functions via NTCP. The inhibitors were evaluated for binding affinity (KD) with NTCP using isothermal titration calorimetry (ITC)-a universal tool for HBV drug screening based on thermodynamic parameters.
Asunto(s)
Hepatitis B , Simportadores , Hepatitis B/tratamiento farmacológico , Virus de la Hepatitis B/fisiología , Hepatocitos/metabolismo , Humanos , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/uso terapéutico , Simportadores/genética , Simportadores/metabolismo , Simportadores/uso terapéuticoRESUMEN
Anaplastic thyroid cancer is an extremely aggressive disease resistant to radioiodine treatment because of loss of sodium iodide symporter (NIS) expression. To enhance prognosis of this fatal cancer, we validated the preclinical efficacy of measles virus (MV)-NIS, the vaccine strain of the oncolytic MV (MV-Edm), modified to include the NIS gene. Western blotting analysis confirmed that a panel of eight anaplastic thyroid cancer (ATC)-derived cell lines do not express NIS protein, but do express CD46, the MV receptor. In vitro cell death assays and in vivo xenograft studies demonstrate the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines. Radioactive iodine uptake along with single-photon emission computed tomography (SPECT)-computed tomography imaging of KTC-3 xenografts after (99)Tc(m) administration confirmed NIS expression in vitro and in vivo, respectively, after virus treatment. Adjuvant administration of RAI, to MV-NIS-treated KTC-3 tumors showed a trend for increased tumor cell killing. As current treatment for ATC is only palliative, and MV-NIS is currently Food and Drug Administration approved for human clinical trials in myeloma, our data indicate that targeting ATC with MV-NIS could prove to be a novel therapeutic strategy for effective treatment of iodine-resistant ATC and will expedite its testing in clinical trials for this aggressive disease.