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1.
Int J Mol Sci ; 24(21)2023 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-37958563

RESUMEN

We aimed to investigate the role of the CD40-CD40 ligand (CD40L) pathway in inflammation-mediated angiogenesis in proliferative diabetic retinopathy (PDR). We analyzed vitreous fluids and epiretinal fibrovascular membranes from PDR and nondiabetic patients, cultures of human retinal microvascular endothelial cells (HRMECs) and Müller glial cells and rat retinas with ELISA, immunohistochemistry, flow cytometry and Western blot analysis. Functional tests included measurement of blood-retinal barrier breakdown, in vitro angiogenesis and assessment of monocyte-HRMEC adherence. CD40L and CD40 levels were significantly increased in PDR vitreous samples. We demonstrated CD40L and CD40 expression in vascular endothelial cells, leukocytes and myofibroblasts in epiretinal membranes. Intravitreal administration of soluble (s)CD40L in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, VEGF, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). sCD40L induced upregulation of VEGF, MMP-9, MCP-1 and HMGB1 in cultured Müller cells and phospo-ERK1/2, p65 subunit of NF-ĸB, VCAM-1 and VEGF in cultured HRMECS. TNF-α induced significant upregulation of CD40 in HRMECs and Müller cells and VEGF induced significant upregulation of CD40 in HRMECs. sCD40L induced proliferation and migration of HRMECs. We provide experimental evidence supporting the involvement of the CD40L-CD40 pathway and how it regulates inflammatory angiogenesis in PDR.


Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Humanos , Ratas , Animales , Retinopatía Diabética/metabolismo , Ligando de CD40/metabolismo , Células Endoteliales/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratas Sprague-Dawley , Inflamación/metabolismo , Diabetes Mellitus/metabolismo
2.
Behav Pharmacol ; 20(4): 356-60, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19584713

RESUMEN

This investigation was undertaken to study the effect of pentoxifylline (PTX) on iminodipropionitrile (IDPN)-induced behavioral abnormalities [excitation with choreiform and circling movements (ECC) syndrome] in rats. The animals were intraperitoneally injected with IDPN (100 mg/kg) daily for 7 days. PTX was administered daily 30 min before IDPN in the doses of 25, 50, and 100 mg/kg for 9 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, and contact inhibition of the righting reflex. The onset of ECC syndrome was observed on day 8 in the group treated with IDPN alone; all animals in this group became dyskinetic on day 10. Co-treatment with PTX dose dependently delayed the onset time and significantly reduced the incidence and severity of IDPN-induced ECC syndrome; high dose of PTX completely inhibited the abnormal behavioral signs in IDPN-treated rats. Administration of IDPN caused significant depletions in cerebral glutathione and vitamin E levels. Treatment with PTX dose dependently attenuated IDPN-induced oxidative stress in rats. The beneficial effects of PTX against IDPN toxicity may be attributed to its antioxidant and anti-inflammatory properties.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Nitrilos/antagonistas & inhibidores , Nitrilos/toxicidad , Pentoxifilina/farmacología , Animales , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/psicología , Glutatión/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/psicología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Vitamina E/metabolismo
3.
Basic Clin Pharmacol Toxicol ; 100(3): 176-81, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17309521

RESUMEN

Occupational and environmental exposure of synthetic nitriles is of potential relevance to human health. Iminodipropionitrile (IDPN), a prototype nitrile toxin, has been shown to produce dyskinetic syndrome in rodents. This study reports the effect of concomitant exposure of rats to hydrocortisone and IDPN on behavioural abnormalities namely excitation, circling and chorea (ECC) syndrome. Four groups of female Wistar rats were given hydrocortisone (0, 10, 30 and 60 mg/kg, gavage, for 10 days) 30 min. before IDPN (100 mg/kg, intraperitoneally for 8 days). Two additional groups of rats were treated with either saline (control group) or 60 mg/kg of hydrocortisone (drug alone group). The animals were observed for neurobehavioural abnormalities including dyskinetic head movement, circling, tail hanging, air righting reflex and contact inhibition of righting reflex. After behavioural studies, the animals were killed, and the discrete brain regions and temporal bones were collected for biochemistry and inner ear histopathology, respectively. Hydrocortisone significantly and dose dependently attenuated the incidence and severity of IDPN-induced behavioural syndrome. Administration of hydrocortisone (60 mg/kg) alone significantly increased glutathione (GSH) levels in olfactory bulb and striatum, whereas IDPN alone significantly reduced GSH levels in olfactory bulb, striatum and hippocampus. Hydrocortisone (60 mg/kg) significantly compensated IDPN-induced depletions of GSH in different brain regions. Hydrocortisone also protected the animals against IDPN-induced vestibular hair cell degeneration. The protective effect of hydrocortisone may be attributed to its anti-inflammatory and antioxidant properties.


Asunto(s)
Antiinflamatorios/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Hidrocortisona/farmacología , Actividad Motora/efectos de los fármacos , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/patología , Femenino , Glutatión/efectos de los fármacos , Glutatión/metabolismo , Células Ciliadas Vestibulares/efectos de los fármacos , Células Ciliadas Vestibulares/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Neurotoxinas/toxicidad , Nitrilos/toxicidad , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Ratas , Ratas Wistar
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