RESUMEN
In an earlier single-dose escalation study to evaluate the safety and pharmacokinetics of orally administered des-aspartate-angiotensin I (DAA-I) in healthy subjects, the plasma level of DAA-I could not be determined because DAA-I is rapidly degraded in the circulation. The present study investigated the oral bioavailability of DAA-I by measuring the prostaglandin E2 metabolite (PGEM) in the plasma samples of the same trial. PGEM is a stable derivative of PGE2, which has been shown to be a biomarker of DAA-I. The data show that plasma from two of the three subjects who were orally administered the efficacious preclinical dose of 0.70 mg/kg DAA-I exhibited a significant PGEM peak at 5-6 h postdose. Plasma of subjects who were administered 0.08 and 1.5 mg/kg DAA-I, the subefficacious and two-times efficacious dose, respectively, did not exhibit a similar PGEM peak. This observation is concordant with the known in vivo actions of DAA-I, especially its hypoglycemic action where maximum efficacy occurred at a dose of 0.7 mg/kg, and decreased to nil at the two-times efficacious dose. The onset of the PGEM peak at 5-6 h postdose was closed to the 4-h onset of absorption of [C14]DAA-I seen in preclinical rat studies, albeit the absorption kinetics between rodents and humans are not identical. The occurrence of polymorphism of enzymes involved in the formation and degradation of PGE2 is common, and this has been attributed to contributing to the variation in response, onset and peak PGEM observed among the three subjects who were administered the efficacious dose.
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Angiotensina I/análogos & derivados , Dinoprostona/análogos & derivados , Angiotensina I/administración & dosificación , Angiotensina I/farmacocinética , Disponibilidad Biológica , Dinoprostona/sangre , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
This study was aimed to evaluate the possible protective effects of ursolic acid (UA) against gamma radiation induced damage both in vitro as well as in vivo. It was observed that the exposure to gamma radiation dose- and time-dependently caused a significant decrease in the cell viability, while the treatment of UA attenuated this cytotoxicity. The production of free radicals including reactive oxygen species (ROS) and NO increased significantly post-irradiation and further induced lipid peroxidation and oxidative DNA damage in cells. These deleterious effects could also be effectively blocked by UA treatment. In addition, UA also reversed gamma irradiation induced inflammatory responses, as indicated by the decreased production of TNF-α, IL-6, and IL-1ß. NF-κB signaling pathway has been reported to be a key mediator involved in gamma radiation-induced cellular damage. Our results further demonstrated that gamma radiation dose- and time-dependently enhanced NF-κB DNA binding activity, which was significantly attenuated upon UA treatment. The post-irradiation increase in the expression of both phospho-p65, and phospho-IκBα was also blocked by UA. Moreover, the treatment of UA was found to significantly prolong overall survival in mice exposed to whole body gamma irradiation, and reduce the excessive inflammatory responses. Given its radioprotective efficacy as described here, UA as an antioxidant and NF-κB pathway blocker, may function as an important pharmacological agent in protecting against gamma irradiation-induced injury.
RESUMEN
Des-aspartate-angiotensin I (DAA-I) is an endogenous angiotensin peptide and a prototype angiotensin receptor agonist (ARA). It acts on the angiotensin AT1 receptor and antagonises the deleterious actions of angiotensin II. DAA-I attenuates animal models of human disease in which angiotensin II has been implicated, such as cardiac hypertrophy, neointima formation, arteriosclerosis, renal failure, post-infarction injuries, diabetes, viral infection, chemical-induced inflammation, heat stroke, cancer, and gamma radiation lethality. DAA-I crosses Caco-2 cells and is effective at sub-nanomolar concentrations. These two properties are responsible for its oral efficacy. A single dose-escalation study was conducted to evaluate the safety, tolerability and pharmacokinetics of orally administered DAA-I in 18 healthy subjects. DAA-I was safe and well tolerated by the subjects, who were administered either 0.08, 0.70 or 1.50 mg/kg of the compound. The heart rate and systolic and diastolic blood pressures determined at each post-dose measurement remained within the clinically acceptable range. Across all cohorts, DAA-I had no substantial effect on blood pressures compared with placebo. Electrocardiographs (ECGs) were normal, and none of the subjects complained of chest discomfort. All clinical laboratory tests obtained before and after DAA-I and placebo treatment were normal. Pharmacokinetic analysis over a 12-h period following DAA-I administration did not show any increase of its level beyond basal concentration. This is in line with studies showing that intravenously administered DAA-I is rapidly metabolized and has a short half-life. We postulate that, during its short systemic sojourn, DAA-I exerts its actions via biased agonism on the angiotensin AT1 receptor.The ClinicalTrial.gov assignment number for this study is NCT02666196.
Asunto(s)
Angiotensina I/análogos & derivados , Administración Oral , Adulto , Angiotensina I/administración & dosificación , Angiotensina I/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
DAA-I (des-aspartate-angiotensin I), an endogenous angiotensin, had been shown earlier to ameliorate animal models of cardiovascular diseases via the angiotensin AT1 receptor and prostaglandins. The present study investigated further the action of DAA-I on the release of PGE2, PGI2, PGF2α and TXA2 in HUVEC. 10(-11)-10(-8)M DAA-I and 15min incubation specifically released PGE2 and PGI2. The release was inhibited by losartan and indomethacin but not by PD123319 and NS398 indicating that the angiotensin AT1 receptor and COX-1 mediate the release. At concentrations higher than 10(-7)M, DAA-I mimics the action of angiotensin II by releasing TXA2 but had no effect on the production of PGF2α. At similar concentrations and 4h incubation, DAA-I increased the release of the 4 prostaglandins via the angiotensin AT1 receptor and COX-2, again mimicking the action of angiotensin II. HUVEC that were preincubated with DAA-I or angiotensin II, released similar profiles of prostaglandins when incubated with arachidonic acid after the angiotensin had been washed off. We postulate that the internalized DAA-I/receptor complex remains active and mediates the conversion of arachidonic acid to the respective prostaglandins. The release of PGE2 and PGI2 via the angiotensin AT1 receptor and COX-1 is a novel specific action of DAA-I and is likely responsible for its beneficial effects seen in earlier studies. This specific action is definable as a biased agonism of the angiotensin AT1 receptor, which identifies DAA-I as a novel biased agonist and potential therapeutic that is able to produce specific prostaglandins at nanomolar concentrations.
Asunto(s)
Angiotensina I/análogos & derivados , Dinoprostona/metabolismo , Epoprostenol/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Receptor de Angiotensina Tipo 1/agonistas , Receptor de Angiotensina Tipo 1/metabolismo , Angiotensina I/farmacología , Ácido Araquidónico/farmacología , Humanos , Factores de TiempoRESUMEN
ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely attenuated the increase in circulating level of two inflammatory cytokines, TNFα and IL-6, in irradiated mice; and this shows that DAA-I exerted additional anti-inflammatory actions, which could also have contributed to its radioprotection. These findings show that DAA-I acts via a novel mechanism of action on the angiotensin AT1 receptor to specifically release PGE2, which mediates radioprotection in the gamma irradiated mice.
Asunto(s)
Angiotensina I/análogos & derivados , Rayos gamma/efectos adversos , Síndromes Mielodisplásicos/tratamiento farmacológico , Protectores contra Radiación/farmacología , Angiotensina I/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Dinoprostona/metabolismo , Femenino , Interleucina-6/metabolismo , Losartán/farmacología , Ratones , Ratones Endogámicos BALB C , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/radioterapia , Receptor de Angiotensina Tipo 1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The review describes DAA-I (des-aspartate-angiotensin-I) as a prototype of a novel class of drugs that acts as agonists on the angiotensin AT1 receptor or ARAs (angiotensin receptor agonists). DAA-I is a component of the renin angiotensin system. Earlier studies showed that it was rapidly metabolized to angiotensin III. However, when administered at doses below the Km of enzymes, DAA-I produces specific actions that antagonize the deleterious actions of angiotensin II. DAA-I exerts protective actions in animal models of eight human pathologies in which angiotensin II is implicated. The pathologies include cardiac hypertrophy, neointima growth and cardiovascular hypertrophy, myocardial-ischemia reperfusion injury, hyperglycemia and insulin resistance, chemical induced inflammation, and exercise-induced skeletal muscle inflammation. Binding of DAA-I to the angiotensin AT1 receptors releases prostaglandins, which could either function as autocrines/paracrines or second messengers and attenuate the deleterious actions of angiotensin II. It is possible that in in vivo DAA-I functions as a physiological antagonist to angiotensin II, and exogenous DAA-I is a novel class of angiotensin receptor drug that could rival the angiotensin receptor blockers.
Asunto(s)
Angiotensina I/análogos & derivados , Receptor de Angiotensina Tipo 1/metabolismo , Angiotensina I/metabolismo , Angiotensina I/farmacología , Angiotensina I/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Humanos , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismoRESUMEN
L6 skeletal muscle cells overexpressed ICAM-1 when treated with H2O2. Maximum effect was observed at 200 µM H2O2. Des-aspartate-angiotensin I (DAA-I) concentration-dependently attenuated the overexpression. Maximum attenuation occurred at 10(-10) M DAA-I. H2O2 activated NFκB and its translocation into the nucleus of L6 muscle cells suggesting that NFκB mediates the H2O2-induced overexpression of ICAM-1. DAA-I inhibited the activation and translocation of NFκB. H2O2 is a major oxidant formed during skeletal muscle contraction and is implicated in oxidative stress and skeletal muscle damage in excessive unaccustomed exercise. The data show that DAA-I has antioxidant action, and its action was further investigated in the soleus muscle of mice subjected to 240 min of eccentric exercise on a rodent treadmill. The eccentric exercise induced superoxide formation and overexpression of ICAM-1 in the soleus muscle of the mice at 3 days post exercise. DAA-I (0.2 nmole/kg/day) administered orally on day 1 (pre-exercise) and 2 days post-exercise attenuated both the ROS formation and ICAM-1 overexpression. Earlier studies show that DAA-I acts as an agonist on the angiotensin AT1 receptor and elicits responses opposing those of angiotensin II. The present and earlier findings support the recent suggestion that angiotensin II is involved in skeletal muscle damage, and curtailment of its actions via ACE inhibitors and losartan protects and improves skeletal muscle damage. These findings open up new avenues for treatment and management of skeletal muscle damage via the interventions of the renin angiotensin system.
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Angiotensina I/análogos & derivados , Peróxido de Hidrógeno/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Oxidantes/farmacología , Angiotensina I/farmacología , Angiotensina I/fisiología , Animales , Línea Celular , Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/citología , Músculo Esquelético/fisiología , Condicionamiento Físico Animal , Ratas , Superóxidos/metabolismoRESUMEN
The high frequency of rhinovirus (RV) infection and the lack of an effective treatment, underline the importance of research on novel anti-rhinoviral agents. The present study investigated the effects of des-aspartate-angiotensin I (DAA-I) on the survival of RV14-infected H1HeLa cells; and the early inflammatory processes in RV14-infected A549 lung epithelial cells. The study rationale was based on earlier findings showing that DAA-I is an effective anti-inflammatory agent, and that symptoms and severity of rhinoviral infection are related to the underling inflammation. RV14 concentration dependently caused the death of H1HeLa cells and DAA-I, at concentrations of 10⻹° to 10⻹² M, attenuated the lethal action of RV14 indicating that that DAA-I exerts antiviral action. Unlike its action on H1HeLa cells, RV14 did not cause apparent cytopathic effect on A549 cells, and these cells were used to study the antiviral action of DAA-I. RV14 induced overexpression of ICAM-1, E-selectin and overproduction of superoxide in A549 cells, and DAA-I attenuated the three increases to basal level at concentrations of 10⻹° to 10⻹² M. Losartan, an angiotensin AT1 receptor antagonist, blocked the inhibitory action of DAA-I on superoxide overproduction indicating that the AT1 receptor mediates the action of DAA-I. The present data represent a novel demonstration of the antiviral action of an angiotensin peptide, and a possible involvement of the renin angiotensin system in viral infection. Indeed the angiotensin AT1 receptor has been reported to be obligatory for the development of virus-induced myocardial injury through the proinflammatory action of angiotensin II via the NF-κB/cytokine pathway.
Asunto(s)
Angiotensina I/análogos & derivados , Antiinflamatorios no Esteroideos/farmacología , Antivirales/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Rhinovirus/efectos de los fármacos , Angiotensina I/efectos adversos , Angiotensina I/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antiinflamatorios no Esteroideos/efectos adversos , Antivirales/efectos adversos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Efecto Citopatogénico Viral/efectos de los fármacos , Selectina E/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Células HeLa , Humanos , Viabilidad Microbiana/efectos de los fármacos , Concentración Osmolar , Receptor de Angiotensina Tipo 1/química , Receptor de Angiotensina Tipo 1/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Rhinovirus/inmunología , Rhinovirus/patogenicidad , Superóxidos/metabolismoRESUMEN
Although clinical studies suggested that blockade of the renin-angiotensin system may prevent diabetes, the mechanism is uncertain. As a follow-up to an earlier study, we investigated how des-aspartate-angiotensin-1 (DAA-1) and its metabolite, angiotensin IV (Ang-IV) improved glucose tolerance in diet-induced hyperglycaemic mice. Male C57BL/6J mice were fed a high-fat-high-sucrose (HFD) or normal (ND) diet for 52 weeks. HFD animals were orally administered either DAA-I (600nmol/kg/day), Ang-IV (400nmol/kg/day) or distilled water. Body weight, blood glucose and insulin were measured fortnightly. Inflammatory and insulin signalling transducers that are implicated in hyperglycaemia were analyzed in skeletal muscles at 52 weeks. HFD animals developed hyperglycemia, hyperinsulinemia and obesity. DAA-I and Ang-IV improved glucose tolerance but had no effect on hyperinsulinemia and obesity. Skeletal muscles of HFD animals showed increased level of ROS, gp91 of NADPH oxidase, pJNK and AT(1)R-JAK-2-IRS-1 complex. Both DAA-I and Ang-IV attenuated these increases. Insulin-induced activation of IR, IRS-1, IRS-1-PI3K coupling, phosphorylation of Akt, and GLUT4 translocation were attenuated in skeletal muscles of HFD animals. The attenuation was significantly ameliorated in DAA-I-treated HFD animals. In corresponding Ang-IV treated animals, insulin induced IRAP and PI3K interaction, activation of pAkt and GLUT4 translocation, but no corresponding activation of IR, IRS-1 and IRS-1-PI3K coupling were observed. DAA-I and Ang-IV improved glucose tolerance, insulin signalling, and para-inflammatory processes linked to hyperglycaemia. DAA-I acts via the angiotensin AT(1) receptor and activates the insulin pathway. Ang-IV acts via IRAP, which couples PI3K and activates the later part of the insulin pathway.
Asunto(s)
Angiotensina II/análogos & derivados , Angiotensina I/análogos & derivados , Intolerancia a la Glucosa/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Insulina/metabolismo , Transducción de Señal/fisiología , Angiotensina I/farmacología , Angiotensina II/farmacología , Animales , Glucemia/análisis , Cistinil Aminopeptidasa/genética , Cistinil Aminopeptidasa/metabolismo , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Sacarosa en la Dieta/administración & dosificación , Sacarosa en la Dieta/efectos adversos , Esquema de Medicación , Hiperglucemia/etiología , Indometacina/farmacología , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Losartán/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The present study investigated the actions of des-aspartate-angiotensin I (DAA-I) on infarct size and three early inflammatory events in acute myocardial ischemia-reperfusion injury in rats. The rationale was based on earlier findings showing that chronic daily administration of DAA-I attenuated infarct size of ischemic-reperfused rat heart, and cardiac hypertrophy in pressure overload rats. Anesthetized rats were subjected to 45 min of ischemia and 5h of reperfusion. Infarcted area, serum creatine kinase, and tissue myeloperoxidase activity were determined. The expression of intercellular adhesion molecule-1 (ICAM-1) was also investigated by immunohistochemistry and Western blotting. Intravenous administration of DAA-I at 5 min post reperfusion reduced myocardial infarct size by 45.5%, lowered serum creatine kinase activity, decreased myeloperoxidase activity in cardiac tissue, and inhibited the expression of ICAM-1 in cardiac capillary endothelium. The maximum effective dose was 1013 pmol/kg, and the cardioprotective actions of DAA-I were blocked by indomethacin. The data showed that the cardioprotection accorded by DAA-I was the result of its anti-inflammatory actions on early inflammatory processes in myocardial ischemia-reperfusion injury. The anti-inflammatory processes were indomethacin sensitive and probably mediated by prostaglandins.
Asunto(s)
Angiotensina I/análogos & derivados , Isquemia Miocárdica/complicaciones , Daño por Reperfusión/complicaciones , Daño por Reperfusión/tratamiento farmacológico , Angiotensina I/farmacología , Angiotensina I/uso terapéutico , Animales , Creatina Quinasa/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patologíaRESUMEN
The present study investigated the protective actions of des-aspartate-angiotensin I (DAA-I) in mice that were intranasally administered 2-chloroethyl ethyl sulfide (CEES), a half sulfur mustard. The protection was dose-dependent, and an oral dose of 75 mg kg⻹ per day administered 18 h post exposure and for the following 13 days, offered maximum protection that increased survival by a third. DAA-I attenuated the early processes of inflammation seen in the CEES-inoculated mice. DAA-I attenuated (i) elevated pulmonary ROS, and gp91-phox protein of NADPH oxidase, a non phagocytic enzyme that generates superoxide and subsequent ROS; (ii) intercellular adhesion molecule-1 (ICAM⻹) that is involved in the extravasation of circulating leucocytes; and (iii) myeloperoxidase activity, which is a surrogate enzymatic measurement of neutrophil infiltration. These actions led to improved histological lung structures, and survival of type-1 pneumocytes. The action of DAA-I on animal survival was blocked by losartan, a selective angiotensin AT1 receptor blocker, indicting that the AT1 receptor mediates the protection. The presence of elevated PGE2 and PGI2 in lung supernatants of DAA-I treated CEES-inoculated mice indicates that the two prostaglandins are involved in signaling the protective actions of DAA-I. This finding complements earlier studies showing that DAA-I acts on an indomethacin-sensitive angiotensin AT1 receptor. The findings of the present study are the first demonstration of an angiotensin peptide as an effective antidote for CEES intoxication. DAA-I is also an effective therapeutic intervention against CEES that was instituted at 18 h post exposure, and challenges conventional assumptions of limited efficacy with delayed action against alkylating agents.
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Angiotensina I/análogos & derivados , Pulmón/efectos de los fármacos , Pulmón/patología , Gas Mostaza/análogos & derivados , Angiotensina I/farmacología , Animales , Líquido del Lavado Bronquioalveolar/química , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Epoprostenol/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Losartán/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Gas Mostaza/toxicidad , NADPH Oxidasas/metabolismo , Peroxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores Inmunológicos/metabolismo , Transducción de SeñalRESUMEN
The threat of a pandemic spread of highly virulent influenza A viruses currently represents a top global public health problem. Mass vaccination remains the most effective way to combat influenza virus. However, current vaccination strategies face the challenge to meet the demands in a pandemic situation. In a mouse model of severe influenza virus-induced pneumonitis, we observed that prior nasal administration of an attenuated strain of Bordetella pertussis (BPZE1) provided effective and sustained protection against lethal challenge with two different influenza A virus subtypes. In contrast to most cross-protective effects reported so far, the protective window offered upon nasal treatment with BPZE1 lasted up to at least 12 weeks, suggesting a unique mechanism(s) involved in the protection. No significant differences in viral loads were observed between BPZE1-treated and control mice, indicating that the cross-protective mechanism(s) does not directly target the viral particles and/or infected cells. This was further confirmed by the absence of cross-reactive antibodies and T cells in serum transfer and in vitro restimulation experiments, respectively. Instead, compared to infected control mice, BPZE1-treated animals displayed markedly reduced lung inflammation and tissue damage, decreased neutrophil infiltration, and strong suppression of the production of major proinflammatory mediators in their bronchoalveolar fluids (BALFs). Our findings thus indicate that protection against influenza virus-induced severe pneumonitis can be achieved through attenuation of exaggerated cytokine-mediated inflammation. Furthermore, nasal treatment with live attenuated B. pertussis offers a potential alternative to conventional approaches in the fight against one of the most frightening current global public health threats.
Asunto(s)
Bordetella pertussis/inmunología , Protección Cruzada , Citocinas/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Inmunidad Adaptativa , Administración Intranasal , Animales , Bordetella pertussis/patogenicidad , Quimiocinas/inmunología , Brotes de Enfermedades/prevención & control , Femenino , Humanos , Vacunas contra la Influenza/inmunología , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae , Neumonía/prevención & control , Neumonía/virología , Tasa de SupervivenciaRESUMEN
This study researched the effects of chicken meat extract on blood glucose and insulin level, membrane glucose transporter-4 (GLUT4), and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in type 2 diabetic KKAy mice and GK rats. Eight-week-old KKAy mice and GK rats and euglycemic control animals, C57BL/6J mice and Wistar rats, were orally administered a liquid commercial chicken meat extract, BRAND'S Essence of Chicken (BEC), for up to 8 weeks. BEC (1.5 ml/kg) had no effect on blood insulin levels, but significantly lessened the hyperglycemia in the diabetic animals. In the BEC-treated diabetic animals, insulin induced a significant increase in plasma membrane GLUT4 and cytosolic tyrosine-phosphorylated IRS-1, indicating that it attenuates insulin resistance. The present findings are the first demonstration of the hypoglycemic action of a dietary protein, and they lend credence to the reported benefits of using chicken meat as a source of protein in the dietary management of diabetic individuals.
Asunto(s)
Glucemia/metabolismo , Pollos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/dietoterapia , Proteínas en la Dieta/farmacología , Hiperglucemia/dietoterapia , Carne , Animales , Diabetes Mellitus Tipo 2/metabolismo , Prueba de Tolerancia a la Glucosa , Hiperglucemia/complicaciones , Insulina/sangre , Resistencia a la Insulina , Masculino , Ratones , Fosforilación/efectos de los fármacos , Ratas , Tirosina/metabolismoRESUMEN
The present study investigated the hypoglycemic action of des-aspartate-angiotensin I (DAA-I), a metabolite of angiotensin I, in two animal models of type 2 diabetes. The rationale was based on our earlier studies demonstrating that DAA-I acts on the angiotensin AT(1) receptor and exerts responses opposing those of angiotensin II and on recent reports that curtailment of angiotensin II formation by angiotensin converting enzyme inhibitors and blockade of the AT(1) receptor attenuate hyperglycemia in type 2 diabetics and diabetic animals. Diabetic KKAy mice and GK rats were administered orally (by gavage) one of the following doses of DAA-I: 400, 600, or 800 nmol/kg.d for 4 and 6 wk, respectively. Control diabetic animals were similarly administered water. Blood glucose of each animal was determined fortnightly by oral glucose tolerance test and blood insulin on the last day of treatment. Animals were killed, and the levels of plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1 in hind limb skeletal muscles were determined by Western blot in insulin-challenged and nonchallenged animals. Orally administered DAA-I had no effect on blood insulin level but exerted dose-dependent hypoglycemic action in KKAy mice and GK rats after 4 and 6 wk of treatment, respectively. At the maximal effective dose of 600 nmol/kg, insulin induced a significant increase in plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1. These findings show that DAA-I is not an insulin secretagogue and exerts hypoglycemic action by attenuating insulin resistance, the first such demonstration indicating that the nonapeptide is involved in glycemic regulation.
Asunto(s)
Angiotensina I/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Transportador de Glucosa de Tipo 4/metabolismo , Hipoglucemiantes/farmacología , Angiotensina I/administración & dosificación , Angiotensina I/análogos & derivados , Animales , Glucemia/metabolismo , Western Blotting , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/administración & dosificación , Inmunoprecipitación , Insulina/sangre , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Fosfodiesterasa I/metabolismo , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Angiotensin 1-7, a heptapeptide derived from metabolism of either angiotensin I or angiotensin II, is a biologically active peptide of the renin-angiotensin system. The present study investigated the effect of angiotensin 1-7 on the vasopressor action of angiotensin II in the renal and mesenteric vasculature of Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and streptozotocin-induced diabetic rats. Angiotensin II-induced dose-dependent vasoconstrictions in the renal vasculature. The pressor response was enhanced in the SHR and reduced in the streptozotocin-diabetic rat compared to WKY rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in the renal vasculature of WKY and SHR rats. However, the ability to reduce angiotensin II response was diminished in diabetic-induced rat kidneys. The effect of angiotensin 1-7 was not inhibited by 1-[(4-(Dimethylamino)-3-methylphenyl] methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate (PD123319), an angiotensin AT(2) receptor antagonist. (D-ALA(7))-Angiotensin I/II (1-7) (D-ALA) (an angiotensin 1-7 receptor antagonist), indomethacin (a cyclo-oxygenase inhibitor), and N(omega)-Nitro-L-Arginine Methyl Ester (L-NAME)(a nitric oxide synthetase inhibitor) abolished the attenuation by angiotensin 1-7 in both WKY rats and SHR, indicating that its action is mediated by angiotensin 1-7 receptor that is either coupled to the release of prostaglandins and/or nitric oxide. The vasopressor responses to angiotensin II in mesenteric vasculature bed was also dose-dependent but smaller in magnitude compared to the renal vasculature. The responses to angiotensin II were relatively smaller in SHR but no significant difference was observed between WKY and streptozotocin-induced diabetic rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in WKY, SHR and diabetic-induced mesenteric bed. The attenuation was observed at the lower concentrations of angiotensin II in WKY and diabetic-induced rats but at higher concentrations in SHR. Similar observation as in the renal vasculature was seen with PD123319, D-ALA, and L-NAME. Indomethacin reversed the attenuation by angiotensin 1-7 only in the SHR mesenteric vascular bed. The present findings support the regulatory role of angiotensin 1-7 in the renal and mesenteric vasculature, which is differentially altered in hypertension and diabetes.
Asunto(s)
Angiotensina II/farmacología , Angiotensina I/farmacología , Antihipertensivos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Experimental/fisiopatología , Relación Dosis-Respuesta a Droga , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Óxido Nítrico/metabolismo , Prostaglandinas/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Angiotensina/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Circulación Esplácnica/efectos de los fármacos , EstreptozocinaRESUMEN
The effects of losartan on angiotensin receptors in hypertrophic rat hearts were studied. The study was prompted by inconsistent findings of either an increase or decrease in the mRNA of the AT1 receptor in the hearts of cardiac hypertrophic rats treated with losartan, and a paucity of information on the effects of losartan on functional angiotensin receptors in the heart. Losartan, administered i.p. to aortic coarcted rats, dose-dependently attenuated the cardiac hypertrophy. Significant effect was observed with a dose of 2.72 micromol/kg/day for four days. Hypertrophy was accompanied by an increase in [125I]-Sar1-Ile8-angiotensin II binding sites (due mainly to an increase in AT2 binding) and AT2 receptor protein in cardiac ventricles of aortic coarcted rats. Treatment with effective anti-hypertrophic doses of losartan dose-dependently downregulated the [125I]-Sar1-Ile8-angiotensin II binding sites, constitutive AT1 receptor protein, and the over expressed AT2 receptor protein. It was suggested that the anti-cardiac hypertrophic action of losartan resulted from its ability to suppress the expression of both the basal and enhanced cardiac angiotensin receptors. This raises the question as to whether such drastic action could form the therapeutic basis for the use of losartan in cardiac pathologies.
Asunto(s)
Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Losartán/farmacología , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , 1-Sarcosina-8-Isoleucina Angiotensina II/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Secuencia de Bases , Cardiomegalia/genética , Cartilla de ADN/genética , Regulación hacia Abajo/efectos de los fármacos , Masculino , Miocardio/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/efectos de los fármacos , Receptor de Angiotensina Tipo 2/genéticaRESUMEN
Pharmacological properties of oxime reactivators, not related to its ability to regenerate or reactivate nerve agent-inhibited acetylcholinesterase located at nerve synapses, have been reported to be important in protecting against poisoning by the nerve agent soman. Such non-reactivation effects have thus far been associated only with bispyridinium oximes. This study investigated the possibility of creating similar non-reactivation therapeutic effects in the mono-pyridinium ring oxime, pralidoxime (2-PAM) through attachment of alkyl groups of increasing chain length to the oxime functional group. Of the 4 derivatives investigated, only the O-benzyl derivative displayed strong sedative effects in mice and mitigated the development of motor convulsions following soman challenge (1.8 x LD50, subcutaneous). Anticonvulsant effects of this compound were enhanced by co-administration of a non-anticonvulsant dose of atropine sulfate. Administration of equivalent amount of other O-derivatives of pralidoxime failed to elicit similar anticonvulsant actions. Electroencephalographic (EEG) and histopathological studies using the rat model, intoxicated with a lethal dose (1.6 x LD50, s.c.) of soman, confirmed O-benzyl derivative neuroprotective capabilities when used as a pretreatment drug. Microdialysis studies revealed that its neuroprotective effect is related to its ability to attenuate soman-induced increase in acetylcholine.
Asunto(s)
Derivados del Benceno/farmacología , Fármacos Neuroprotectores/farmacología , Compuestos de Pralidoxima/farmacología , Soman/toxicidad , Ácido 3,4-Dihidroxifenilacético/metabolismo , Acetilcolina/metabolismo , Análisis de Varianza , Animales , Anticonvulsivantes/farmacología , Atropina/farmacología , Derivados del Benceno/química , Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Sinergismo Farmacológico , Electroencefalografía/efectos de los fármacos , Femenino , Ácido Homovanílico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Ratones , Microdiálisis , Oximas , Compuestos de Pralidoxima/química , Compuestos de Piridinio/química , Compuestos de Piridinio/farmacología , Ratas , Ratas Wistar , Convulsiones/mortalidad , Convulsiones/fisiopatología , Convulsiones/prevención & control , Serotonina/metabolismo , Tasa de Supervivencia , Factores de TiempoRESUMEN
The binding of 125I-[Sar1,Ile8]angiotensin II and 125I-angiotensin II to ventricular membranes of rat heart was studied. Displacement of bound 125I-[Sar1,Ile8]angiotensin II by its cold equivalents, angiotensin I, angiotensin II, angiotensin III, des-aspartate-angiotensin I, losartan, PD123319 and CGP42112B supports the presence of the AT1 and the near absence of the AT2 angiotensin receptor in adult rat ventricle. The presence of binding sites for des-aspartate-angiotensin I could account for its reported cardioprotective actions. Binding of 125I-angiotensin II but not that of 125I-[Sar1,Ile8]angiotensin II was partially displaced by GppNHp suggesting that a portion of the receptor population was in the active state with dissociated G-protein. Saturation experiments carried out in the absence and presence of 1 mM GppNHp showed similar magnitude of decrease in the number of receptors (Bmax from 26.2+/-1.3 to 15.7+/-1.1 fmol/mg protein) in [125I]-angiotensin II binding. However, the guanine nucleotide had no effect on the binding of 125I-[Sar1,Ile8]angiotensin II as has also been reported elsewhere, and may suggest that Sar1-Ile8-angiotensin II, being a partial agonist, binds to both the G-protein coupled and uncoupled states of the angiotensin receptors. The present study demonstrates that des-aspartate-angiotensin I binds to angiotensin receptors in the heart, and provides further evidence for its involvement in the pathophysiology of the organ.
Asunto(s)
Angiotensina I/farmacología , Ventrículos Cardíacos/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 2 de Angiotensina II , Animales , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 2/metabolismoRESUMEN
The bidirectional transport of the angiotensin peptides--des-Asp-angiotensin I (DAAI), angiotensins III and IV--were studied using human intestinal Caco-2 monolayers. The peptides had low permeability rates but were relatively stable to enzymatic hydrolysis. DAAI was transported by diffusion while angiotensins III and IV were transported by an energy requiring, carrier-mediated process. The physicochemical properties and solution conformations of the peptides were investigated in an attempt to establish structure-transport correlations. Among the three peptides, DAAI was the most hydrophobic, had the highest hydrogen bonding potential and was the only peptide to have a random solution conformation, as determined from circular dichroism, two-dimensional (1)H NMR and molecular modelling. On the other hand, the more hydrophilic angiotensin IV had less hydrogen bonding potential and a solution conformation characterized by a beta turn. These factors may influence the transport characteristics of DAAI and angiotensin IV.