RESUMO
AIM: Hypoxia/oxidative stress can alter the pharmacokinetics (PK) of CPU86017-RS, a novel antiarrhythmic agent. The aim of this study was to investigate the mechanisms underlying the alteration of PK of CPU86017-RS by hypoxia/oxidative stress. METHODS: Male SD rats exposed to normal or intermittent hypoxia (10% O2) were administered CPU86017-RS (20, 40 or 80 mg/kg, ig) for 8 consecutive days. The PK parameters of CPU86017-RS were examined on d 8. In a separate set of experiments, female SD rats were injected with isoproterenol (ISO) for 5 consecutive days to induce a stress-related status, then CPU86017-RS (80 mg/kg, ig) was administered, and the tissue distributions were examined. The levels of Mn-SOD (manganese containing superoxide dismutase), endoplasmic reticulum (ER) stress sensor proteins (ATF-6, activating transcription factor 6 and PERK, PRK-like ER kinase) and activation of NADPH oxidase (NOX) were detected with Western blotting. Rat liver microsomes were incubated under N2 for in vitro study. RESULTS: The Cmax, t1/2, MRT (mean residence time) and AUC (area under the curve) of CPU86017-RS were significantly increased in the hypoxic rats receiving the 3 different doses of CPU86017-RS. The hypoxia-induced alteration of PK was associated with significantly reduced Mn-SOD level, and increased ATF-6, PERK and NOX levels. In ISO-treated rats, the distributions of CPU86017-RS in plasma, heart, kidney, and liver were markedly increased, and NOX levels in heart, kidney, and liver were significantly upregulated. Co-administration of the NOX blocker apocynin eliminated the abnormalities in the PK and tissue distributions of CPU86017-RS induced by hypoxia/oxidative stress. The metabolism of CPU86017-RS in the N2-treated liver microsomes was significantly reduced, addition of N-acetylcysteine (NAC), but not vitamin C, effectively reversed this change. CONCLUSION: The altered PK and metabolism of CPU86017-RS induced by hypoxia/oxidative stress are produced by mitochondrial abnormalities, NOX activation and ER stress; these abnormalities are significantly alleviated by apocynin or NAC.
Assuntos
Antiarrítmicos/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , NADPH Oxidases/metabolismo , Estresse Oxidativo , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Ativação Enzimática , Meia-Vida , Masculino , Microssomos Hepáticos/enzimologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To observe the effects of moxibustion at Yongquanï¼KI 1ï¼ on the cognitive function and lower limb motor function in patients with post-stroke cognitive impairment of kidney essence deficiency. METHODS: Eighty-four patients with post-stroke cognitive impairment of kidney essence deficiency were randomly divided into an observation groupï¼42 casesï¼1 case dropped offï¼and a control groupï¼42 casesï¼1 case dropped offï¼.The control group was treated with medicationï¼electroacupunctureï¼rehabilitation training and repetitive transcranial magnetic stimulationï¼rTMSï¼ï¼on the basis of the treatment as the control groupï¼moxibustion at bilateral Yongquanï¼KI 1ï¼was adopted in the observation group.Both groups were treated once a dayï¼5 days a week with 2-day intervalï¼4 weeks were required. The Montreal cognitive assessment (MoCA) score, mini-mental state examination (MMSE) score, Fugl-Meyer assessment-lower extremity (FMA-LE) score, Berg balance scale (BBS) score, functional independence measure (FIM) score, modified fall efficacy scale (MFES) score and scale for the differentiation of syndromes of vascular dementia (SDSVD) score before and after treatment were observed in the two groups. RESULTS: After treatmentï¼the MoCA, MMSE, FMA-LE, BBS, FIM and MFES scores were higher than those before treatment in both groups (P<0.05), and the scores in the observation group were higher than those in the control group (P<0.05). After treatmentï¼the SDSVD scores were lower than those before treatment in both groups (P< 0.05), and the SDSVD score in the observation group was lower than that in the control group (P< 0.05). CONCLUSION: Moxibustion at Yongquanï¼KI 1ï¼ can improve the cognitive function and motor and balance function of lower limbs in patients with post-stroke cognitive impairment of kidney essence deficiencyï¼reduce the risk of fall and improve the quality of life.
Assuntos
Disfunção Cognitiva , Demência Vascular , Moxibustão , Acidente Vascular Cerebral , Humanos , Cognição , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Rim , Extremidade Inferior , Qualidade de Vida , Acidente Vascular Cerebral/complicaçõesRESUMO
OBJECTIVES: Pharmacokinetics (PK) of argirein might be changed in response to mitochondrial (MITO) dysfunction and activated nicotinamide adenine dinucleotide phosphate oxidase (NOX) on hypoxia. We hypothesized that hypoxic changes in MITO and NOX could alter PK and tissue distribution of argirein. We tested if these changes in PK of argirein by hypoxia could be relieved by apocynin (APO), a blocker of NOX, through normalizing MITO and NOX. METHODS: Male Sprague-Dawley rats were exposed to hypoxia (O2 10% ± 5% 8 h per day) for 7 days and treated with APO (80 mg/kg, i.g.) in the last 4 days. The PK and tissue distribution of argirein were monitored by measuring its main metabolite rhein using HPLC analysis. Manganese superoxide dismutase (MnSOD) and NOX were assayed. KEY FINDINGS: The PK parameters and concentrations of rhein in the kidney, liver, heart and testes were significantly altered under hypoxia, accompanied with a reduced MnSOD and upregulated NOX compared with the normal. Altered argirein PK and distribution in these organs were relieved following APO administration. CONCLUSION: Abnormal PK and distribution of argirein by assaying its metabolite rhein are significant, consequent to hypoxic injury that is significantly ameliorated by APO through normalizing MITO and NOX.
Assuntos
Acetofenonas/farmacologia , Antraquinonas/farmacocinética , Arginina/farmacocinética , Hipóxia/metabolismo , Mitocôndrias , NADPH Oxidases/metabolismo , Superóxido Dismutase/metabolismo , Animais , Antraquinonas/metabolismo , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Arginina/metabolismo , Combinação de Medicamentos , Estresse do Retículo Endoplasmático , Inibidores Enzimáticos/farmacologia , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: Insulin resistance represents a mechanism underlying defect metabolism of carbohydrate and lipid linked to inflammatory reactions in diabetic liver. We hypothesized that the changes may be secondary to endoplasmic reticulum (ER) stress, which could be alleviated by either argirein or valsartan. METHODS: Hepatosteatosis in diabetic liver was induced in rats fed with a high-fat diet (HFD) for 12 weeks combined with a single low dose of streptozotocin (STZ 35 mg/kg, ip). Interventions (mg/kg/d, po)with either argirein (50, 100 and 200) or valsartan (12) were conducted in the last 4 weeks. KEY FINDINGS: In diabetic liver fat was significantly accumulated in association with elevated hepatic glucose, serum insulin and homeostasis model assessment of insulin resistance value. Downregulated glucose transporter 4, insulin receptor substrate-1 and leptin receptor (P < 0.01) were found relative to normal, where DNA ladder, downregulated B cell lymphoma/leukemia-2, upregulated B cell lymphoma/leukemia-2 Associated X protein and upregulated ER stress chaperones such as Bip/GRP78 (also known as Binding Protein, BiP), PKR-like ER kinase (PERK), p-PERK/PERK and C/EBP homologous protein were significant. These abnormalities were significantly ameliorated by argirein and valsartan. CONCLUSIONS: Hepatosteatosis induced by HFD/low STZ manifests insulin resistance and apoptosis, linked to an entity of low-grade inflammation due to activated ER stress sensors. With anti-inflammatory activity either argirein or valsartan blunts hepatosteatosis through normalizing ER stress and apoptosis in the diabetic liver.
Assuntos
Antraquinonas/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Arginina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Combinação de Medicamentos , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glutationa Peroxidase/sangue , Glutationa Peroxidase/metabolismo , Glicogênio/metabolismo , Proteínas de Choque Térmico/metabolismo , Insulina/sangue , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/metabolismo , Masculino , PPAR alfa/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores para Leptina/metabolismo , Tetrazóis/farmacologia , Fator de Transcrição CHOP/metabolismo , Valina/análogos & derivados , Valina/farmacologia , Valsartana , eIF-2 Quinase/metabolismoRESUMO
Male hypogonadism is frequently accompanied with type 2 diabetes due to testicular dysfunction, but the origin of the pathogenesis is not known. We measured whether pro-inflammatory factors including endoplasmic reticulum (ER) stress chaperones and inhibitory κBß (IκBß) contribute to testis damage in type 2 diabetic rats produced by a high-fat diet (HFD) and low dose streptozotocin (STZ). We determined whether these can be attenuated by the anti-inflammatory activity of argirein a derivative of rhein as compared to valsartan. Reduced testosterone and LH (luteinizing hormone) levels in serum were significant in association with a decrease in the levels of mRNA and steroidogenic acute regulatory protein (StAR), insulin receptor substrate (IRS-1), activated IκBß and ER stress chaperone C/EBP homologous protein (CHOP) in the diabetic testis and sperm count, motility and sexual behaviors were reduced in vivo. Additionally, Leydig cells cultured with high glucose showed upregulated IκBß, ER stress sensor PERK (PKR-like ER kinase) and p-Akt/Akt in vitro. These changes may be due to a component of inflammation linked to activated NADPH oxidase and were significantly alleviated by either argirein or valsartan. In conclusion, diabetic testopathy induced by a HFD and low STZ is characterized by an entity of inflammation and is alleviated by argirein and valsartan through normalizing activated IκBß and ER stress.