RESUMO
Acute kidney injury (AKI), a common complication in hospitalized patients, is associated with high morbidity and mortality rates. However, there are currently no approved or effective therapeutics for AKI. AKI is primarily caused by ischemia/reperfusion (I/R) injury, with oxidative stress from reactive oxygen species (ROS) being a major contributor. This study aimed to evaluate the efficacy of an alkaline extract of the leaves of Sasa sp. (SE) using mouse renal I/R injury and hypoxia/reoxygenation (H/R) models in NRK-52E cells. Renal function parameters were measured, and histopathological evaluations were performed to assess the efficacy of SE. In addition, to determine the mechanisms underlying the effects of SE on renal I/R injury, its effects on malondialdehyde (MDA) of oxidative stress and interleukin (IL)-6 and IL-1ß of inflammatory cytokines were evaluated. SE (0.03, 0.3, and 3 g/kg) improved renal function in a dose-dependent manner. In addition, SE ameliorated tubular injury and, reduced IL-6, IL-1ß and MDA. Also, SE ameliorated cell death, ROS production, and inflammatory cytokine production in H/R-exposed NRK-52E cells. SE showed antioxidant and anti-inflammatory activities in the AKI. These results indicate the potential of SE as a medicinal compound for the prevention and treatment of AKI.
Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Sasa , Humanos , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Sasa/metabolismo , Injúria Renal Aguda/etiologia , Estresse Oxidativo , Rim/patologia , Traumatismo por Reperfusão/metabolismoRESUMO
Non-alcoholic steatohepatitis (NASH), which is on the rise due to the increasing obese population and changing lifestyles, causes fibrosis over time and carries the risk of progression to cirrhosis and hepatocellular carcinoma. However, there are no approved effective treatments for NASH. Recent studies suggest that increased lipid metabolism and reduced nitric oxide content are responsible for NASH; 3-amino-4-hydroxy benzoic acid (AHBA) was identified as an inhibitor for the phosphatase activity of soluble epoxy hydrolase, which in turn inhibits lipid metabolism and endothelial nitric oxide synthase activity. The aim of this study was to assess the efficacy of AHBA in a mouse model of NASH. NASH was induced in mice by streptozotocin administration and a high-fat diet loading. The efficacy of AHBA was determined by measuring liver function using serum and liver samples and conducting a morphological assessment. AHBA considerably attenuated the increase in the liver weight and alkaline phosphatase content, which occurred due to the progression of NASH. Hepatocellular steatosis, inflammatory cell infiltration, and hepatocellular ballooning of hepatocytes remained unaltered. In contrast, AHBA treatment significantly ameliorated the fibrotic alterations within liver tissue that were induced by the onset of NASH. These results demonstrate the potential of AHBA as a therapeutic pharmaceutical compound that can treat NASH.
Assuntos
Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/patologia , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/complicações , Modelos Animais de Doenças , Dieta Hiperlipídica/efeitos adversos , Neoplasias Hepáticas/metabolismo , Ácido Benzoico/farmacologia , Ácido Benzoico/uso terapêutico , Ácido Benzoico/metabolismo , Camundongos Endogâmicos C57BLRESUMO
SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs-RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe-/-) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe-/- mice ex vivo. Although administration of SMTP-44D to Apoe-/- mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe-/- mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe-/- mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.
Assuntos
Aterosclerose , Placa Aterosclerótica , Animais , Camundongos , Placa Aterosclerótica/genética , Placa Aterosclerótica/complicações , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Aterosclerose/metabolismo , Lipoproteínas LDL , Produtos Finais de Glicação Avançada/metabolismo , Apolipoproteínas E/metabolismo , Apolipoproteínas , Camundongos KnockoutRESUMO
BACKGROUND: The long-term safety and utility of intravascular ultrasound (IVUS)-guided zero-contrast percutaneous coronary intervention (PCI) in patients with chronic kidney disease (CKD) are unknown.MethodsâandâResults: A total of 698 consecutive patients treated with PCI (1,061 procedures) in our center were studied. Patients with acute coronary syndrome, who are on maintenance hemodialysis, and who had a planned rotational atherectomy were excluded. Finally, they were divided into 2 groups: zero-contrast PCI (n=55, 78 procedures) and conventional PCI (n=462, 670 procedures). After propensity score matching, 50 patients were matched for each group to evaluate long-term outcomes. Primary endpoints were major adverse cardiovascular events (MACE), including all-cause death, non-fatal myocardial infarction (MI), and clinically driven target lesion revascularization. All patients in the zero-contrast PCI group had stage 3-5 CKD with an estimated glomerular filtration rate of 38.3±14.8 mL/min/1.73 m2. Zero-contrast PCI was successful in all 78 procedures without renal events such as acute kidney injury or emergent hemodialysis and procedural complications such as coronary perforation or periprocedural MI. During a follow-up period of 32 months, 7 patients died (1 cardiac, 6 non-cardiovascular), and 4 patients were introduced to renal replacement therapy. The incidence of MACE was similar between the zero-contrast and conventional PCI groups (log-rank, P=0.95). CONCLUSIONS: IVUS-guided zero-contrast PCI might be safe and feasible in patients with CKD with satisfactory acute and long-term renal and cardiovascular outcomes.
Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio , Intervenção Coronária Percutânea , Insuficiência Renal Crônica , Angiografia Coronária/métodos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Ultrassonografia de Intervenção/métodosRESUMO
SMTP-7, a fungal metabolite, is reported to have a high degree of availability for the ischemia-reperfusion (IR)-induced acute kidney injury (AKI) model. Cisplatin, a widely used anticancer drug, has serious side effects, such as AKI. Hence, we aimed to examine the effect of SMTP-7 on cisplatin-induced AKI in this study. Significant increases in blood urea nitrogen (BUN) and serum creatinine (Scr) were observed at 72 h after the intravenous infusion of cisplatin (20 mg/kg). Histologically, necrosis and dilatation (hyaline casts) as well as regeneration were observed in proximal tubules. SMTP-7 inhibited the elevation on BUN and Scr caused by cisplatin dose dependently. The efficacy of SMTP-7 was notable when the drug was administered on the day after cisplatin treatment, whereas the repeated administration of the drug did not result in an enhanced efficacy. Moreover, 10 mg/kg of SMTP-7 considerably ameliorated tubular necrosis and dilatation. The cisplatin treatment also caused an up-regulation of tumor necrosis factor-α (TNF-α) mRNA expression prior to the elevation of the levels of BUN and Scr. Administration of SMTP-7 (10 mg/kg) at 24 h after the cisplatin infusion alleviated the up-regulation of TNF-α mRNA expression. These findings suggest that SMTP-7 exhibits a renoprotective effect against cisplatin infusion based on the inhibition of the expression of pro-inflammatory cytokines such as TNF-α and may be expected a new effective drug for the treatment of cisplatin-induced AKI.
Assuntos
Injúria Renal Aguda , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Traumatismo por Reperfusão , Camundongos , Animais , Cisplatino/toxicidade , Fator de Necrose Tumoral alfa/genética , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Necrose/induzido quimicamente , Necrose/tratamento farmacológico , RNA MensageiroRESUMO
Diabetic neuropathy (DN) is a major complication of diabetes mellitus. We have previously reported the efficacy of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) for DN through its potential antioxidant and anti-inflammatory activities. However, the mechanisms underlying the antioxidant and anti-inflammatory activities of SMTP-44D remain unclear. The present study aimed to explore the mechanism of these effects of SMTP-44D in regard to its inhibition of soluble epoxide hydrolase (sEH) in immortalized mouse Schwann cells (IMS32) following high glucose treatment. IMS32 cells were incubated in a high glucose medium for 48 h and then treated with SMTP-44D for 48 h. After incubation, the ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), oxidative stress markers, such as NADPH oxidase-1 and malondialdehyde, inflammatory factors, such as the ratio of nuclear to cytosolic levels of NF-κB and the levels of IL-6, MCP-1, MMP-9, the receptor for the advanced glycation end product (RAGE), and apoptosis, were evaluated. SMTP-44D treatment considerably increased the ratio of EETs to DHETs and mitigated oxidative stress, inflammation, RAGE induction, and apoptosis after high glucose treatment. In conclusion, SMTP-44D can suppress the induction of apoptosis by exerting antioxidant and anti-inflammatory effects, possibly through sEH inhibition. SMTP-44D can be a potential therapeutic agent against DN.
Assuntos
Antioxidantes , Neuropatias Diabéticas , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Epóxido Hidrolases , Glucose , Camundongos , Fenol , Fenóis/farmacologia , Células de Schwann , StachybotrysRESUMO
We established a novel mouse model of chronic kidney disease (CKD) using acetic acid and compared it with the 5/6-nephrectomized mouse model. In our novel model, significant increases were observed in blood biochemical values and urinary parameters. Moreover, a decrease in creatinine clearance (Ccr) was observed. This model also demonstrated a higher survival rate than the 5/6-nephrectomized model. Observed histological changes in our model included cell infiltration in the renal interstitium, tubular dilation, regenerated tubules, and glomerulosclerosis. Inflammation of the renal interstitium was particularly remarkable. TNF-α, IL-1ß, and ICAM-1 mRNA expression were up-regulated prior to elevation of mean blood pressure and prior to changes in blood biochemical values and urinary parameters. Up-regulation of TGF-ß mRNA and down-regulation of nephrin mRNA were also observed at 12 weeks after acetic acid treatment. However, no correlation between the progression of CKD and the decrease in renal blood flow was observed. Finally, repeated losartan administration attenuated the effects of acetic acid-induced renal injury. Our findings suggest that chronic kidney conditions associated with this model may be triggered by interstitial inflammation. Moreover, we suggest that this model is useful for understanding the pathophysiological mechanisms of CKD, and for evaluating the effects of therapeutic agents.
Assuntos
Ácido Acético/efeitos adversos , Modelos Animais de Doenças , Insuficiência Renal Crônica/etiologia , Animais , Creatina/metabolismo , Expressão Gênica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Rim/patologia , Losartan/uso terapêutico , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Taxa de Depuração Metabólica , Camundongos Endogâmicos , Nefrectomia/efeitos adversos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Community pharmacies in Japan have long been advocated as effective sources of nonprescription medicines and health-related advice. Consumers sometimes self-treat symptoms of minor illnesses without consulting a pharmacist because the benefits of such consultations are not adequately recognized. The aim of this study was to investigate the use and impact of pharmacist consultations before purchase of nonprescription laxatives. An online survey was conducted July 14-22, 2012 with 500 respondents (250 men, 250 women), ranging 20-60 years old. All participants had purchased nonprescription laxatives for constipation within the past year. Stratified analysis was used to compare responses in groups that had and had not consulted a pharmacist before purchase. Consulting a pharmacist appears to improve consumers' awareness and makes them more likely to use appropriate medication. Those who consulted a pharmacist were better able to identify side effects and take appropriate action than the group that did not consult the pharmacist. Those who consulted a pharmacist were also significantly more likely to say that they would consult a pharmacist in the future. These results indicate that it is important for consumers to be able to consult with pharmacists, to improve consumers' awareness of side effects and to self-medicate appropriately, and hence improve their quality of life. Pharmacists in community pharmacy could be more active in health promotion campaigns, such as drug safety, campaigns, to raise their public profile. Increased public awareness of what pharmacists in community pharmacy do will make it easier for patients to consult with them.
Assuntos
Laxantes/uso terapêutico , Medicamentos sem Prescrição/uso terapêutico , Farmacêuticos , Relações Profissional-Paciente , Adulto , Idoso , Serviços Comunitários de Farmácia/estatística & dados numéricos , Constipação Intestinal/tratamento farmacológico , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Automedicação , Inquéritos e Questionários , Adulto JovemRESUMO
Phosphorylation of regulatory light chain (MLC) activates myosin II, which enables it to promote contractile and motile activities of cells. We report here a novel signaling mechanism that activates MLC phosphorylation and smooth muscle contraction. Contractile agonists activated Rac1, and Rac1 inhibition diminished agonist-induced MLC phosphorylation, thus inhibiting smooth muscle contraction. Rac1 inhibits the activity of MLC phosphatase (MLCP) but not that of MLC kinase, through a phosphatase that targets MYPT1 (a regulatory subunit of MLCP) and CPI-17 (a MLCP specific inhibitor) rather than through the RhoA-Rho dependent kinase (ROCK) pathway. Rac1 inhibition decreased the activity of protein kinase C (PKC), which also contributes to the change in CPI-17 phosphorylation. We propose that activation of Rac1 increases the activity of PKC, which increases the phosphorylation of CPI-17 and MYPT1 by inhibiting the phosphatase that targets these proteins, thereby decreasing the activity of MLCP and increasing phosphorylation of MLC. Our results suggest that Rac1 coordinates with RhoA to increase MLC phosphorylation by inactivation of CPI-17/MYPT1 phosphatase, which decreases MLCP activity thus promoting MLC phosphorylation and cell contraction.
Assuntos
Proteínas Musculares/metabolismo , Miosina Tipo II/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Fosfoproteínas/metabolismo , Proteína Fosfatase 1/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , RatosRESUMO
The present study compares gene expression and infarct area in a mouse model of embolic stroke after thrombolysis with t-PA and SMTP-7. Embolic occlusion was induced by transfer of acetic acid-induced embolus into the brain. t-PA or SMTP-7 was administered 3 h after embolization. Changes in gene expression were evaluated using microarray and RT-PCR analysis. To determine the involvement of reactive oxygen species in the response to t-PA, the free radical scavenger edaravone was infused immediately before t-PA administration. The expressions of 459 genes involved in the inflammatory response, cell-to-cell signaling, cell movement, and inflammatory disease were altered by embolic occlusion. Twenty-two of those genes were upregulated after t-PA but not SMTP-7 administration. Differences between the t-PA- and SMTP-7-treated groups in the expression of genes including the proinflammatory genes Il6, Stat3, S100a8, and Mmp9 were confirmed with RT-PCR. Edaravone ameliorated the overexpression of these genes. Our data demonstrate differences in gene expression following treatment with SMTP-7 or t-PA that likely explain the difference in therapeutic time windows of the two drugs. ROS are involved in the overexpression of proinflammatory genes. The wide therapeutic time window may be achieved through an anti-oxidative effect and inhibition of proinflammatory gene overexpression.
Assuntos
Benzopiranos/uso terapêutico , Pirrolidinonas/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Animais , Antioxidantes , Antipirina/análogos & derivados , Antipirina/farmacologia , Benzopiranos/administração & dosagem , Benzopiranos/farmacologia , Calgranulina A/genética , Calgranulina A/metabolismo , Modelos Animais de Doenças , Edaravone , Sequestradores de Radicais Livres/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Inflamação/genética , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos , Pirrolidinonas/administração & dosagem , Pirrolidinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Acidente Vascular Cerebral/metabolismo , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/farmacologiaRESUMO
Little is known about the neuroimmune mechanisms responsible for the switch from fever to hypothermia observed in severe forms of systemic inflammation. We evaluated whether bacterial lipopolysaccharide (LPS) acting directly on the brain could promote a fever-hypothermia switch as well as the hypotension that is often associated with hypothermia in models of systemic inflammation. At an ambient temperature of 22°C, freely moving rats received intracerebroventricular (i.c.v.) injections of LPS at doses ranging from 0.5 to 25µg. Despite the use of such high doses, the prevailing thermal response was fever. To investigate if a hypothermic response could be hidden within the prevailing febrile response, rats were pretreated with a cyclooxygenase-2 inhibitor (SC-236, 3.5mg/kg i.v.) known to block fever, but this strategy also failed to reveal any consistent hypothermic response following i.c.v. LPS. At the doses tested, i.c.v. LPS was similarly ineffective at inducing hypotension. Additional doses of LPS did not need to be tested because the 25-µg dose was already sufficient to induce both hypothermia and hypotension when administered peripherally (intra-arterially). An empirical 3D model of the interplay among body temperature, arterial pressure and heart rate following intra-arterial LPS reinforced the strong association of hypothermia with hypotension and, at the same time, exposed a bell-shaped relationship between heart rate and body temperature. In summary, the present study demonstrates that hypothermia and hypotension are triggered exclusively by LPS acting outside the brain and provides an integrated model of the thermal and cardiovascular responses to peripheral LPS.
Assuntos
Hipotensão/induzido quimicamente , Hipotermia/induzido quimicamente , Inflamação/induzido quimicamente , Lipopolissacarídeos/farmacologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Febre/induzido quimicamente , Injeções Intraventriculares , Lipopolissacarídeos/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Pirazóis/farmacologia , Ratos , Ratos Wistar , Sulfonamidas/farmacologiaRESUMO
The spatiotemporal dynamics of intracellular calcium within the middle cerebral artery (MCA) isolated from stroke-prone spontaneously hypertensive rats (SHR-SP) were investigated using real-time confocal laser microscopy. At 3 months of age (prestroke), rhythmical changes in the [Ca(2+)](i) during the tonic phase were found to precede vasomotion following application of 5-HT, but not other stimuli. These responses were not observed at 1 month of age; moreover, the MCA lost both responses post-stroke (5 months of age). When [Ca(2+)](i) was analysed in arteriolar smooth muscle cells, rhythmical changes in [Ca(2+)](i) occurred during the same cycle. Thus, these processes were synchronized. The synchronized rhythmical changes in [Ca(2+)](i) were abolished following application of 100 nM ketanserin and 10 µM nicardipine. Treatment with 60 nM charybdotoxin and 10 µM cyclopiazonic acid also significantly reduced rhythmical elevations in [Ca(2+)](i). In addition, rhythmical changes in [Ca(2+)](i) became unsynchronized following treatment with 100 µM carbenoxolone, a gap junction blocker. Connexin 45 mRNA and protein expression were both elevated in the MCA of SHR-SP. Taken together, these findings suggest that rhythmical changes in [Ca(2+)](i) of the MCA are dependent upon the 5-HT(2) receptor-mediated release of calcium from intracellular stores which, in turn, activates voltage-dependent calcium channels to enable an influx of calcium into smooth muscle cells. Subsequently, charybdotoxin-sensitive potassium channels are activated and provide a negative feedback pathway to regulate [Ca(2+)](i). Moreover, the co-ordinated synchronization of rhythmical changes in [Ca(2+)](i) across smooth muscle cells was found to be dependent upon gap junctions.
Assuntos
Cálcio/metabolismo , Artéria Cerebral Média/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Canais de Cálcio/metabolismo , Conexinas/metabolismo , Retroalimentação Fisiológica/fisiologia , Junções Comunicantes/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores 5-HT2 de Serotonina/metabolismo , Serotonina/metabolismoRESUMO
Some asymptomatic patients with diabetes mellitus (DM) have critical coronary artery disease (CAD), although the guidelines do not recommend aggressive screening for CAD in asymptomatic patients. Chronic kidney disease (CKD) is among the serious co-morbidities of severe systemic atherosclerosis. Thus, CKD may be associated with potential myocardial ischaemia. Therefore, the present study aimed to determine the impact of CKD on the incidence of silent myocardial ischaemia (SMI) and the long-term outcomes in asymptomatic patients with DM. This study investigated 461 consecutive patients with DM. All patients who were asymptomatic and self-sufficient in daily life underwent the ergometer exercise (ERG) test. Coronary angiography was performed if the stress test was positive, or if the patient did not achieve 90% of the target heart rate. The primary end point included major adverse cardiac and cerebrovascular events (MACCE) including death, non-fatal myocardial infarction and stroke. The median follow-up duration after study enrolment was 35 months for the entire cohort of 461 patients. Eighty-one patients were diagnosed with SMI. The estimated glomerular filtration rate was significantly lower in the SMI group (70.5 ± 23.8 vs. 81.8 ± 30.0 mL/min/1.73 m2, P < 0.001). SMI occurred more frequently in patients with advanced CKD [27/103, (26.2%) in stages 3-5], whereas only 5/68 (7.3%) patients without CKD, 13/81 (16.0%) patients with stage 1 CKD and 36/209, (17.2%) in stage 2, had SMI. The Kaplan-Meier curves revealed that, patients with SMI had poor clinical outcomes (log-rank: P = 0.016). The incidence of MACCE (log-rank: P = 0.009) was higher in patients with severe CKD > stage 3a in the SMI subgroup. Urinary albumin (mg/gCr) was associated with MACCE in the SMI subgroup [HR 3.37, 95%CI (1.170-9.521), P = 0.025] after adjusting for age, sex, and conventional risk factors. SMI was more prevalent in patients with CKD and the incidence was proportional to the CKD stage in asymptomatic patients with DM. Those Patients with CKD and SMI exhibited poor clinical outcomes. CKD may be a key factor for the identification and management of SMI in asymptomatic patients with DM in routine clinical practice.Trial Registration: UMIN000038340.
Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Isquemia Miocárdica , Insuficiência Renal Crônica , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus/epidemiologia , Humanos , Isquemia Miocárdica/complicações , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/epidemiologia , Prognóstico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Fatores de RiscoRESUMO
In clinical practice, pregabalin is orally administered for neuropathic pain, but causes severe central nervous system side effects, such as dizziness, which results in dose limitation or discontinuation. To reduce the central side effects of pregabalin, we developed four pregabalin preparations for transdermal application: 0.4% aqueous solution, pluronic lecithin organogel (PLO gel), hydrophilic cream, and lipophilic cream. Transdermal permeabilities of pregabalin among the four formulations were compared in vitro using hairless mouse skin. The longitudinal distribution of pregabalin within the skin was analyzed using mass spectrometric (MS) imaging. Furthermore, the in vivo analgesic effects of the formulations were evaluated using the von Frey filament test in a mouse model of diabetic neuropathy (DN). The PLO gel showed the highest permeability of pregabalin, followed by the aqueous solution, and no permeation was observed in the two cream formulations. The MS imaging analysis showed that pregabalin was distributed up to the dermis in the PLO gel 1 h after application, while the aqueous solution was distributed near the epidermis. A significant analgesic effect (p < .05) was observed 1.5 h after PLO gel application in the DN model mice, but the aqueous solution had no effect. This study indicated for the first time that pregabalin penetrated beyond the skin epidermis up to the dermis, from the PLO gel formulation, and that the application of this formulation exhibited an in vivo analgesic effect in the mouse model of DN.
Assuntos
Lecitinas , Poloxâmero , Analgésicos/uso terapêutico , Animais , Géis/química , Lecitinas/química , Camundongos , Pregabalina/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Thrombolysis therapy using tissue-type plasminogen activator (t-PA) is occasionally accompanied by harmful outcomes, including intracerebral hemorrhage. We have reported that Stachybotrys microspora triprenyl phenol-7 (SMTP-7), a candidate thrombolytic drug, has excellent therapeutic effect on cerebral infarction in embolic stroke model in mice; however, little is known regarding whether this agent influences cerebrovascular inflammation following thrombolytic reperfusion. The current study aimed to compare the effects of recombinant t-PA (rt-PA) and SMTP-7 on cerebrovascular inflammation. METHODS: The impact of rt-PA- and SMTP-7-induced thrombolytic reperfusion on leukocyte dynamics was investigated in a photochemically induced thrombotic middle cerebral artery occlusion (tMCAo) model in mice. RESULTS: Both rt-PA and SMTP-7 administration in tMCAo mice (each 10 mg/kg) resulted in thrombolytic reperfusion. The SMTP-7-administered mice showed relatively mild rolling and attachment of leukocytes to the vascular wall in the middle cerebral vein, with weak peroxynitrite reactions and proinflammatory gene expression (IL-1ß, TNF-α, ICAM-1, and VCAM-1); thus, a small infarct volume compared with rt-PA-administered mice. In vitro study suggested that rt-PA at 20 µg/mL, but not SMTP-7 at a similar concentration, promotes cytokine-induced reactive oxygen species generation in cultured endothelial cells; moreover, SMTP-7 suppressed cytokine-induced VCAM-1 induction in the cells and leukocyte/ endothelial cell adhesions. CONCLUSIONS: Relatively mild cerebrovascular inflammation and cerebral infarction in the SMTP-7 mice, compared with in rt-PA mice, is thought to be caused at least in part by direct antioxidative actions of SMTP-7 in ECs.
Assuntos
Benzopiranos/toxicidade , Infarto da Artéria Cerebral Média/patologia , Embolia Intracraniana/patologia , Pirrolidinonas/toxicidade , Traumatismo por Reperfusão/patologia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/toxicidade , Animais , Benzopiranos/antagonistas & inibidores , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/etiologia , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/etiologia , Embolia Intracraniana/tratamento farmacológico , Embolia Intracraniana/etiologia , Lasers , Masculino , Camundongos , Pirrolidinonas/antagonistas & inibidores , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/antagonistas & inibidoresRESUMO
We have previously shown that lysophosphatidic acid (LPA), a bioactive plasma lysophospholipid, markedly accelerates shear stress-induced Ca2+ responses in cultured vascular endothelial cells (ECs). This study aimed to demonstrate the impact of LPA and luminal shear stress on vasomotor regulation in the isolated rat mesenteric artery (MA) using a videomicroscopic technique. Although the addition of LPA to the perfusate in a concentration range of 0.03-0.3 µM had no significant effect on the basal MA tone, LPA in a similar concentration range led to increased phenylephrine-induced MA contraction and reduced acetylcholine-induced MA relaxation under physiological shear conditions. These vasomodulatory actions of LPA, which vanished upon removal of ECs, were positively dependent on luminal shear stress levels and were markedly inhibited by the LPA receptor antagonist Ki16425, the cyclooxygenase inhibitor indomethacin, and the thromboxane A2 receptor antagonist SQ29548. These data thus suggest that LPA can modify the agonist-induced vasomotor responses in MAs in a shear stress-dependent manner. This effect of LPA was mediated through ECs, the LPA receptor, and cyclooxygenase/thromboxane A2 signaling.
Assuntos
Lisofosfolipídeos/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Receptores de Ácidos Lisofosfatídicos/agonistas , Estresse Mecânico , Vasodilatação/efeitos dos fármacos , Animais , Fenômenos Biomecânicos , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Microscopia de Vídeo , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Ratos , Ratos Wistar , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Vasodilatação/fisiologiaRESUMO
Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD), complicates existing CKD, and can lead to the end-stage renal disease. However, there are no approved effective therapeutics for AKI. Recent studies have suggested that inflammation and oxidative stress are the primary causes of AKI. We previously reported the potential anti-inflammatory and antioxidant activities of Stachybotrys microspora triprenyl phenol-7 (SMTP-7). The aim of the present study was to evaluate the efficacy of SMTP-7 in AKI model mice. AKI was induced in mice by ischemia of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the removal of right kidney. The efficacy of SMTP-7 was determined by measuring the renal function using urine and serum samples and morphological assessment. For deciphering the mechanism of action of SMTP-7, inflammatory cytokines and oxidative stress in kidney were detected. SMTP-7 (0.01, 0.1, 1, 10 mg/kg) dose-dependently improved the renal function. In addition, it improved the damage to renal tubules and exhibited anti-inflammatory and antioxidant activities in the kidney of AKI mice. These results indicate the potential of SMTP-7 as a medicinal compound for the treatment of AKI.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzopiranos/farmacologia , Pirrolidinonas/farmacologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Benzopiranos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Infusões Intravenosas , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Pirrolidinonas/uso terapêutico , Stachybotrys/metabolismoRESUMO
A pivotal trial indicated that an initial invasive strategy did not improve the clinical outcomes in patients with moderate or severe ischemic heart disease and advanced chronic kidney disease (CKD) as compared with an initial conservative strategy. It is well known that contrast-induced nephropathy (CIN) is associated with worse prognosis after percutaneous coronary intervention (PCI). Minimum contrast PCI may lower the risk of CIN and improve the clinical outcomes of ischemic heart disease and advanced CKD. Here we report a case involving a 46-year-old woman with ischemic cardiomyopathy who was scheduled to start hemodialysis for end-stage diabetic nephropathy but exhibited improved renal function in accordance with the left ventricular function after PCI with an extremely low contrast dose. Accordingly, dialysis was not performed, and the patient did not require it for >2 years after coronary revascularization. The present case supports aggressive examination and revascularization for severe heart failure with an extremely low amount of contrast, even if the patient has complex coronary lesions and end-stage CKD.
RESUMO
The aim of the present study was to establish a novel embolic model of cerebral infarction and to evaluate the effect of Stachybotrys microspora triprenyl phenol-7 (SMTP-7), a novel fungal triprenyl phenol metabolite. Thrombotic occlusion was induced by transfer of acetic acid-induced embolus into the brain. The regional cerebral blood flow was measured by a laser Doppler flowmeter to check the ischemic condition. Infarction area was assessed by 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological scores were determined by a modified version of the method described by Longa et al. Emboli were accumulated at the temporal or parietal region of the middle cerebral artery. Additionally, we found that this model showed decreased cerebral blood flow and increased infarction area and neurological scores. Treatment with tissue plasminogen activator (t-PA) reduced infarction area and the neurological scores in a dose-dependent manner; moreover, the decreased cerebral blood flow recovered. SMTP-7 also reduced these values. The therapeutic time window of SMTP-7 was longer than that of t-PA. These results indicate that this model may be useful for understanding the pathophysiological mechanisms of cerebral infarction and evaluating the effects of therapeutic agents. Additionally, SMTP-7 is a promising approach to extend the therapeutic time window. Therefore, this novel compound may represent a novel approach for the treatment of cerebral infarction.
Assuntos
Benzopiranos/metabolismo , Benzopiranos/uso terapêutico , Infarto Cerebral/tratamento farmacológico , Modelos Animais de Doenças , Embolia Intracraniana/tratamento farmacológico , Pirrolidinonas/metabolismo , Pirrolidinonas/uso terapêutico , Stachybotrys , Animais , Benzopiranos/isolamento & purificação , Infarto Cerebral/diagnóstico , Infarto Cerebral/fisiopatologia , Avaliação Pré-Clínica de Medicamentos/métodos , Gerbillinae , Embolia Intracraniana/patologia , Embolia Intracraniana/fisiopatologia , Masculino , Pirrolidinonas/isolamento & purificaçãoRESUMO
Diabetic neuropathy (DN) is one of the major complications of diabetes. However, there are few approved effective therapies for painful or insensate DN. Recent studies have implicated oxidative stress and inflammation in the pathogenesis of DN, and suppressing these could be an important therapeutic strategy. We previously reported that Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) exhibits both antioxidant and anti-inflammatory activities. The aim of this study was to evaluate the effects of SMTP-44D in a mouse model of streptozotocin-induced DN. SMTP-44D was administered for 3 weeks after the disease induction, and its effects were evaluated on the basis of mechanical and thermal thresholds, blood flow in the bilateral hind paw, and blood flow and conduction velocity in the sciatic nerve. Furthermore, the levels of inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 and malondialdehyde (MDA), in the sciatic nerve were assessed. Neurological degeneration was assessed by measuring myelin thickness and g-ratio in the sciatic nerve. SMTP-44D treatment significantly improved allodynia, hyperalgesia, blood flow, and conduction velocity in DN model mice in a dose-dependent manner. Neurological degeneration was also significantly improved, accompanied by decreased levels of inflammatory factors (TNF-α, 57.8%; IL-1ß, 51.4%; IL-6, 62.8%; and MDA, 40.7% reduction rate against the diabetes mellitus + normal saline group). Thus, SMTP-44D can improve allodynia and hyperalgesia in DN without affecting the body weight and blood glucose levels, which may be due to its antioxidant and anti-inflammatory properties. In conclusion, SMTP-44D could be a potential therapeutic agent for the treatment of DN.