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Background: The effectiveness and side effects between different medical treatments in patients with primary hyperaldosteronism have not been systematically studied. Objective: To analyze the efficacy between different mineralocorticoid receptor antagonists (MRAs) and epithelial sodium channel (ENaC) inhibitors in a network meta-analysis (NMA) framework, while also evaluating adverse events. Design: Systematic review and NMA. Data sources and methods: The systematic review and NMA was reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, MEDLINE, the Cochrane library, and Excerpta Medica database (EMBASE) were searched for randomized controlled trials (RCTs) involving adult patients with primary hyperaldosteronism until 23 June 2023. Studies that compared the efficacy and side effects of different medical treatments of primary hyperaldosteronism were included. The primary outcomes included the effect on blood pressure, serum potassium, and major adverse cardiovascular events. The secondary outcomes were adverse events related to MRAs (hyperkalemia and gynecomastia). Frequentist NMA and pairwise meta-analysis were conducted. Results: A total of 5 RCTs comprising 392 participants were included. Eplerenone, esaxerenone, and amiloride were compared to spironolactone and demonstrated comparable effect on the reduction of systolic blood pressure. In comparison to spironolactone, eplerenone exhibited a less pronounced effect on reducing diastolic blood pressure [-4.63 mmHg; 95% confidence interval (CI): -8.87 to -0.40 mmHg] and correcting serum potassium (-0.2 mg/dL; 95% CI: -0.37 to -0.03 mg/dL). Spironolactone presented a higher risk of gynecomastia compared with eplerenone (relative risk: 4.69; 95% CI: 3.58-6.14). Conclusion: The present NMA indicated that the blood pressure reduction and potassium-correcting effects of the three MRAs may demonstrate marginal differences, with confidence levels in the evidence being very low. Therefore, further research is needed to explore the efficacy of these MRAs, especially regarding their impact on mortality and cardiovascular outcomes. Trial registration: PROSPERO (CRD: 42023446811).
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Background and Objectives: In peritoneal dialysis (PD) therapy, intra-abdominal adhesions (IAAs) can cause catheter insertion failure, poor dialysis function, and decreased PD adequacy. Unfortunately, IAAs are not readily visible to currently available imaging methods. The laparoscopic approach for inserting PD catheters enables direct visualization of IAAs and simultaneously performs adhesiolysis. However, a limited number of studies have investigated the benefit/risk profile of laparoscopic adhesiolysis in patients receiving PD catheter placement. This retrospective study aimed to address this issue. Materials and Methods: This study enrolled 440 patients who received laparoscopic PD catheter insertion at our hospital between January 2013 and May 2020. Adhesiolysis was performed in all cases with IAA identified via laparoscopy. We retrospectively reviewed data, including clinical characteristics, operative details, and PD-related clinical outcomes. Results: These patients were classified into the adhesiolysis group (n = 47) and the non-IAA group (n = 393). The clinical characteristics and operative details had no remarkable between-group differences, except the percentage of prior abdominal operation history was higher and the median operative time was longer in the adhesiolysis group. PD-related clinical outcomes, including incidence rate of mechanical obstruction, PD adequacy (Kt/V urea and weekly creatinine clearance), and overall catheter survival, were all comparable between the adhesiolysis and non-IAA groups. None of the patients in the adhesiolysis group suffered adhesiolysis-related complications. Conclusions: Laparoscopic adhesiolysis in patients with IAA confers clinical benefits in achieving PD-related outcomes comparable to those without IAA. It is a safe and reasonable approach. Our findings provide new evidence to support the benefits of this laparoscopic approach, especially in patients with a risk of IAAs.
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Laparoscopía , Diálisis Peritoneal , Humanos , Estudios Retrospectivos , Catéteres de Permanencia , Diálisis Renal , Diálisis Peritoneal/efectos adversos , Laparoscopía/efectos adversos , Laparoscopía/métodos , PeritoneoRESUMEN
Background: Although a recent study reported that fibrates are associated with a low risk of cardiovascular (CV) death and can postpone the need for long-term hemodialysis in patients with advanced chronic kidney disease (CKD), little is known regarding whether the CV protective effects of fibrates extend to patients with end-stage renal disease (ESRD). The present study compared CV outcomes and mortality among patients with ESRD treated with fibrates, statins, neither, or their combination. Methods: This cohort study extracted data from Taiwan's National Health Insurance Research Database (NHIRD). Adult patients with ESRD and hyperlipidemia were identified and categorized into four groups (fibrate, statin, combination, and non-user groups) according to their use of different lipid-lowering therapies within 3 months prior to the commencement of permanent dialysis. Inverse probability of treatment weighting was used to balance the baseline characteristics of the groups. The follow-up outcomes were all-cause mortality, CV death, and major adverse cardiac and cerebrovascular events (MACCEs). Results: Compared with the non-user and statin groups, the fibrate group did not exhibit significantly lower risks of all-cause mortality [fibrate vs. non-user: hazard ratio (HR), 0.97; 95% confidence interval (CI), 0.92-1.03; statin vs. fibrate: HR, 0.95; 95% CI, 0.90-1.01], CV death (fibrate vs. non-user: HR, 0.97; 95% CI, 0.90-1.05; statin vs. fibrate: HR, 0.97; 95% CI, 0.90-1.06), and MACCEs (fibrate vs. non-user: HR, 1.03; 95% CI, 0.96-1.10; statin vs. fibrate: HR, 0.94; 95% CI, 0.87-1.004). The combination of fibrates and statins (specifically moderate- to high-potency statins) did not result in lower risks of all-cause mortality, CV death, or MACCEs compared with statins alone. Conclusion: In patients with ESRD, the use of fibrates might be not associated with reduced mortality or CV risks, regardless of whether they are used alone or in combination with statins.
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Metabolic syndrome (MS) has been an important health issue in the world, and insulin resistance (IR) is one of the characteristics of MS, increasing the risk for the onset and poor prognosis of type 2 diabetes mellitus (T2D). However, the interactional effect of obesity or abnormal body composition on the correlation between gut microbiota and IR in T2D patients is not well-explored. This cross-sectional study used a body composition monitor to evaluate lean tissue mass and fat tissue mass. IR was calculated using homeostatic model assessment-insulin resistance (HOMA-IR). Eight pairs of 16S rRNA gene primers specific to Firmicutes, Bacteroidetes, Clostridium leptum group, Faecalibacteriumprausnitzii, B acteroides, Bifidobacterium, Akkermansia muciniphila, and Escherichia coli were utilized to measure their abundance by qPCR. One hundred and fifty-four T2D patients were enrolled and stratified by the median HOMA-IR (2.5) and body mass index (BMI) of 25 kg/m2. A lower abundance of A. muciniphila was found in T2D patients with high HOMA-IR and BMI respectively. HOMA-IR and BMI had a synergistic effect on the reduction of the abundance of A. muciniphila. After adjusting metabolic factors, the low abundance of A. muciniphila significantly increased the risk for greater severity of IR. Furthermore, the negative correlation between A. muciniphila and IR was only found in T2D patients with high lean tissue. In conclusion, decreased abundance of fecal A. muciniphila enhanced the severity of IR in Asians with T2D, especially those having lean mass, and this significant relationship was independent of obesity.
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BACKGROUND: Inflammation is a common pathophysiological trait found in both hypertension and cardiac vascular disease. Recent evidence indicates that fractalkine (FKN) and its receptor CX3CR1 have been linked to inflammatory response in the brain of hypertensive animal models. Here, we investigated the role of CX3CR1-microglia in nitric oxide (NO) generation during chronic inflammation and systemic blood pressure recovery in the nucleus tractus solitarii (NTS). METHODS: The hypertensive rat model was used to study the role of CX3CR1-microglia in NTS inflammation following hypertension induction by oral administration of 10% fructose water. The systolic blood pressure was measured by tail-cuff method of non-invasive blood pressure. The CX3CR1 inhibitor AZD8797 was administered intracerebroventricularly (ICV) in the fructose-induced hypertensive rat. Using immunoblotting, we studied the nitric oxide synthase signaling pathway, NO concentration, and the levels of FKN and CX3CR1, and pro-inflammatory cytokines were analyzed by immunohistochemistry staining. RESULTS: The level of pro-inflammatory cytokines IL-1ß, IL-6, TNF-α, FKN, and CX3CR1 were elevated two weeks after fructose feeding. AZD8797 inhibited CX3CR1-microglia, which improved the regulation of systemic blood pressure and NO generation in the NTS. We also found that IL-1ß, IL-6, and TNF-α levels were recovered by AZD8797 addition. CONCLUSION: We conclude that CX3CR1-microglia represses the nNOS signaling pathway and promotes chronic inflammation in fructose-induced hypertension. Collectively, our results reveal the role of chemokines such as IL-1ß, IL-6, and TNF-α in NTS neuroinflammation with the involvement of FKN and CX3CR1.
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Receptor 1 de Quimiocinas CX3C/metabolismo , Hipertensión/metabolismo , Inflamación/metabolismo , Microglía/metabolismo , Núcleo Solitario/patología , Animales , Presión Sanguínea , Citocinas/metabolismo , Fructosa/toxicidad , Hipertensión/inducido químicamente , Hipertensión/complicaciones , Inflamación/etiología , Ratas , Ratas Endogámicas WKY , Núcleo Solitario/metabolismoRESUMEN
G protein-coupled receptors (GPCRs) are important drug targets. Blocking angiotensin II (Ang II) type 1 receptor signaling alleviates hypertension and improves outcomes in patients with heart failure. Changes in structure and trafficking of GPCR, and desensitization of GPCR signaling induce pathophysiological processes. We investigated whether Ang II, via induction of AT1R and µ-opioid receptor (µOR) dimerization in the nucleus tractus solitarius (NTS), leads to progressive hypertension. Ang II signaling increased µOR and adrenergic receptor α2A (α2A-AR) heterodimer levels and decreased expression of extracellular signal-regulated kinases 1/2T202/Y204, ribosomal protein S6 kinaseT359/S363, and nNOSS1416 phosphorylation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression was abolished in the NTS of adult spontaneously hypertensive rats (SHRs). Endomorphin-2 was overexpressed in NTS of adult SHRs compared with that in 6-week-old Wistar-Kyoto rats (WKY). Administration of µOR agonist into the NTS of WKY increased blood pressure (BP), decreased nitric oxide (NO) production, and decreased DDAH1 activity. µOR agonist significantly reduced the activity of DDAH1 and decreased neuronal NO synthase (nNOS) phosphorylation. The AT1R II inhibitor, losartan, significantly decreased BP and abolished AT1R-induced formation of AT1R and µOR, and α2A-AR and µOR, heterodimers. Losartan also significantly increased the levels of nNOSS1416 phosphorylation and DDAH1 expression. These results show that Ang II may induce expression of endomorphin-2 and abolished DDAH1 activity by enhancing the formation of AT1R and µOR heterodimers in the NTS, leading to progressive hypertension.
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Angiotensina II/metabolismo , Presión Sanguínea/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo I/metabolismo , Núcleo Solitario/efectos de los fármacos , Amidohidrolasas , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Dimerización , Quinasas MAP Reguladas por Señal Extracelular , Hipertensión/fisiopatología , Losartán/farmacología , Masculino , Óxido Nítrico/metabolismo , Oligopéptidos/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Angiotensina Tipo 1 , Receptores Opioides mu/agonistas , Transducción de Señal , Núcleo Solitario/enzimologíaRESUMEN
SCOPE: In the Natural Medicines database, coenzyme Q10 (CoQ10) is classified as possibly effective for the treatment of hypertension. Patients with hypertension frequently have a significant deficiency of the antioxidant CoQ10. Furthermore, reactive oxygen species are overproduced in the nucleus tractus solitarii (NTS) during the cardiovascular regulation of hypertension in vivo. However, the molecular mechanisms by which CoQ10 modulates cardiovascular functions in the NTS are unclear. In this study, the effects of CoQ10 on superoxide generation, downstream NO signaling in the NTS, and blood pressure were evaluated in rats with fructose-induced hypertension. METHODS AND RESULTS: Treatment with oral CoQ10 for 4 weeks abolished nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activation, decreased p38 phosphorylation, and increased superoxide dismutase 2 production in the NTS of fructose-fed rats. The serum levels of uric acid decrease in response to CoQ10 treatment in fructose-fed rats. Oral CoQ10 reduced blood pressure by inducing Akt and nNOS phosphorylation in NTS of fructose-induced hypertensive rats. CONCLUSION: Oral CoQ10 decreases blood pressure by negatively regulating fructose-induced NADPH oxidase levels, abolishing ROS generation, reducing p38 phosphorylation, and enhancing the Akt-nNOS pathway in the NTS. These results support the beneficial effects of CoQ10 in oxidative stressassociated hypertension.
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Antihipertensivos/farmacología , Depuradores de Radicales Libres/farmacología , Óxido Nítrico Sintasa de Tipo I/metabolismo , Núcleo Solitario/efectos de los fármacos , Ubiquinona/análogos & derivados , Animales , Fructosa/efectos adversos , Transportador de Glucosa de Tipo 1/metabolismo , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Insulina/metabolismo , Masculino , NADPH Oxidasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Núcleo Solitario/metabolismo , Superóxido Dismutasa/metabolismo , Ubiquinona/farmacología , Ácido Úrico/sangreRESUMEN
Moxibustion () is a traditional Chinese medicine therapy performed using Artemisia argyii. Zusanli (, ST36) is an acupoint in the stomach meridian, long associated in ancient Chinese medical practices with the extension of life span when moxibustion is applied to it. The aim of this study was to investigate changes in insulin-like growth factor 1 (IGF-1) levels after application of moxibustion to ST36. Four healthy men and women participated in this 28-day trial and were randomly divided into 2 groups. Group A received moxibustion treatment from days 1 to 14, while group B received moxibustion treatment from days 15 to 28. Blood samples were taken 5 times during this study to measure serum IGF-1 (s-IGF-1) levels. The s-IGF-1 levels increased in both groups after 7 and 14 d of moxibustion therapy (group A: 11.02% [7 d] and 29.65% [14 d]; group B: 169.12% [7 d] and 274.85% [14 d]). After moxibustion therapy had been completed (day 14), s-IGF-1 levels continued to increase in group A (increases on day 21 and day 28 were 53.19% and 61.45%, respectively). There were no adverse events in either group. The s-IGF-1 levels were significantly raised in both groups after 7 and 14 d of moxibustion therapy. Moreover, once therapy had been completed, s-IGF-1 levels continued to increase in group A up to 14 d after the treatment.
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Factor I del Crecimiento Similar a la Insulina/metabolismo , Moxibustión , Adulto , Femenino , Humanos , Masculino , Proyectos PilotoRESUMEN
Type 2 diabetes are at a high risk of complications related to hypertension, and reports have indicated that insulin levels may be associated with blood pressure (BP). Fructose intake has recently been reported to promote insulin resistance and superoxide formation. The aim of this study is to investigate whether fructose intake can enhance superoxide generation and impair insulin signaling in the NTS and subsequently elevate BP in rats with fructose-induced hypertension. Treatment with fructose for 4 weeks increased the BP, serum fasting insulin, glucose, homeostatic model assessment-insulin resistance, and triglyceride levels and reduced the serum direct high-density lipoprotein level in the fructose group. The Tempol treatment recovered the fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that fructose increased the p38- and fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1S307) and suppressed AktS473 and neuronal nitric oxide synthase phosphorylation. Similarly, fructose was able to impair insulin sensitivity and increase insulin levels in the NTS. Fructose intake also increased the production of superoxide in the NTS. The results of this study suggest that fructose might induce central insulin resistance and elevate BP by enhancing superoxide production and activating p38 phosphorylation in the NTS.
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Diabetes Mellitus Experimental/metabolismo , Fructosa/administración & dosificación , Hipertensión/metabolismo , Resistencia a la Insulina , Núcleo Solitario/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Antioxidantes/farmacología , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Óxidos N-Cíclicos/farmacología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Fructosa/antagonistas & inhibidores , Regulación de la Expresión Génica , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Insulina/sangre , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Lipoproteínas HDL/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal , Núcleo Solitario/metabolismo , Núcleo Solitario/patología , Marcadores de Spin , Superóxidos/agonistas , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismo , Triglicéridos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
Hypertensive rats with chronic kidney disease (CKD) exhibit enhanced gamma-aminobutyric acid (GABA)B receptor function and regulation within the nucleus tractus solitarii (NTS). For CKD with hypertension, renal denervation (RD) interrupts the afferent renal sympathetic nerves, which are connecting to the NTS. The objective of the present study was to investigate how RD improves CKD-induced hypertension. Rats underwent 5/6 nephrectomy for 8 weeks, which induced CKD and hypertension. RD was induced by applying phenol to surround the renal artery in CKD. RD improved blood pressure (BP) by lowering sympathetic nerve activity and markedly restored the baroreflex response in CKD. The GABAB receptor expression was increased in the NTS of CKD; moreover, the central GABA levels were reduced in the cerebrospinal fluid, and the peripheral GABA levels were increased in the serum. RD restored the glutamic acid decarboxylase activity in the NTS in CKD, similar to the effect observed for central treatment with baclofen, and the systemic administration of gabapentin reduced BP. RD slightly improved renal function and cardiac load in CKD. RD may improve CKD-induced hypertension by modulating the baroreflex response, improving GABA system dysfunction and preventing the development and reducing the severity of cardiorenal syndrome type 4 in CKD rats.
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Barorreflejo/fisiología , Hipertensión Renal/terapia , Hipertensión/terapia , Riñón/inervación , Nefritis/terapia , Insuficiencia Renal Crónica/terapia , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Desnervación/métodos , Humanos , Hipertensión/complicaciones , Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipertensión Renal/metabolismo , Hipertensión Renal/fisiopatología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Nefrectomía/efectos adversos , Nefritis/metabolismo , Nefritis/fisiopatología , Neuronas Aferentes/efectos de los fármacos , Fenol/efectos adversos , Ratas , Receptores de GABA-B/metabolismo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiopatologíaRESUMEN
The Taiwanese government subsidizes healthcare providers offering preventive medicine to patients to help reduce the threats of chronic sickness and halt skyrocketing medical expenditures. Usually, nurses are the primary workers who perform community health promotion; however, because of the chronic shortage of working nurses, many Taiwan hospitals have closed wards and deferred the responsibility of promoting primary prevention. With a community health promotion platform integrating interactive response features and Web sites for community patients and hospital staff, a case hospital efficiently sustained the community health services. The objective of this study was to assess the impact of the integrated community health promotion platform for conducting education. Fifty-four patients/residents were invited to join a quasi-experiment of health education, and a follow-up survey was conducted to assess the acceptance of the community health promotion platform from both the experimental group of learners/users and the hospital staff. The results showed that the community health promotion platform was effective in improving participant health awareness. The experimental group outperformed the control group, with higher posttest scores and longer knowledge retention. Furthermore, users indicated a high acceptance of the community health promotion platform.
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Instrucción por Computador , Educación en Salud/métodos , Educación en Salud/organización & administración , Conocimientos, Actitudes y Práctica en Salud , Promoción de la Salud/organización & administración , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , TaiwánRESUMEN
Heme oxygenase (HO)-1 confers transient resistance against oxidative damage, including renal ischemia-reperfusion injury (IRI). We investigated the potential protective effect of HO-1 induction in a mouse model of renal IRI induced by bilateral clamping of the kidney arteries. The mice were randomly assigned to five groups to receive an intraperitoneal injection of PBS, hemin (an HO-1 inducer, 100µmol/kg), hemin+ZnPP (an HO-1 inhibitor, 5mg/kg), hemin+PD98059 (a MEK-ERK inhibitor, 10mg/kg) or a sham operation. All of the groups except for the sham-operated group underwent 25min of ischemia and 24 to 72h of reperfusion. Renal function and tubular damage were assessed in the mice that received hemin or the vehicle treatment prior to IRI. The renal injury score and HO-1 protein levels were evaluated via H&E and immunohistochemistry staining. Hemin-preconditioned mice exhibited preserved renal cell function (BUN: 40±2mg/dl, creatinine: 0.53±0.06mg/dl), and the tubular injury score at 72h (1.65±0.12) indicated that tubular damage was prevented. Induction of HO-1 induced the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. However, these effects were abolished with ZnPP treatment. Kidney function (BUN: 176±49mg/dl, creatinine: 1.54±0.39mg/dl) increased, and the tubular injury score (3.73±0.09) indicated that tubular damage also increased with ZnPP treatment. HO-1-induced tubular epithelial proliferation was attenuated by PD98059. Our findings suggest that HO-1 preconditioning promotes ERK1/2 phosphorylation and enhances tubular recovery, which subsequently prevents further renal injury.
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Brucellosis is a bacterial zoonotic disease which can be easy to misdiagnose in clinical microbiology laboratories. In the present study, we have tried to improve the current clinical method for detecting Brucella spp. and its antibiotic characteristics. Our method begins with detecting the clinical isolate through traditional biochemical methods and automatic identification systems. Then, we move on to editing the sequence for BLAST allows us to compare 16s rRNA sequences with sequences from other species, allowing the gene level to be determined. Next, the phylogenetic analysis of multiple genetic loci is able to determine the evolutionary relationships between our bacteria strain and those from other locations. Finally, an anti-microbial susceptibility test hones in on the level of antibacterial activity that the bacteria displays. Employing these four steps in concert is extremely effective in identifying rare bacteria. Thus, when attempting to determine the identity of rare bacteria such as Brucella, utilizing these four steps from our research should be highly effective and ultimately prevent further identification errors and misdiagnoses. The standards we have suggested to identify rare bacteria strains is applicable not only to Brucella, but also to other rarely encountered bacteria.
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BACKGROUND AND PURPOSE: µ-Opioid receptors, pro-opiomelanocortin and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS) and µ receptor agonists given to the NTS dose-dependently increased BP. However, the molecular mechanisms of this process remain unclear. In vitro, µ receptors heterodimerize with α2A -adrenoceptors. We hypothesized that α2A -adrenoceptor agonists would lose their depressor effects when their receptors heterodimerize in the NTS with µ receptors. EXPERIMENTAL APPROACH: We microinjected µ-opioid agonists and antagonists into the NTS of rats and measured changes in BP. Formation of µ receptor/α2A -adrenoceptor heterodimers was assessed with immunofluorescence and co-immunoprecipitation methods, along with proximity ligation assays. KEY RESULTS: Immunofluorescence staining revealed colocalization of α2A -adrenoceptors and µ receptors in NTS neurons. Co-immunoprecipitation revealed interactions between α2A -adrenoceptors and µ receptors. In situ proximity ligation assays confirmed the presence of µ receptor/α2A -adrenoceptor heterodimers in the NTS. Higher levels of endogenous endomorphin-1 and µ receptor/α2A -adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the µ receptor agonist [D-Ala(2) , MePhe(4) , Gly(5) -ol]-enkephalin (DAMGO), but not that of the α2A -adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased µ receptor/α2A -adrenoceptor heterodimer formation and BP elevation. The NO-dependent BP-lowering effect of α2A -adrenoceptor agonists was blunted following increased formation of µ receptor/α2A -adrenoceptor heterodimers in the NTS of hypertensive rats and DAMGO-treated normotensive rats. CONCLUSIONS AND IMPLICATIONS: Increases in endogenous µ receptor agonists in the NTS induced µ receptor/α2A -adrenoceptor heterodimer formation and reduced the NO-dependent depressor effect of α2A -adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.
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Tronco Encefálico/metabolismo , Dimerización , Hipertensión/metabolismo , Multimerización de Proteína , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Opioides mu/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Tronco Encefálico/efectos de los fármacos , Encefalina Ala(2)-MeFe(4)-Gli(5)/administración & dosificación , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Hipertensión/inducido químicamente , Masculino , Microinyecciones , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/farmacología , Oligopéptidos/metabolismo , Ratas , Ratas Endogámicas SHR , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/metabolismoRESUMEN
Stroke is one of the disorders for which clinically effective therapeutic modalities are most needed, and numerous ways have been explored to attempt to investigate their feasibilities. However, ischemic- or hemorrhagic-induced inflammatory neuron death causes irreversible injuries and infarction regions, and there are currently no truly effective drugs available as therapy. It is therefore urgent to be able to provide a fundamental treatment method to regenerate neuronal brain cells, and therefore, the use of stem cells for curing chronic stroke could be a major breakthrough development. In this review, we describe the features and classification of stroke and focus on the benefits of adipose tissue-derived stem cells and their applications in stroke animal models. The results show that cell-based therapies have resulted in significant improvements in neuronal behaviors and functions through different molecular mechanisms, and no safety problems have so far arisen after transplantation. Further, we propose a clinical possibility to create a homing niche by reducing the degree of invasive intracerebroventricular transplantation and combining it with continuous intravenous administration to achieve a complete cure.
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Tejido Adiposo/citología , Trasplante de Células Madre , Células Madre/citología , Accidente Cerebrovascular/terapia , Animales , Diferenciación Celular , Enfermedad Crónica , Humanos , Inmunomodulación , Neovascularización Fisiológica , Factores de Crecimiento Nervioso/metabolismo , Células Madre/metabolismoRESUMEN
BACKGROUND: Bilateral lesions of nucleus tractus solitarii in rat result in acute hypertension, pulmonary edema, and death within hours. The hypertension results from excessive catecholamine release. Catecholamine can activate connexin43 to regulate cell death. There is no study investigating the cardiopulmonary impacts of different adrenergic blockers and apoptosis mechanism in rat model. METHODS: The authors microinjected 6-hydroxydopamine into nucleus tractus solitarii of the rat (n = 8 per group) and evaluated the cardiopulmonary changes after treatment with different concentrations of α1-blockers, α2-blockers, ß-blockers, and α-agonists. RESULTS: In the rat model, the authors found that prazosin (0.15 mg/kg) treatment could preserve cardiac output and reverse neutrophil infiltrations in lungs and lead to prevent pulmonary hemorrhagic edema. The time-dependent increases in connexin43 and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells induced by 6-hydroxydopamine lesions were decreased after prazosin treatment (terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells at 6 h: 64.01 ± 2.41% vs. 24.47 ± 3.10%; mean ± SD, P < 0.001, in heart, and 80.83 ± 2.52% vs. 2.60 ± 1.03%, P < 0.001, in lung). However, propranolol caused further compromise of the already impaired cardiac output with consequence of rapid death. Phenylephrine enhanced the phenotype in the link between connexin43 expressions and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells but not yohimbine. Connexin43 expressions and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were more decreased with prazosin (0.15 and 0.3 mg/kg) than that with prazosin (0.05 mg/kg) treatment. CONCLUSIONS: α1-Receptors are the keystones of the phenotype. In some brainstem encephalitis and brain injury with nucleus tractus solitarii involvement, early α1-receptor blockade treatment may prevent acute death from tissue apoptosis. α-Blockers can also decrease cerebral perfusion pressure, and further studies are needed in translation to brain injury with increased intracranial pressure.
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Antagonistas Adrenérgicos alfa/farmacología , Antagonistas Adrenérgicos beta/farmacología , Tronco Encefálico/patología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Antagonistas Adrenérgicos alfa/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Tronco Encefálico/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Gasto Cardíaco/fisiología , Hipertensión/etiología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND PURPOSE: Oxidative stress is an important pathogenic factor in the development of hypertension. Resveratrol, the main antioxidant in red wine, improves NO bioavailability and prevents cardiovascular disease. The aim of this study was to examine whether resveratrol decreases the generation of reactive oxygen species (ROS), thereby reducing BP in rats with fructose-induced hypertension. EXPERIMENTAL APPROACH: Rats were fed 10% fructose with or without resveratrol (10 mg·kg(-1) ·day(-1) ) for 1 week or for 4 weeks with resveratrol treatment beginning at week 2; systolic BP (SBP) was measured by tail-cuff method. Endogenous in vivo O2 (-) production in the nucleus tractus solitarii (NTS) was determined with dihydroethidium. Real-time PCR and immunoblotting analyses were used to quantify RNA and protein expression levels. KEY RESULTS: In fructose-fed rats, ROS levels in the NTS were higher, whereas the NO level was significantly decreased. Also, RNA and protein levels of NADPH oxidase subunits (p67, p22-phox) were elevated, superoxide dismutase 2 (SOD2) reduced and AMP-activated PK (AMPK) T172 phosphorylation levels in the NTS were lower in fructose-fed rats. Treatment with the AMPK activator resveratrol decreased levels of NADPH oxidase subunits and ROS, and increased NO and SOD2 levels in the NTS of fructose-fed rats. Administration of resveratrol, in combination with fructose at week 0 and later at week 2, significantly reduced the SBP of fructose-fed rats. CONCLUSIONS AND IMPLICATIONS: Collectively, resveratrol decreased BP through the phosphorylation of AMPK, Akt and neuronal NOS in fructose-fed rats. These novel findings suggest that resveratrol may be a potential pharmacological candidate for the treatment of hypertension.
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Antioxidantes/farmacología , Hipertensión/metabolismo , Núcleo Solitario/efectos de los fármacos , Estilbenos/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Fructosa , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Masculino , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxidos de Nitrógeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismo , Resveratrol , Núcleo Solitario/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1RESUMEN
Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and formation of superoxide. In a previous study, we revealed that inhibition of superoxide production in the nucleus tractus solitarii (NTS) reduces blood pressure. Caffeine displays significant antioxidant ability in protecting membranes against oxidative damage and can lower the risk of insulin resistance. However, the mechanism through which caffeine improves fructose-induced insulin resistance is unclear. The aim of this study was to investigate whether caffeine consumption can abolish superoxide generation to enhance insulin signaling in the NTS, thereby reducing blood pressure in rats with fructose-induced hypertension. Treatment with caffeine for 4 weeks decreased blood pressure, serum fasting glucose, insulin, homeostatic model assessment-insulin resistance, and triglyceride levels and increased the serum direct high-density lipoprotein level in fructose-fed rats but not in control rats. Caffeine treatment resulted in the recovery of fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that caffeine reduced the fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1(S307)) and reversed Akt(S473) and neuronal nitric oxide synthase phosphorylation. Similarly, caffeine was able to improve insulin sensitivity and decrease insulin levels in the NTS evoked by fructose. Caffeine intake also reduced the production of superoxide and expression of receptor of advanced glycation end product in the NTS. These results suggest that caffeine may enhance insulin receptor substrate 1-phosphatidylinositol 3-kinase-Akt-neuronal nitric oxide synthase signaling to decrease blood pressure by abolishing superoxide production in the NTS.
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Cafeína/uso terapéutico , Hipertensión/tratamiento farmacológico , Resistencia a la Insulina , Núcleo Solitario/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/uso terapéutico , Modelos Animales de Enfermedad , Fructosa/toxicidad , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Insulina/sangre , Masculino , Ratas , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacos , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Clinical studies indicate that statins have a BP-lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP through the up-regulation of endothelial NOS (eNOS) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin-mediated BP regulation in the nucleus tractus solitarii (NTS). EXPERIMENTAL APPROACH: To investigate the involvement of Ras and other signalling pathways in simvastatin-induced effects on BP, BP and renal sympathetic nerve activity (RSNA) were determined in spontaneously hypertensive rats (SHRs) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras-specific inhibitor (farnesyl thiosalicylic acid, FTS), a geranylgeranyltransferase inhibitor (GGTI-2133), a PI3K inhibitor (LY294002) or a MAPK-ERK kinase (MEK) inhibitor (PD98059). KEY RESULTS: FTS significantly attenuated the decrease in BP and increased NO evoked by simvastatin and reversed the decrease in basal RSNA induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS significantly abolished simvastatin-induced phosphorylation of ERK1/2, ribosomal protein S6 kinase (RSK), Akt and decreased eNOS phosphorylation. Likewise, administration of Akt and ERK1/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS-positive cells in the NTS. CONCLUSIONS AND IMPLICATIONS: Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras-mediated activation of the PI3K-Akt and ERK1/2-RSK signalling pathways, which then up-regulates eNOS activation.
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Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo III/metabolismo , Transducción de Señal/efectos de los fármacos , Simvastatina/farmacología , Núcleo Solitario/efectos de los fármacos , Proteínas ras/metabolismo , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Hipertensión/enzimología , Hipertensión/fisiopatología , Riñón/inervación , Masculino , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Endogámicas SHR , Proteínas Quinasas S6 Ribosómicas/metabolismo , Núcleo Solitario/enzimología , Núcleo Solitario/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Factores de Tiempo , Proteína de Unión al GTP rac1/metabolismo , Proteínas ras/antagonistas & inhibidoresRESUMEN
OBJECTIVES: Among enterovirus 71 infections, brainstem encephalitis progressing abruptly to cardiac dysfunction and pulmonary edema causes rapid death within several hours. However, no currently known early indicators and treatments can monitor or prevent the unexpectedly fulminant course. We investigate the possible mechanisms and treatment of fatal enterovirus 71 infections to prevent the abrupt progression to cardiac dysfunction and pulmonary edema by using an animal model. DESIGN: Treatment study. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: We microinjected 6-hydroxydopamine or vitamin C into nucleus tractus solitarii of the rat and evaluated the cardiopulmonary changes after treatment with ganglionic blocker. MEASUREMENTS AND MAIN RESULTS: The time course of changes in the heart and lungs of rats with brainstem lesions were investigated. Rats were administered 6-hydroxydopamine to induce brainstem lesions, causing acute hypertension in 10 minutes and acute elevations of catecholamines accompanied by acute cardiac dysfunction and increased strong expressions of connexin 43 gap junction protein in heart and lung specimens by immunohistochemical staining within 3 hours. Severe pulmonary hemorrhagic edema was produced within 6 hours, and the rats expired rapidly within 7 hours. After hexamethonium treatment, it was found that the acute hypertension induced by 6-hydroxydopamine lesions was immediately reversed and the acute high rise of catecholamine serum level was significantly attenuated within 3 hours, accompanied by preserved cardiac output and decreased expressions of connexin 43 in the heart and lungs. No pulmonary edema occurred and the rats survived for more than 14 hours. CONCLUSIONS: Early hexamethonium treatment attenuates acute excessive release of catecholamines to prevent cardiac dysfunction and pulmonary edema for increasing survival rate.