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Introduction: The morbidity and mortality of acute ischemic hypoxic encephalopathy in newborns have not been dramatically modified over the last 20 years. The purpose of this review is to describe the use of hyperbaric oxygenation therapy (HBOT) in the management of acute ischemic hypoxic encephalopathy in newborns. Methods: A review of the medical literature was conducted on the use of HBOT in the pathophysiology of this condition and its impact on outcomes of patients treated at an early stage. Results: When HBOT is administered promptly, it can promote the survival of the penumbra, modulate the cytokine storm, modify inflammatory cascades, restore mitochondrial function, inhibit apoptosis, reinstate cellular communication and cytoskeleton function, reinstall the functioning of the kinase system, reduce cytotoxic and tissue edema, promote microcirculation, and provide an antioxidant effect. All these secondary mechanisms aid in saving, rescuing, and protecting the marginal tissue. Conclusion: When used promptly, HBOT is a non-invasive adjunct treatment that can preserve the marginal tissue affected by ischemia, hypoxia, meet the metabolic needs of the penumbra, reduce inflammatory cascades, prevent the extension of the damaged tissue, and modulate ischemia-reperfusion injury.
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BACKGROUND: The preclinical efficacy of mesenchymal stem cell (MSC) therapy after intravenous infusion has been promising, but clinical studies have yielded only modest results. Although most preclinical studies have focused solely on the ischemic lung, it is crucial to evaluate both lungs after ischemia-reperfusion injury, considering the various mechanisms involved. This study aimed to bridge this gap by assessing the acute effects of bone marrow MSC(BM) infusion before ischemic insult and evaluating both ischemic and non-ischemic lungs after reperfusion. METHODS: Eighteen male Wistar rats (403 ± 23 g) were anesthetized and mechanically ventilated using a protective strategy. After baseline data collection, the animals were randomized to 3 groups (n = 6/group): (1) SHAM; (2) ischemia-reperfusion (IR), and (3) intravenous MSC(BM) infusion followed by IR. Ischemia was induced by complete clamping of the left hilum, followed by 1 h of reperfusion after clamp removal. At the end of the experiment, the right and left lungs (non-ischemic and ischemic, respectively) were collected for immunohistochemistry and molecular biology analysis. RESULTS: MSC(BM)s reduced endothelial cell damage and apoptosis markers and improved markers associated with endothelial cell integrity in both lungs. In addition, gene expression of catalase and nuclear factor erythroid 2-related factor 2 increased after MSC(BM) therapy. In the ischemic lung, MSC(BM) therapy mitigated endothelial cell damage and apoptosis and increased gene expression associated with endothelial cell integrity. Conversely, in the non-ischemic lung, apoptosis gene expression increased in the IR group but not after MSC(BM) therapy. CONCLUSION: This study demonstrates distinct effects of MSC(BM) therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury. The findings underscore the importance of evaluating both lung types in ischemia-reperfusion studies, offering insights into the therapeutic potential of MSC(BM) therapy in the context of lung injury.
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Background: Continuous investment and systematic evaluation of program accomplishments are required to achieve excellence in ST-segment elevation myocardial infarction (STEMI) care, especially in resource-limited settings. Therefore, this study evaluates the impact of problem-driven interventions on reperfusion use rate in a long-term operating STEMI network from a low- to middle-income country. Methods: This is a healthcare improvement evaluation study of Salvador's public STEMI network in a quasi-experimental design, comparing data from 2009 to 2010 (pre-intervention) and 2019-2020 (post-intervention). There were evaluated all confirmed STEMI cases assisted in both periods. The interventions, implemented since 2017, included: expanding the support team, defining criteria to be a spoke, and initiating continuous education activities. The primary outcome was the rate of patients undergoing reperfusion, with secondary outcomes being time from door-to-ECG (D2E) and ECG-to-STEMI-team trigger (E2T). Results: Over ten years, the network's coverage increased by 300,000 individuals, and expanded by 1,800 km2. A total of 885 records were analyzed, 287 in the pre-intervention group (182 men [63·4%]; mean [SD] age 62·1 [12·5] years) and 598 in the post-intervention group (356 men [59·5%]; mean [SD] age 61.9 [11·8] years). It was noticed a substantial increase in reperfusion delivery rate (90 [31%] vs. 431 [73%]; P = 001) and reductions in time from D2E (159 [83-340] vs. 29 [15-63], P = 001), and E2T (31 [21-44] vs. 16 [6-40], P = 001). Conclusion: The strategies adopted by Salvador's STEMI network were associated with significant improvements in the rate of patients undergoing reperfusion and in D2E and E2T. However, the mortality rate remains high.
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BACKGROUND: Despite the well-recognized effectiveness of Ruscus aculetus extract combined or not with ascorbic acid (AA) and hesperidine methyl chalcone (HMC) on ischemia reperfusion (I/R) injury protection, little is known about the contribution of each constituent for this effect. OBJECTIVE: To investigate the effects of AA and HMC combined or not with Ruscus extract on increased macromolecular permeability and leukocyte-endothelium interaction induced by I/R injury. METHODS: Hamsters were treated daily during two weeks with filtered water (placebo), AA (33, 100 and 300âmg/kg/day) and HMC (50, 150 and 450âmg/kg/day) combined or not with Ruscus extract (50, 150 and 450âmg/kg/day). On the day of experiment, the cheek pouch microcirculation underwent 30âmin of ischemia, and the number of rolling and adherent leukocytes and leaky sites were evaluated before ischemia and during 45âmin of reperfusion. RESULTS: Ruscus extract combined with AA and HMC (Ruscus extract mixture) significantly prevented post-ischemic increase in leukocyte rolling and adhesion and macromolecular permeability compared to placebo and these effects were more prominent than AA and HMC alone on leukocyte adhesion and macromolecular leakage. CONCLUSION: Ruscus extract mixture were more effective than its isolated constituents in protect the hamster cheek pouch microcirculation against I/R injury.
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Ácido Ascórbico , Leucócitos , Extratos Vegetais , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Cricetinae , Masculino , Chalconas/farmacologia , Chalconas/uso terapêutico , Mesocricetus , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Hesperidina/análogos & derivadosRESUMO
Mild hyperbaric oxygen therapy (mHBOT) is an adjuvant therapy used in conditions where tissue oxygenation is reduced and is implemented using pressures less than 1.5 ATA and 100% O2 (instead of the classical HBOT at 1.9-3 ATA) which results in cheaper, easier to implement, and equally effective. mHBOT is offered for wellness and beauty and as an anti-aging strategy, in spite of the absence of studies on the cardiovascular system. Consequently, we investigated the impact of mHBOT on the cardiovascular system. Mechanical and energetic parameters of isolated heart submitted to ischemia/reperfusion injury and arterial contractile response from mHBOT-exposed rats were evaluated. In the heart, mHBOT increased pre-ischemic velocity of contraction and ischemic end-diastolic pressure and developed pressure and contractile economy during reperfusion. mHBOT decreased infarct size and increased the plasma nitrite levels. In the artery, mHBOT increased acetylcholine sensitivity. mHBOT protects the heart during ischemia/reperfusion and affects vascular relaxation.
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Oxigenoterapia Hiperbárica , Traumatismo por Reperfusão Miocárdica , Ratos Wistar , Vasodilatação , Animais , Oxigenoterapia Hiperbárica/métodos , Ratos , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Coração/fisiologia , Coração/fisiopatologia , Contração MiocárdicaRESUMO
Hemorrhagic shock (HS), a leading cause of preventable death, is characterized by severe blood loss and inadequate tissue perfusion. Reoxygenation of ischemic tissues exacerbates organ damage through ischemia-reperfusion injury. SUMOylation has been shown to protect neurons after stroke and is upregulated in response to cellular stress. However, the role of SUMOylation in organ protection after HS is unknown. This study aimed to investigate SUMOylation-mediated organ protection following HS. Male Wistar rats were subjected to HS (blood pressure of 40 ± 2 mmHg, for 90 min) followed by reperfusion. Blood, kidney, and liver samples were collected at various time points after reperfusion to assess organ damage and investigate the profile of SUMO1 and SUMO2/3 conjugation. In addition, human kidney cells (HK-2), treated with the SUMOylation inhibitor TAK-981 or overexpressing SUMO proteins, were subjected to oxygen and glucose deprivation to investigate the role of SUMOylation in hypoxia/reoxygenation injury. The animals presented progressive multiorgan dysfunction, except for the renal system, which showed improvement over time. Compared to the liver, the kidneys displayed distinct patterns in terms of oxidative stress, apoptosis activation, and tissue damage. The global level of SUMO2/3 in renal tissue was also distinct, suggesting a differential role. Pharmacological inhibition of SUMOylation reduced cell viability after hypoxia-reoxygenation damage, while overexpression of SUMO1 or SUMO2 protected the cells. These findings suggest that SUMOylation might play a critical role in cellular protection during ischemia-reperfusion injury in the kidneys, a role not observed in the liver. This difference potentially explains the renal resilience observed in HS animals when compared to other systems.
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Ratos Wistar , Choque Hemorrágico , Sumoilação , Animais , Masculino , Choque Hemorrágico/metabolismo , Sumoilação/efeitos dos fármacos , Sumoilação/fisiologia , Ratos , Humanos , Rim/metabolismo , Rim/patologia , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo , Linhagem CelularRESUMO
Acute kidney injury (AKI) is a public health concern associated with high rates of mortality, even in milder cases. One of the reasons for the difficulty in managing AKI in patients is due to its association with pre-existing comorbidities, such as diabetes. In fact, diabetes increases the susceptibility to develop more severe AKI after renal ischemia. However, the long-term effects of this association are not known. Thus, an experimental model was designed to evaluate the chronic effects of renal ischemia/reperfusion (IR) in streptozotocin (STZ)-treated mice. We focused on the glomerular and tubulointerstitial damage, as well as kidney function and metabolic profile. It was found that pre-existing diabetes may potentiate progressive kidney disease after AKI, mainly by exacerbating proinflammatory and sustaining fibrotic responses and altering renal glucose metabolism. To our knowledge, this is the first report that highlights the long-term effects of renal IR on diabetes. The findings of this study can support the management of AKI in clinical practice.NEW & NOTEWORTHY This study demonstrated that early diabetes potentiates progressive kidney disease after ischemia/reperfusion (IR)-induced acute kidney injury, mainly by exacerbating pro-inflammatory and sustaining fibrotic responses and altering renal glucose metabolism. Thus, these findings will contribute to the therapeutic support of patients with type 1 diabetes with eventual renal IR intervention in clinical practice.
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Injúria Renal Aguda , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Progressão da Doença , Rim , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Masculino , Rim/metabolismo , Rim/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/etiologia , Camundongos Endogâmicos C57BL , Estreptozocina , FibroseRESUMO
Numerous natural antioxidants commonly found in our daily diet have demonstrated significant benefits for human health and various diseases by counteracting the impact of reactive oxygen and nitrogen species. Their chemical properties enable a range of biological actions, including antihypertensive, antimicrobial, anti-inflammatory, anti-fibrotic, and anticancer effects. Despite promising outcomes from preclinical studies, ongoing debate persists regarding their reproducibility in human clinical models. This controversy largely stems from a lack of understanding of the pharmacokinetic properties of these compounds, coupled with the predominant focus on monotherapies in research, neglecting potential synergistic effects arising from combining different antioxidants. This study aims to provide an updated overview of natural antioxidants, operating under the hypothesis that a multitherapeutic approach surpasses monotherapy in efficacy. Additionally, this study underscores the importance of integrating these antioxidants into the daily diet, as they have the potential to prevent the onset and progression of various diseases. To reinforce this perspective, clinical findings pertaining to the treatment and prevention of non-alcoholic fatty liver disease and conditions associated with ischemia and reperfusion phenomena, including myocardial infarction, postoperative atrial fibrillation, and stroke, are presented as key references.
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Renal ischaemia and reperfusion (I/R) is caused by a sudden temporary impairment of the blood flow. I/R is a prevalent cause of acute kidney injury. As nitric oxide generated by inducible nitric oxide synthase (iNOS) has detrimental effects during I/R, the pharmacological blockade of iNOS has been proposed as a potential strategy to prevent I/R injury. The aim of this study was to improve the understanding of 1400W (an iNOS inhibitor) on renal I/R as a pharmacological strategy against kidney disease. BALB/c mice received 30 min of bilateral ischaemia, followed by 48 h or 28 days of reperfusion. Vehicle or 1400W (10 mg/kg) was administered 30 min before inducing ischaemia. We found that after 48 h of reperfusion 1400W decreased the serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin and proliferating cell nuclear antigen 3 in the I/R animals. Unexpectedly, we observed mRNA upregulation of genes involved in kidney injury, cell-cycle arrest, inflammation, mesenchymal transition and endothelial activation in the renal medulla of sham animals treated with 1400W. We also explored if 1400W promoted chronic kidney dysfunction 28 days after I/R and did not find significant alterations in renal function, fibrosis, blood pressure or mortality. The results provide evidence that 1400W may have adverse effects in the renal medulla. Importantly, our data point to 1400W-induced endothelial dysfunction, establishing therapeutic limitations for its use. KEY POINTS: Acute kidney injury is a global health problem associated with high morbidity and mortality. The pharmacological blockade of inducible nitric oxide synthase (iNOS) has been proposed as a potential strategy to prevent AKI induced by ischaemia and reperfusion (I/R). Our main finding is that 1400W, a selective and irreversible iNOS inhibitor with low toxicity that is proposed as a therapeutic strategy to prevent kidney I/R injury, produces aberrant gene expression in the medulla associated to tissue injury, cell cycle arrest, inflammation, mesenchymal transition and endothelial activation. The negative effect of 1400W observed in the renal medulla at 48 h from drug administration, is transient as it did not translate into a chronic kidney disease condition.
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Resumen El tratamiento del infarto agudo de miocardio con elevación del segmento ST tiene barreras dependiendo de la región geográfica. La angioplastia coronaria primaria es el tratamiento de elección, siempre y cuando sea realizada dentro de tiempo y por operadores experimentados. Sin embargo, cuando no está disponible, la administración de fibrinólisis y el envío para angioplastia de rescate, en caso de reperfusión negativa, es la mejor estrategia. De la misma manera, la angioplastia coronaria, como parte de una estrategia farmacoinvasiva, es la mejor alternativa cuando hay reperfusión positiva. El desarrollo de redes de tratamiento del infarto aumenta el número de pacientes reperfundidos dentro de los tiempos recomendados y mejora los desenlaces. En América Latina, los programas nacionales para el tratamiento del infarto deben centrarse en mejorar los resultados y el éxito a largo plazo depende de trabajar hacia objetivos definidos y obtener métricas de rendimiento, por lo tanto, estos deben desarrollar métricas para cuantificar su desempeño. El siguiente documento discute todas estas alternativas y sugiere oportunidades de mejora.
Abstract The treatment of ST-segment elevation myocardial infarction has barriers depending on the geographic region. Primary coronary angioplasty is the treatment of choice, if it is performed on time and by experienced operators. However, when it is not available, the administration of fibrinolysis and referral for rescue angioplasty, in case of negative reperfusion, is the best strategy. In the same way, coronary angioplasty, as part of a pharmacoinvasive strategy, is the best alternative when there is positive reperfusion. The development of infarct treatment networks increases the number of patients reperfused within the recommended times and improves outcomes. In Latin America, national myocardial infarction treatment programs should focus on improving outcomes, and long-term success depends on working toward defined goals and enhancing functionality, therefore programs should develop capacity to measure their performance. The following document discusses all of these alternatives and suggests opportunities for improvement.
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Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM2.5) and a decline in renal function. PM2.5 exerts harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischaemia-reperfusion injury (IRI) involves biological processes similar to those involved in PM2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM2.5 exposure on IRI-induced AKI. Through a unique environmentally controlled setup, mice were exposed to urban PM2.5 or filtered air for 12 weeks before IRI followed by euthanasia 48 h after surgery. Animals exposed to PM2.5 and IRI exhibited reduced glomerular filtration, impaired urine concentration ability, and significant tubular damage. Further, PM2.5 aggravated local innate immune responses and mitochondrial dysfunction, as well as enhancing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation. This increased renal senescence and suppressed the anti-ageing protein klotho, leading to early fibrotic changes. In vitro studies using proximal tubular epithelial cells exposed to PM2.5 and hypoxia/reoxygenation revealed heightened activation of the STING pathway triggered by cytoplasmic mitochondrial DNA, resulting in increased tubular damage and a pro-inflammatory phenotype. In summary, our findings imply a role for PM2.5 in sensitising proximal tubular epithelial cells to IRI-induced damage, suggesting a plausible association between PM2.5 exposure and heightened susceptibility to CKD in individuals experiencing AKI. Strategies aimed at reducing PM2.5 concentrations and implementing preventive measures may improve outcomes for AKI patients and mitigate the progression from AKI to CKD. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Injúria Renal Aguda , Camundongos Endogâmicos C57BL , Material Particulado , Traumatismo por Reperfusão , Animais , Injúria Renal Aguda/patologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Traumatismo por Reperfusão/patologia , Material Particulado/efeitos adversos , Material Particulado/toxicidade , Camundongos , Masculino , Poluição do Ar/efeitos adversos , Modelos Animais de Doenças , Rim/patologia , Rim/metabolismo , Transdução de Sinais , Taxa de Filtração GlomerularRESUMO
BACKGROUND: It has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death. OBJECTIVE: To examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model. METHODS: Isolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca2+ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis. RESULTS: AR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR. CONCLUSIONS: Our data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.
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Óxido Nítrico , Animais , Concentração de Íons de Hidrogênio , Óxido Nítrico/metabolismo , Masculino , Ratos , Ratos Wistar , Óxido Nítrico Sintase Tipo III/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , NG-Nitroarginina Metil Éster/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Óxido Nítrico Sintase/metabolismoRESUMO
BACKGROUND: Cuproptosis is known to regulate diverse physiological functions in many diseases, but its role in regulating Myocardial Ischemia-Reperfusion Injury (MI/RI) remains unclear. METHODS: For this purpose, the MI/RI microarray datasets GSE61592 were downloaded from the Gene Expression Omnibus (GEO) database, and the Differently Expressed Genes (DEGs) in MI/RI were identified using R software. Moreover, the MI/RI mice model was established to confirm further the diagnostic value of Pyruvate Dehydrogenase B (Pdhb), Dihydrolipoamide S-acetyltransferase (Dlat), and Pyruvate dehydrogenase E1 subunit alpha 1 (Pdhα1). RESULTS: The analysis of microarray datasets GSE61592 revealed that 798 genes were upregulated and 768 were downregulated in the myocardial tissue of the ischemia-reperfusion injury mice. Furthermore, Dlat, Pdhb, Pdhα1, and cuproptosis-related genes belonged to the downregulated genes. The receiver operating characteristics curve analysis results indicated that the Dlat, Pdhb, and Pdhα1 levels were downregulated in MI/RI and were found to be potential biomarkers for MI/RI diagnosis and prognosis. Similarly, analysis of Dlat, Pdhb, and Pdhα1 levels in the MI/RI mice revealed Pdhb being the key diagnostic marker. CONCLUSIONS: This study demonstrated the prognostic value of cuproptosis-related genes (Dlat, Pdhb, and Pdhα1), especially Pdhb, MI/RI, providing new insight into the MI/RI treatment.
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Biologia Computacional , Traumatismo por Reperfusão Miocárdica , Animais , Traumatismo por Reperfusão Miocárdica/genética , Camundongos , Regulação para Baixo/genética , Masculino , Modelos Animais de Doenças , Regulação para Cima , Camundongos Endogâmicos C57BL , Perfilação da Expressão Gênica/métodos , Piruvato Desidrogenase (Lipoamida)/genética , Biomarcadores/análise , Acetiltransferases/genéticaRESUMO
Ischemia-reperfusion injury (IRI) during liver transplantation has been implicated in the recurrence of hepatocellular carcinoma (HCC). This systematic review aimed to evaluate interventions to reduce IRI during liver transplantation for HCC and their impact on oncologic outcomes. A comprehensive literature search retrieved four retrospective studies involving 938 HCC patients, utilising interventions such as post-operative prostaglandin administration, hypothermic machine perfusion, and normothermic machine perfusion. Overall, treated patients exhibited reduced post-operative hepatocellular injury and inflammation and significantly enhanced recurrence-free survival. Despite these promising results, the impact of these interventions on overall survival remains unclear. This underscores the imperative for further prospective research to comprehensively understand the efficacy of these interventions in HCC patients undergoing transplantation. The findings highlight the potential benefits of these strategies while emphasising the need for continued investigation into their overall impact.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Traumatismo por Reperfusão , Humanos , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/etiologia , Transplante de Fígado/métodos , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Resultado do Tratamento , AloenxertosRESUMO
OBJECTIVE: The current study aimed to explore the potential protective effect of Passiflora Incarnata L., (PI) in treating IR injury after testicular torsion in rats. MATERIALS AND METHODS: This research investigated the impact of PI on IR damage in male Wistar albino rats. Animals were divided to three groups: group 1 (sham), group 2 (IR), and group 3 (IR+PI). RESULTS: The malondialdehyde (MDA), myeloperoxidase (MPO) and glutathione (GSH) levels did not significantly differ across the groups (p = 0.830, p = 0.153 and p=0.140, respectively). However, Group 3 demonstrated a superior total antioxidant status (TAS) value compared to Group 2 (p = 0.020). Concurrently, Group 3 presented a significantly diminished mean total oxidant status (TOS) relative to Group 2 (p = 0.009). Furthermore, Group 3 showed a markedly improved Johnsen score relative to Group 2 (p < 0.01). IR caused cell degeneration, apoptosis, and fibrosis in testicular tissues. PI treatment, however, mitigated these effects, preserved seminiferous tubule integrity and promoted regular spermatogenesis. Furthermore, it reduced expression of tumor necrosis factor-alpha (TNF-α), Bax, and Annexin V, signifying diminished inflammation and apoptosis, thereby supporting cell survival (p < 0.01, p < 0.01, p < 0.01, respectively). CONCLUSIONS: This study revealed that PI significantly reduces oxidative stress and testicular damage, potentially benefiting therapies for IR injuries.
OBJETIVO: Explorar el posible efecto protector de Passiflora incarnata L. (PI) en el tratamiento de la lesión por isquemia-reperfusión (IR) después de una torsión testicular en ratas. MÉTODO: Se estudió el impacto de Passiflora incarnata en el daño por IR en ratas Wistar albinas machos. Los animales se dividieron tres grupos: 1 (simulado), 2 (IR) y 3 (IR+PI). RESULTADOS: Los niveles de malondialdehyde (MDA), myeloperoxidase (MPO) y glutathione (GSH) no difirieron significativamente entre los grupos (p = 0.830, p = 0.153 y p = 0.140, respectivamente). Sin embargo, el grupo 3 tuvo un valor de estado antioxidante total (TAS) superior en comparación con el grupo 2 (p = 0.020). Al mismo tiempo, el grupo 3 presentó un estado oxidante total (TOS) medio significativamente disminuido en comparación con el grupo 2 (p = 0.009). El grupo 3 mostró una mejora notable en la puntuación de Johnsen en comparación con el grupo 2 (p < 0.01). La IR causó degeneración celular, apoptosis y fibrosis en los tejidos testiculares. El tratamiento con PI mitigó estos efectos, preservó la integridad de los túbulos seminíferos y promovió la espermatogénesis regular. Además, redujo la expresión de factor de necrosis tumoral alfa, Bax y anexina V, lo que significa una disminución de la inflamación y de la apoptosis, respaldando así la supervivencia celular (p < 0.01, p < 0.01 y p < 0.01, respectivamente). CONCLUSIONES: Este estudio reveló que PI reduce significativamente el estrés oxidativo y el daño testicular, beneficiando potencialmente las terapias para lesiones por IR.
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Modelos Animais de Doenças , Passiflora , Ratos Wistar , Traumatismo por Reperfusão , Torção do Cordão Espermático , Animais , Masculino , Torção do Cordão Espermático/complicações , Torção do Cordão Espermático/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Ratos , Passiflora/química , Extratos Vegetais/uso terapêutico , Extratos Vegetais/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Fitoterapia , Malondialdeído/análise , Malondialdeído/metabolismo , Testículo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Glutationa/metabolismo , Peroxidase/metabolismo , Peroxidase/análise , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Espermatogênese/efeitos dos fármacosRESUMO
INTRODUCTION AND OBJECTIVES: Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors. PATIENTS AND METHODS: 12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq. RESULTS: Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response. CONCLUSIONS: In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI.
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Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica , Transplante de Fígado , Fígado , Traumatismo por Reperfusão , Transplante de Fígado/efeitos adversos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Perfilação da Expressão Gênica/métodos , Transcriptoma , Adulto , IdosoRESUMO
For the ischemic preconditioning (IPC) intervention, the accuracy of the protocol is paramount for mediating its possible ergogenic effects. However, the lack of standardization and widespread use of arbitrary cuff pressures (ranging from 130 to >300 mmHg) have been predominantly observed, potentially affecting the results and compromising the reproducibility of findings. Thus, the purpose of this study was to determine an appropriate cuff pressure during IPC. Seventeen healthy male participants were enrolled in the study. Anthropometric measurements were initially conducted, followed by systolic and diastolic blood pressure measurements. Subsequently, we determined the individual thigh occlusion pressure (TOP) for the right leg using a hand-held Doppler device. Based on these findings, we developed an estimation equation for TOP, considering the current brachial systolic blood pressure (SBP) values. We then conducted a retrospective analysis of its capacity to mediate occlusion. We observed the ability to estimate TOP using the equation (p = 0.01; ES: 0.86), presenting ~6% superiority in absolute values for occlusion compared to direct measurement (TOP equation: 169.9 ± 9.1; TOP direct measured: 161.2 ± 11.1). However, TOP estimation was insufficient to produce complete occlusion in two out of 17 subjects (11.8%). In conclusion, the estimation of TOP incorporating SBP values may offer a valid and practical means for cuff administration during IPC protocols with potential to minimize adverse effects and maximize its positive effects.
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Cetaceans and pinnipeds are lineages of mammals that have independently returned to the aquatic environment, acquiring varying degrees of dependence on it while sharing adaptations for underwater living. Here, we focused on one critical adaptation from both groups, their ability to withstand the ischemia and reperfusion experienced during apnea diving, which can lead to the production of reactive oxygen species (ROS) and subsequent oxidative damage. Previous studies have shown that cetaceans and pinnipeds possess efficient antioxidant enzymes that protect against ROS. In this study, we investigated the molecular evolution of key antioxidant enzyme genes (CAT, GPX3, GSR, PRDX1, PRDX3, and SOD1) and the ROS-producing gene XDH, in cetaceans and pinnipeds lineages. We used the ratio of non-synonymous (dN) to synonymous (dS) substitutions as a measure to identify signatures of adaptive molecular evolution in these genes within and between the two lineages. Additionally, we performed protein modeling and variant impact analyzes to assess the functional consequences of observed mutations. Our findings revealed distinct selective regimes between aquatic and terrestrial mammals in five of the examined genes, including divergences within cetacean and pinniped lineages, between ancestral and recent lineages and between crowns groups. We identified specific sites under positive selection unique to Cetacea and Pinnipedia, with one site showing evidence of convergent evolution in species known for their long and deep-diving capacities. Notably, many sites under adaptive selection exhibited radical changes in amino acid properties, with some being damaging mutations in human variations, but with no apparent detrimental impacts on aquatic mammals. In conclusion, our study provides insights into the adaptive changes that have occurred in the antioxidant systems of aquatic mammals throughout their evolutionary history. We observed both distinctive features within each group of Cetacea and Pinnipedia and instances of convergence. These findings highlight the dynamic nature of the antioxidant system in response to challenges of the aquatic environment and provide a foundation for further investigations into the molecular mechanisms underlying these adaptations.
Assuntos
Antioxidantes , Caniformia , Cetáceos , Evolução Molecular , Animais , Cetáceos/genética , Cetáceos/metabolismo , Caniformia/genética , Antioxidantes/metabolismo , Filogenia , Adaptação Fisiológica/genética , Espécies Reativas de Oxigênio/metabolismo , Seleção GenéticaRESUMO
Introduction and purpose: Basilar artery occlusion (BAO) is still one of the most devastating neurological conditions associated with high morbidity and mortality. In the present study, we aimed to assess the role of posterior circulation collaterals as predictors of outcome in the BASICS trial and to compare two grading systems (BATMAN score and PC-CS) in terms of prognostic value. Methods: We performed a sub-analysis of the BASICS trial. Baseline clinical and imaging variables were analyzed. For the imaging analysis, baseline CT and CTA were analyzed by a central core lab. Only those patients with good or moderate quality of baseline CTA and with confirmed BAO were included. Multivariable binary logistic regression analysis was used to test the independent association of clinical and imaging characteristics with a favorable outcome at 3 months (defined as a modified Rankin Score of ≤3). ROC curve analysis was used to assess and compare accuracy between the two collateral grading systems. Results: The mean age was 67.0 (±12.5) years, 196 (65.3%) patients were males and the median NIHSS was 21.5 (IQR 11-35). Median NCCT pc-ASPECTS was 10 (IQR10-10) and median collateral scores for BATMAN and PC-CS were 8 (IQR 7-9) and 7 (IQR 6-8) respectively. Collateral scores were associated with favorable outcome at 3 months for both BATMAN and PC-CS but only with a modest accuracy on ROC curve analysis (AUC 0.62, 95% CI [0.55-0.69] and 0.67, 95% CI [0.60-0.74] respectively). Age (OR 0.97, 95% CI [0.95-1.00]), NIHSS (OR 0.91, 95% CI [0.89-0.94]) and collateral score (PC-CS - OR 1.2495% CI [1.02-1.51]) were independently associated with clinical outcome. Conclusion: The two collateral grading systems presented modest prognostic accuracy. Only the PC-CS was independently associated with a favorable outcome at 3 months.
RESUMO
Defined as systemic hypotension caused by intense vasodilation due to the loss of systemic vascular resistance, vasoplegic syndrome (VS) is associated with elevated morbidity and mortality in humans. Although vasopressors such as norepinephrine and vasopressin are the first-choice drugs for VS treatment, several other drugs such as methylene blue (MB) can be used as adjuvant therapy including rescue therapy. To develop new pharmacological strategies to reduce the risk of VS, we investigated the effects of treatments with MB (2 mg/kg/IV), omeprazole (OME, 10 mg/kg/IV), and their combination in an animal model of cardiac ischemia-reperfusion (CIR). The ventricular arrhythmia (VA), atrioventricular block (AVB), and lethality (LET) incidence rates caused by CIR (evaluated via ECG) and serum levels of the cardiac lesion biomarkers creatine kinase-MB (CK-MB) and troponin I (TnI) in adult rats pretreated with saline solution 0.9% and submitted to CIR (SS + CIR group) were compared to those pretreated with MB (MB + CIR group), OME (OME + CIR group), or the MB + OME combination (MB + OME + CIR group). The AVB and LET incidence rates in the MB + CIR (100%), OME + CIR (100%), and MB + OME + CIR (100%) groups were significantly higher compared to the SS + CIR group (60%). The serum level of CK-MB in these groups were also significantly higher compared to the SS + CIR group, demonstrating that the treatments before CIR with MB, OME, and MB + OME produced similar effects in relation to cardiac function and the occurrence of lesions. These results demonstrate that the treatment of animals subjected to the CIR protocol with OME produced the same effects promoted by the treatment with MB, which may suggest the possibility of using OME alone or in combination with MB in medical clinics in treatment of VS.