Ongoing Oxidative Stress Research Articles

Liraglutide Improves Diabetic Cardiomyopathy by Downregulation of Cardiac Inflammatory and Apoptosis Markers.

Diabetic cardiomyopathy is one of the leading causes of mortality for people with diabetes worldwide. The majority of the formalistic alterations in the heart associated with diabetic cardiomyopathy have been found to be primarily caused by the ongoing oxidative stress brought on by hyperglycemia, which leads to the dysfunctional reactions of apoptosis and inflammation. Liraglutide, a long-acting counterpart of glucagon-like peptide-1, has been demonstrated to have a number of therapeutic applications in medicine and other biological processes. The PubMed database was searched using the terms liraglutide, DCM, and all associated inflammatory markers. There has been a lot of research on liraglutide's potential to protect the heart from cardiomyopathy brought on by diabetes. Liraglutide's therapeutic actions as an antioxidant, antihyperglycemic, anti-apoptotic, and anti-inflammatory medicine may help to lessen diabetic cardiomyopathy. The most recent studies on the effects of liraglutide therapy on DCM are presented in this review, along with an explanation of the underlying mechanisms.

Evaluation of diagnostic potential of maternal serum ischemia modified albumin in cases of pre-eclampsia.

The underlying causes and mechanisms of pre-eclampsia (PE), its exact etiology remains unclear and poorly understood. Hypoxia, ischemia, and oxidative stress induced by free radicals have been associated with development of PE. Ischemia-modified albumin (IMA) is a chemically modified albumin due to oxidative stress. IMA, a serum biomarker of hypoxia, ischemia, and oxidative free radicals is a potential biomarker for PE. The aim of the current proposal was to study serum IMA as a diagnostic biomarker of pre-eclampsia (PE) in pregnant females and to evaluate the correlation between serum IMA and different markers of pre-eclampsia (BP, urinary protein, LFT, KFT, serum total protein & uric acid). A total of 60 pregnant women aged between 21 and 35 years were recruited (30 PE cases and 30 normal pregnancy). Serum IMA was measured by spectrophotometric method developed by Bar-Or D. BP and biochemical parameters (urinary protein, LFT, KFT, serum total protein & uric acid) were also assayed and compared between two groups. Correlation analysis was done for analyzing the relationship between serum IMA and biochemical parameters. The mean serum IMA was significantly higher in normotensive pregnant females (0.93 ABSU) than PE cases (0.71 ABSU). Kidney function and liver function parameters were more deranged in PE cases than in controls. Serum IMA was positively correlated with serum creatinine (r=0.322), serum uric acid (r=0.54) and urinary protein (0.376) whereas negatively correlated with total serum bilirubin (r=-0.515) and serum albumin (r=-0.380). Elevated serum IMA concentrations in normotensive pregnant controls as compared to PE cases suggest that apart from ongoing ischemia and oxidative stress in placenta IMA values are influenced by many other mechanisms in pregnancy.

Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.

This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds. We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone. NAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM (p = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake. In IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.

Measurement of 8-hydroxy-2'-deoxyguanosine in serum and cerebrospinal fluid of horses with neuroaxonal degeneration and other causes of proprioceptive ataxia.

Eight-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative damage evaluated in human neurodegenerative disease, has potential to correlate with postmortem diagnosis of neuroaxonal dystrophy/degenerative myeloencephalopathy (NAD/DM) in horses. We hypothesized that 8-OHdG will be higher in CSF and serum from NAD/DM horses compared with horses with other neurologic diseases (CVSM, EPM) and a control group of neurologically normal horses. We also hypothesized that 8-OHdG will be higher in CSF compared with serum from NAD/DM horses. Fifty client-owned horses with postmortem diagnoses: 20 NAD/DM, 10 CVSM, 10 EPM, and 10 control horses. Serum and CSF samples were obtained between November 2010 and March 2022. Case-control study using biobanked samples was performed and commercial competitive ELISA kit (Highly Sensitive 8-OHdG Check ELISA) utilized. Concentration of 8-OHdG was quantitated in both CSF and serum and compared between groups. No correlation was established between the measures of 8-OHdG in serum and CSF and group. CSF median [8-OHdG] for NAD/DM was 169.9 pg/mL (IQR25-75 : 67.18-210.6), CVSM 157.1 pg/mL (IQR25-75 : 132.1-229.1), EPM 131.4 pg/mL (IQR25-75 : 102.1-193.2), and control 149.8 pg/mL (IQR25-75 : 113.3-196.4). Serum median [8-OHdG] for NAD/DM was 130 pg/mL (IQR25-75 : 51.73-157.2), CVSM 125.8 pg/mL (IQR25-75 : 62.8-170.8), EPM 120.6 pg/mL (IQR25-75 : 87.23-229.7), and control 157.6 pg/mL (IQR25-75 : 97.15-245.6). Poisson regression analysis showed no difference established once confounding variables were considered. Eight-OHdG did not aid in antemortem diagnosis of NAD/DM in this cohort of horses. At the time of diagnosis horses with NAD/DM do not have ongoing oxidative stress.

The protective effect of crocin against testicular toxicity induced by ionizing radiation via AKT/FOXO pathway.

Crocin, a pharmacologically active component of Crocus sativus L. (saffron), has been informed to be beneficial in the treatment of stress-related oxidative impairment. In the present study, we examined the protective role of crocin against testicular damage induced by radiation (acute and fractionated) and the alteration of the AKT/FOXO signaling pathway. Male Wister albino rats were exposed to acute dose of 6 Gy and a fractionated dose of gamma radiation (2 Gy every 2 days up to 6 Gy total doses). Rats were pretreated intraperitoneally with crocin in a dose of 50 mg/kg for seven consecutive days prior to exposure to irradiation at a level of 6 Gy and during the fractionated irradiation of rats. Control groups were run concurrently. Ionizing radiation caused changes in the level of oxidative stress biomarkers manifested as elevation of thiobarbituric acid reactive substance, total nitrate/nitrite and reactive oxygen species (ROS) associated with a decrease in catalase as well as in the level of inflammatory parameters (decrease in expression of Nrf2 which was related to a significant increase in expression of NF-κB p65). Irradiation produced cellular damage characterized by an increase in serum lactate dehydrogenase. These findings were aligned with increased expression of the forkhead box O-1 (FOXO-1) and activation of protein kinase B (AKT) pathway. Irradiation of rats led to reduction in serum testosterone level and testicular weights. Pretreatment with the indicated dose of crocin shielded against the changes in all the evaluated parameters. Administration of crocin can be introduced as a novel preclinical approach for regulation of testicular damage induced by radiation; via controlling the ongoing oxidative stress and inflammatory reaction as well as activation FOXO/AKT signaling pathway.

Pancreatic Stellate Cells and the Targeted Therapeutic Strategies in Chronic Pancreatitis.

Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients.

Pharmacotherapies in Older Adults with COPD: Challenges and Opportunities.

Older adults have a higher prevalence of chronic obstructive pulmonary disease (COPD), which will likely increase substantially in the coming decades owing to aging populations and increased long-term exposure to risk factors for this disease. COPD in older adults is characterized by low-grade chronic systemic inflammation, known as inflamm-aging. It contributes substantially to age-associated pulmonary changes that are clinically expressed by reduced lung function, poor health status, and limitations in activities of daily living. In addition, inflamm-aging has been associated with the onset of many comorbidities commonly encountered in COPD. Furthermore, physiologic changes that are often seen with aging can influence the optimal treatment of older patients with COPD. Therefore, variables such as pharmacokinetics, pharmacodynamics, polypharmacy, comorbidities, adverse drug responses, drug interactions, method of administration, and social and economic issues that impact nutrition and adherence to therapy must be carefully evaluated when prescribing medication to these patients because each of them alone or together may affect the outcome of treatment. Current COPD medications focus mainly on alleviating COPD-related symptoms, so alternative treatment approaches that target the disease progression are being investigated. Considering the importance of inflamm-aging, new anti-inflammatory molecules are being evaluated, focusing on inhibiting the recruitment and activation of inflammatory cells, blocking mediators of inflammation thought to be important in the recruitment or activation of these inflammatory cells or released by these cells. Potential therapies that may slow the aging processes by acting on cellular senescence, blocking the processes that cause it (senostatics), eliminating senescent cells (senolytics), or targeting the ongoing oxidative stress seen with aging need to be evaluated.

Brain Trauma and the Secondary Cascade in Humans: Review of the Potential Role of Vitamins in Reparative Processes and Functional Outcome

An estimated sixty-nine million people sustain a traumatic brain injury each year. Trauma to the brain causes the primary insult and initiates a secondary biochemical cascade as part of the immune and reparative response to injury. The secondary cascade, although a normal physiological response, may also contribute to ongoing neuroinflammation, oxidative stress and axonal injury, continuing in some cases years after the initial insult. In this review, we explain some of the biochemical mechanisms of the secondary cascade and their potential deleterious effects on healthy neurons including secondary cell death. The second part of the review focuses on the role of micronutrients to neural mechanisms and their potential reparative effects with regards to the secondary cascade after brain injury. The biochemical response to injury, hypermetabolism and excessive renal clearance of nutrients after injury increases the demand for most vitamins. Currently, most research in the area has shown positive outcomes of vitamin supplementation after brain injury, although predominantly in animal (murine) models. There is a pressing need for more research in this area with human participants because vitamin supplementation post-trauma is a potential cost-effective adjunct to other clinical and therapeutic treatments. Importantly, traumatic brain injury should be considered a lifelong process and better evaluated across the lifespan of individuals who experience brain injury.

Oxidative stress and related metabolic alterations are induced in ex situ perfusion of donated hearts regardless of the ventricular load or leukocyte depletion

We sought to determine the role of donor blood circulating leukocytes in mediating oxidative stress and inflammation during normothermic ex situ heart perfusion (ESHP). Normothermic ESHP allows preservation of donated heart in a perfused, dynamic state, preventing ischemia. However, the cardiac function declines during ESHP, limiting the potential of this method for improvement of the outcomes of transplantation and expanding the donor pool. Extracorporeal circulation-related oxidative stress plays a critical role in the functional decline of the donor heart. Hearts from domestic pigs were perfused in working mode (WM, whole blood-based or leukocyte-depleted blood-based perfusate) or nonworking mode. Markers of oxidative stress and responsive glucose anabolic pathways were induced in the myocardium regardless of left ventricular load. Myocardial function during ESHP as well as cardioprotective mechanisms were preserved better in WM. Leukocyte-depleted perfusate did not attenuate tissue oxidative stress or perfusate proinflammatory cytokines and did not improve functional preservation. Although ESHP is associated with ongoing oxidative stress and metabolic alteration in the myocardium, preserved cardioprotective mechanisms in WM may exert beneficial effects. Leukocyte depletion of the perfusate may not attenuate inflammation and oxidative stress effectively or improve the functional preservation of the heart during ESHP.

Novel Role of Mammalian Cell Senescence-Sustenance of Muscle Larvae of Trichinella spp.

Muscle larva of the parasitic nematode Trichinella spp. lives in a portion of muscle fibre transformed to a nurse cell (NC). Based on our previous transcriptomic studies, NC growth arrest was inferred to be accompanied by cellular senescence. In the current study, NC was proven to display the following markers of senescence: high senescence-associated β-galactosidase activity, lipid deposition, DNA damage, and cell cycle inhibition. Moreover, the nuclear localization of Activator Protein 1 (c-Fos, c-Jun, and FosB), as well as the upregulation of numerous AP-1 target genes in the NC, remained in accord with AP-1 recently identified as a master transcription factor in senescence. An increase in reactive oxygen species generation and the upregulation of antioxidant defence enzymes, including glutathione peroxidases 1 and 3, catalase, superoxide dismutases 1 and 3, and heme oxygenase 1, indicated an ongoing oxidative stress to proceed in the NC. Interestingly, antioxidant defence enzymes localized not only to the NC but also to the larva. These results allowed us to hypothesize that oxidative stress accompanying muscle regeneration and larval antigenic properties lead to the transformation of a regenerating myofibre into a senescent cell. Cellular senescence apparently represents a state of metabolism that sustains the long-term existence of muscle larva and ultimately provides it with the antioxidant capacity needed during the next host colonization. Senotherapy, a therapeutic approach aimed at selective elimination of senescent cells, can thus be viewed as potentially effective in the treatment of trichinosis.

Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with lower plasma glutathione (GSH) levels due to oxidative stress. However, plasma levels may not reflect brain GSH levels. Individuals with post-acute sequelae of COVID-19 (PASC) have a higher prevalence of cognitive fatigue, which might be related to altered brain γ-aminobutyric-acid (GABA) levels. Hence, our study aims to measure the brain GSH and GABA levels in PASC. 29 PASC participants and 24 uninfected controls were recruited for this study. Each was evaluated with detailed neuropsychiatric assessments and an edited proton MRS (Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy, HERMES) method to measure GABA and GSH concentrations in predominantly grey matter (GM) and predominantly white matter (WM) brain frontal voxels. PASC participants were 219 ± 137 days since their COVID-19 diagnosis. Nine individuals with PASC were hospitalized. Compared to controls, individuals with PASC had similar levels of GABA in both brain regions, but lower GSH and greater age-related GSH decline in the frontal GM region. The lower-than-normal frontal GM GSH level in participants with PASC suggest that they have ongoing oxidative stress in the brain, and that older individuals may be even more vulnerable to oxidative stress.

Constitutive expression of inducible nitric oxide synthase in healthy rat urothelium?

Background Contrasting findings have been reported regarding a possible constitutive expression of inducible nitric oxide synthase (iNOS) in a normal mammalian bladder. The current study was designed to further investigate such putative iNOS expression. Materials and methods The experiments were conducted with paraffin-embedded archival material from the urinary bladder of 6 normal, male Sprague–Dawley rats. In addition, two normal female mice (C57BL/6) were sacrificed and the urinary bladders were harvested. The occurrence of iNOS mRNA was examined by the RNAScope in situ hybridization method. Protein expression of iNOS and 3-nitrotyrosine (the latter used as an indicator of oxidative stress) was investigated by immunohistochemistry. Results No expression of iNOS mRNA was observed in the bladder tissue. iNOS protein and 3-nitrotyrosine were strongly expressed in the urothelium. iNOS was also expressed perinuclearly in the detrusor. Conclusions Although the RNAScope methodology could not demonstrate mRNA for iNOS in the normal urinary bladder, the results by immunohistochemistry strongly suggest the occurrence of iNOS in particular, in the urothelium. Positive reactivity for 3-nitrotyrosine may indicate ongoing oxidative stress of the urothelium. The finding of perinuclear iNOS immunoreactivity could suggest an intracrine signaling function by iNOS to the nucleus.

The evaluation of the health risk in ice hockey players based on the predictors that characterize the tension of adaptive organism systems

Objective: to search for markers of health risk in ice hockey players by the blood parameters.Materials and methods: a total of 40 blood parameters (that characterize nutrient metabolism, humoral immunity, oxidative and nitrosative stress, the system of antioxidant protection) in hockey players with different body weights were evaluated 2.5, 4, and 6 months of the playing season (n = 39).Results: the levels of uric acid and creatinine indicated insufficient recreation of the organism after the games. Creatine phosphokinase­MB and AST indicated the influence on the cardiovascular muscle (verified by the De Ritis ratio). Dyslipidemia was the main factor of cardiovascular risk. Cortisol indicated the prevalence of catabolic processes and psychoemotional tension. The changes in the levels of immunoglobulins and C­reactive protein could result from a compensatory reaction of the organism to stress. The oxidized glutathione indicated the accumulation of products of lipid peroxidation and ongoing oxidative stress. The insufficiency in vitamins of groups B and E could decrease the effectiveness of enzymatic systems and enzymatic links of the oxidant system. The insufficiency of chrome could impair carbohydrate and fat metabolism.Conclusion: predictors for prenosological diagnostics of general health were established. They included urea, total cholesterol of high and low density, vitamin­mineral balance parameters, isoform of creatine kinase, aspartate aminotransferase, cortisol, and glutathione. Professional activity had the most negative influence on the health of sportsmen with lower body weight.

Surface stiffness depended gingival mesenchymal stem cell sensitivity to oxidative stress

Mesenchymal stem cells (MSCs) are widely used in the fields of cell therapy and tissue engineering, due to their wide spectrum of differentiation potential, immunomodulation function and ongoing oxidative stress (OS) reduction. Nevertheless, OS impact is often overlooked in these research fields. It is not only responsible for the induction and development of many ailments, e.g., diabetes, lung fibrosis, and cancer, moreover, OS causes stem cell death and senescence during cell therapy and tissue engineering practices. As MSCs are used to treat various tissues, they interact with different tissue-specific mechanical environments, thus it is important to understand how the mechanical environment impacts MSC sensitivity to OS. In this work, for the first time, as known to the authors, it was shown that gingival MSCs (GMSCs) sensitivity to OS depends on the stiffness of the surface, on which the cells are grown. Furthermore, the activity and expression of mitogen activated protein kinases ERK, JNK, and p38 were surface stiffness dependent. GMSCs isolated from intermediate/stiff gingiva tissue (~20 kPa) have shown the best proliferative and survival properties, then grown on the stiffest tissues mimicking polyacrylamide hydrogels (40 kPa). Therefore, MSC source might determine their sensitivity to OS in different stiffness environments and should be accounted when developing a treatment strategy.

Mushroom-Derived Medicine? Preclinical Studies Suggest Potential Benefits of Ergothioneine for Cardiometabolic Health.

Medicinal use of mushrooms has been documented since ancient times, and in the modern world, mushrooms have a longstanding history of use in Eastern medicine. Recent interest in plant-based diets in Westernized countries has brought increasing attention to the use of mushrooms and mushroom-derived compounds in the prevention and treatment of chronic diseases. Edible mushrooms are the most abundant food sources of the modified amino acid, ergothioneine. This compound has been shown to accumulate in almost all cells and tissues, but preferentially in those exposed to oxidative stress and injury. The demonstrated cytoprotectant effect of ergothioneine has led many to suggest a potential therapeutic role for this compound in chronic conditions that involve ongoing oxidative stress and inflammation, including cardiovascular and metabolic diseases. However, the in vivo effects of ergothioneine and its underlying therapeutic mechanisms in the whole organism are not as clear. Moreover, there are no well-defined, clinical prevention and intervention trials of ergothioneine in chronic disease. This review highlights the cellular and molecular mechanisms of action of ergothioneine and its potential as a Traditional, Complementary and Alternative Medicine for the promotion of cardiometabolic health and the management of the most common manifestations of cardiometabolic disease.

Nephrolepis exaltata - Hibiscus rosa-sinensis combination herbal mask decreases levels of reactive oxygen species in nasal wash

BackgroundPoor air and mask quality in the work environment increase the risks of inflammation, reactive oxygen species (ROS) production, ongoing oxidative stress, and superoxide dismutase 3 (SOD3) levels in the airways. The study aimed to investigate the effect of the Nephrolepis exaltata - Hibiscus rosa-sinensis (NE-HRS) combination herbal mask on the airways, as measured by ROS and SOD3 levels in the nasal wash of textile industry workers.MethodsThis was a pre- and post-test randomized controlled trial, consisting of 30 subjects with ³5-year working time, conducted for eight weeks and monitored every ten days. Subjects were randomized into 3 groups, regular surgical mask group (n=10), NE-HRS combination herbal mask group (n=10) and factory mask group (n=10). SOD3 and ROS levels were determined using ELISA. Data were analyzed with One-way ANOVA and multiple comparison tests.Results ROS levels decreased significantly in all groups (p=0.004). Regular surgical masks decreased ROS levels by 67.90 ± 50.66 pg/mL, NE-HRS combination herbal masks by 49.91 ± 45.06 pg/mL, and factory masks by 193.96 ± 128.36 pg/ml. SOD3 levels also decreased but not significantly (p=0.053). Differences in ROS levels between surgical mask and NE-HRS combination herbal mask was not significant (p=0.796). ConclusionHerbal masks laminated with NE-HRS combination significantly reduced ROS levels among textile industry workers. NE-HRS combination herbal masks have a similar protective effect to the regular surgical mask.

Neither Excessive Nitric Oxide Accumulation nor Acute Hyperglycemia Affects the N-Acetylaspartate Network in Wistar Rat Brain Cells.

The N-acetylaspartate network begins in neurons with N-acetylaspartate production catalyzed by aspartate N-acetyltransferase from acetyl-CoA and aspartate. Clinical studies reported a significant depletion in N-acetylaspartate brain level in type 1 diabetic patients. The main goal of this study was to establish the impact of either hyperglycemia or oxidative stress on the N-acetylaspartate network. For the in vitro part of the study, embryonic rat primary neurons were treated by using a nitric oxide generator for 24 h followed by 6 days of post-treatment culture, while the neural stem cells were cultured in media with 25–75 mM glucose. For the in vivo part, male adult Wistar rats were injected with streptozotocin (65 mg/kg body weight, ip) to induce hyperglycemia (diabetes model) and euthanized 2 or 8 weeks later. Finally, the biochemical profile, NAT8L protein/Nat8l mRNA levels and enzymatic activity were analyzed. Ongoing oxidative stress processes significantly affected energy metabolism and cholinergic neurotransmission. However, the applied factors did not affect the N-acetylaspartate network. This study shows that reduced N-acetylaspartate level in type 1 diabetes is not related to oxidative stress and that does not trigger N-acetylaspartate network fragility. To reveal why N-acetylaspartate is reduced in this pathology, other processes should be considered.

Altered Cerebrospinal Fluid (CSF) in Children with Ataxia Telangiectasia

Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia and immunodeficiency. The neurological decline may be caused by multiple factors of which ongoing inflammation and oxidative stress may play a dominant role. The objective of the present investigation was to determine cerebrospinal fluid (CSF) proteins and possible low-grade inflammation and its relation to age and neurological deterioration. In the present study, we investigated 15 patients with A-T from 2 to 16 years. Our investigation included blood and CSF tests, clinical neurological examination, A-T score, and MRI findings. The albumin ratio (AR) was analyzed to determine the blood–brain-barrier function. In addition, inflammatory cytokines (IL-1α, IL-6, IL-8, IL-12 p40, IL-17A, IFN-γ, TNF-α) were measured by the multiplex cytometric bead array. We compared the results with those from an age-matched control group. Three of the A-T patients were analyzed separately (one after resection of a cerebral meningioma, one after radiation and chemotherapy due to leukemia, one after stem cell transplantation). Patient had significantly more moderate and severe side effects due to CSF puncture (vomiting, headache, need for anti-emetic drugs) compared with healthy controls. Total protein, albumin, and the AR increased with age indicating a disturbed blood barrier function in older children. There were no differences for cytokines in serum and CSF with the exception of IL-2, which was significantly higher in controls in serum. The AR is significantly altered in A-T patients, but low-grade inflammation is not detectable in serum and CSF.

Transcriptional and free radical responses to LVAD therapy

BackgroundMyocardial recovery with Left ventricular assistant device (LVAD) therapy is dichotomous with some patients obtaining remission from end-stage heart failure whereas most require transplantation or remain on pump support long term. Our goal was to determine transcriptional and free radical responses to LVAD treatment.MethodsTissues were collected from patients before and after LVAD placement in non-ischemic dilated cardiomyopathy patients (n = 14) along with controls (n = 3). RNA sequencing (RNASeq) analysis quantified transcriptional profiles by using a custom targeted panel of heart failure related genes on the PGM sequencer. The differential expression analysis between groups was conducted using edgeR (Empirical analysis of digital gene expression data in R) package in Bioconductor. Ingenuity Pathway Analysis (IPA) was carried out on differentially expressed genes to understand the biological pathways involved. Electron Paramagnetic Resonance (EPR) Spectroscopy was utilized to measure levels of free radicals in whole blood collected pre- and post-LVAD implantation (n = 16).ResultsThirty-five genes were differentially expressed in pre-LVAD failing hearts compared to controls. In response to LVAD therapy, only Pyruvate dehydrogenase kinase 4 (PDK4) and period circadian protein homolog 1 (PER1) were altered with 34 heart failure related genes still differentially expressed post-LVAD compared to controls. IPA showed that DNA methylation-related genes were upregulated in both pre- and post-LVAD and was persistent with a Z-score of 2.00 and 2.36 for DNA Methyltransferase 3A (DNMT3A) and DNA methyltransferase 3B (DNMT3B), respectively. Inhibition of micro RNA21 (mir21) was also significant on pathway analysis in the post-LVAD population with a Z-score of − 2.00. Levels of free radicals in blood of pre- and post-LVAD patients did not change significantly.ConclusionLVAD therapy does not reverse many of the transcriptional changes associated with heart failure. Persistent changes in gene expression may be related to ongoing oxidative stress, continued DNA methylation, or changes in metabolism. PDK4 is a key regulator of glucose metabolism and its increased expression by LVAD therapy inhibited pyruvate metabolism.

SUN-309 PLASMA CADMIUM AND RISK OF LATE GRAFT FAILURE AND KIDNEY FUNCTION DECLINE IN KIDNEY TRANSPLANT RECIPIENTS

The kidney is the most sensitive organ to cadmium-induced toxicity, particularly in conditions of long-term ongoing oxidative stress. We hypothesized that, in kidney transplant recipients (KTR), the nephrotoxic exposure to cadmium represents an overlooked hazard for preserved graft functioning. We performed a longitudinal cohort study of 672 adult KTR with a functioning graft ≥1 year, recruited at a university setting (2008-2011). A Kaplan-Meier curve, log-rank test, and multivariable-adjusted Cox proportional-hazards regression analyses were performed to assess the prospective association of plasma cadmium with the primary endpoint death-censored graft failure (defined as restart of dialysis or re-transplantation) and the secondary endpoint kidney function decline (defined as doubling of serum creatinine or graft failure). Subgroup prospective analyses were performed according to significant effect-modifiers. Median plasma cadmium was 58 (IQR, 43‒75) ng/L. During 4.9 (IQR, 3.4‒5.5) years of follow-up, 78 KTR developed graft failure (13, 26, and 39 events across tertiles of cadmium; P<0.001). Plasma cadmium associated with increased risk of graft failure (HR 1.96, 95% CI 1.56‒2.47 per 2log ng/L; P<0.001), particularly among patients with abnormal liver enzyme levels (HR 2.62, 95% CI 1.73‒3.95 per 2log ng/L; P<0.001). A dose-response relationship was observed, with a HR of 2.67 (95% CI 1.36‒5.26 per 2log ng/L; P<0.001) and 4.31 (95% CI 2.25‒8.22 per 2log ng/L; P<0.001) for patients in tertile 2 and 3 of plasma cadmium distribution, respectively. Our findings were independent of adjustment for donor, recipient, and transplant characteristics, robust in sensitivity analyses without outliers, and consistent over the secondary end-point kidney function decline. A seemingly significant association of cadmium with all-cause mortality was lost in graft failure-censored analyses.Table 1Association of plasma cadmium with risk of death-censored graft failure (nevents=78) and kidney function decline (nevents=95)ModelsCadmium per 2log (ng/L)HR (95% CI)P valueDeath-Censored Graft FailureCrude1.89 (1.47‒2.43)<0.001Model 11.96 (1.56‒2.47)<0.001Model 21.96 (1.40‒2.75)<0.001Model 31.96 (1.40‒2.76)<0.001Model 42.01 (1.45‒2.79)<0.001Kidney Function DeclineCrude1.66 (1.29‒2.15)<0.001Model 11.78 (1.41‒2.26)<0.001Model 21.77 (1.28‒2.44)0.001Model 31.75 (1.27‒2.42)0.001Model 41.75 (1.27‒2.42)<0.001 Open table in a new tab Multivariable model 1 was adjusted for age and sex. Subsequently, additive adjustment was performed for eGFR, proteinuria, primary kidney disease, transplant vintage, acute rejection, cold ischemia time, human leukocyte antigens mismatches, and deceased donor status (model 2); body mass index, systolic blood pressure, blood glucose, and presence of diabetes (model 3); and, smoking and alcohol use (model 4). View Large Image Figure ViewerDownload Hi-res image Download (PPT) In KTR, plasma cadmium is independently associated with increased risk of kidney function decline and late graft failure. Cadmium-targeted interventions may represent novel risk-management strategies to decrease the burden of late kidney graft failure.