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Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease.
Gritter, M, Vogt, L, Yeung, SMH, Wouda, RD, Ramakers, CRB, de Borst, MH, Rotmans, JI, Hoorn, EJ
Nephron. 2018;(1):48-57
Abstract
BACKGROUND/AIMS: Dietary potassium (K+) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K+ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the "K+ in CKD" study. METHODS The K+ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15-44 mL/min/1.73 m2), and an average eGFR decline > 2 mL/min/1.73 m2/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K+ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K+ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K+ concentrations. CONCLUSION The K+ in CKD study will demonstrate if K+ sup-plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects.
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2.
Protective Mechanisms of Butyrate on Inflammatory Bowel Disease.
Silva, JPB, Navegantes-Lima, KC, Oliveira, ALB, Rodrigues, DVS, Gaspar, SLF, Monteiro, VVS, Moura, DP, Monteiro, MC
Current pharmaceutical design. 2018;(35):4154-4166
Abstract
Inflammatory bowel disease (IBD) is a multifactorial chronic disease, commonly associated with alteration in the composition and function of gut microbiota. This process can lead to a decreased production of short chain fatty acids (SCFAs) by the gut microbiota, mainly butyrate, which is an important immunomodulatory molecule in the intestine. Butyrogenic bacteria normally produces butyrate through carbohydrate fermentation or amino acids degradation pathways. This molecule plays an important protective role in intestinal homeostasis acting in both adaptive immunity and innate immunity. This review summarizes the current knowledge about the role of butyrate on the development of IBD and the protective mechanisms of this metabolite on the intestinal mucosa and the whole body, as reported by in vitro and in vivo studies. Thus, butyrate can regulate the activation of regulatory T cells, increasing the acetylation of histones and decreasing the activation of NF-κB. In addition, it can also stimulate the mucus production from epithelial cells and the rearrangement of tight junction proteins.
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N-Acetylcysteine protects human bronchi by modulating the release of neurokinin A in an ex vivo model of COPD exacerbation.
Calzetta, L, Rogliani, P, Facciolo, F, Rinaldi, B, Cazzola, M, Matera, MG
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018;:1-8
Abstract
AIMS: N-Acetylcysteine (NAC) reduces the risk of exacerbation of chronic obstructive pulmonary disease (COPD). Although NAC also has anti-inflammatory activity, the detailed mechanism leading to its protective role remains to be elucidated. We tested the impact of NAC against the effects of lipopolysaccharide (LPS) in an ex vivo model of COPD exacerbation, and investigated the role of neurokinin A (NKA) in this context. MAIN METHODS Isolated airways from COPD patients were incubated overnight with LPS (100 ng/ml). NAC was tested at concentrations resembling the plasma levels elicited by oral administration of NAC at 200 mg/day (very low dose), 600 mg/day (low dose) and 1.200 mg/day (high dose). KEY FINDINGS NAC at high concentrations normalized the peroxidase activity, H2O2, malondialdehyde (MDA), nitric oxide, glutathione (GSH), total antioxidant capacity (TAC), and interleukin 6 (IL-6) (overall change 34.32% ± 4.22%, P < 0.05 vs. LPS-treated). NAC at low concentrations modulated peroxidase activity, H2O2, MDA, GSH, TAC, and IL-6 (overall change 34.88% ± 7.39%, P < 0.05 vs. LPS-treated). NAC at very-low concentrations was effective on peroxidase activity, H2O2, GSH, and IL-6 (overall change 35.05 ± 7.71%, P < 0.05 vs. LPS-treated). Binary logistic regression analysis indicated that the modulatory effect of NAC on NKA levels was associated with a reduction of pro-oxidant factors and IL-6, and selectively blocking the NK2 receptor abolished such an association. SIGNIFICANCE This study demonstrates that, along with its well-known antioxidant activity, the protective effect of NAC against the detrimental effect of LPS is due to the modulation of NKA and IL-6 levels.
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Prevention of progression in Parkinson's disease.
Aaseth, J, Dusek, P, Roos, PM
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. 2018;(5):737-747
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Abstract
Environmental influences affecting genetically susceptible individuals seem to contribute significantly to the development of Parkinson's disease (PD). Xenobiotic exposure including transitional metal deposition into vulnerable CNS regions appears to interact with PD genes. Such exposure together with mitochondrial dysfunction evokes a destructive cascade of biochemical events, including oxidative stress and degeneration of the sensitive dopamine (DA) production system in the basal ganglia. Recent research indicates that the substantia nigra degeneration can be decelerated by treatment with iron binding compounds such as deferiprone. Interestingly compounds known to decrease PD risk including caffeine, niacin, nicotine and salbutamol also possess iron binding properties. Adequate function of antioxidative mechanisms in the vulnerable brain cells can be restored by acetylcysteine supplementation to normalize intracellular glutathione activity. Other preventive measures to reduce deterioration of dopaminergic neurons may involve life-style changes such as intake of natural antioxidants and physical exercise. Further research is recommended to identify therapeutic targets of the proposed interventions, in particular protection of the DA biosynthesis by oxygen radical scavengers and iron binding agents.
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A Systematic Review on the Protective Effect of N-Acetyl Cysteine Against Diabetes-Associated Cardiovascular Complications.
Dludla, PV, Dias, SC, Obonye, N, Johnson, R, Louw, J, Nkambule, BB
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018;(4):283-298
Abstract
INTRODUCTION Heart failure is the leading cause of death in patients with diabetes. No treatment currently exists to specifically protect these patients at risk of developing cardiovascular complications. Accelerated oxidative stress-induced tissue damage due to persistent hyperglycemia is one of the major factors implicated in deteriorated cardiac function within a diabetic state. N-acetyl cysteine (NAC), through its enhanced capacity to endogenously synthesize glutathione, a potent antioxidant, has displayed abundant health-promoting properties and has a favorable safety profile. OBJECTIVE An increasing number of experimental studies have reported on the strong ameliorative properties of NAC. We systematically reviewed the data on the cardioprotective potential of this compound to provide an informative summary. METHODS Two independent reviewers systematically searched major databases, including PubMed, Cochrane Library, Google scholar, and Embase for available studies reporting on the ameliorative effects of NAC as a monotherapy or in combination with other therapies against diabetes-associated cardiovascular complications. We used the ARRIVE and JBI appraisal guidelines to assess the quality of individual studies included in the review. A meta-analysis could not be performed because the included studies were heterogeneous and data from randomized clinical trials were unavailable. RESULTS Most studies support the ameliorative potential of NAC against a number of diabetes-associated complications, including oxidative stress. We discuss future prospects, such as identification of additional molecular mechanisms implicated in diabetes-induced cardiac damage, and highlight limitations, such as insufficient studies reporting on the comparative effect of NAC with common glucose-lowering therapies. Information on the comparative analysis of NAC, in terms of dose selection, administration mode, and its effect on different cardiovascular-related markers is important for translation into clinical studies. CONCLUSIONS NAC exhibits strong potential for the protection of the diabetic heart at risk of myocardial infarction through inhibition of oxidative stress. The effect of NAC in preventing both ischemia and non-ischemic-associated cardiac damage is also of interest. Consistency in dose selection in most studies reported remains important in dose translation for clinical relevance.
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Perioperative renal protection.
Canet, E, Bellomo, R
Current opinion in critical care. 2018;(6):568-574
Abstract
PURPOSE OF REVIEW The present article reviews the recent literature on the main aspects of perioperative acute kidney injury (AKI). RECENT FINDINGS AKI occurs in 1 in every 10 surgical patients, with cardiac, orthopedic, and major abdominal surgeries being the procedures associated with the highest risk. Overall, complex operations, bleeding, and hemodynamic instability are the most consistent procedure-related risk factors for AKI. AKI increases hospital stay, mortality, and chronic kidney disease, gradually with severity. Furthermore, delayed renal recovery negatively impacts on patients' outcomes. Cell cycle arrest biomarkers seem promising to identify high-risk patients who may benefit from the bundles recommended by the Kidney Disease: Improving Global Outcomes guidelines. Hemodynamic management using protocol-based administration of fluids and vasopressors helps reducing AKI. Recent studies have highlighted the benefit of personalizing the blood pressure target according to the patient's resting reference, and avoiding both hypovolemia and fluid overload. Preliminary research has reported encouraging renoprotective effects of angiotensin II and nitric oxide, which need to be confirmed. Moreover, urinary oxygenation monitoring appears feasible and a fair predictor of postoperative AKI. SUMMARY AKI remains a frequent and severe postoperative complication. A personalizedmulticomponent approach might help reducing the risk of AKI and improving patients' outcomes.
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Protective effect of nicorandil on myocardial injury following percutaneous coronary intervention in older patients with stable coronary artery disease: Secondary analysis of a randomized, controlled trial (RINC).
Kawakita, N, Ejiri, K, Miyoshi, T, Kohno, K, Nakahama, M, Doi, M, Munemasa, M, Murakami, M, Nakamura, K, Ito, H, et al
PloS one. 2018;(4):e0194623
Abstract
BACKGROUND Our previous study examined an effect of remote ischemic preconditioning (RIPC) or intravenous nicorandil on reduction of periprocedural myocardial injury (pMI) following percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD). We further investigated the effect of RIPC or nicorandil on pMI in older patients. METHODS Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control, intravenous nicorandil, or upper-limb RIPC groups. This substudy analyzed patients aged >65 years (n = 282) from the principal cohort. The primary outcome was the incidence of pMI following PCI. We defined pMI as an elevated level of high-sensitive cardiac troponin T or creatine kinase myocardial band 12 or 24 hours after PCI. RESULTS We found that pMI following PCI was significantly reduced in the nicorandil group compared with the control group (37.2% vs. 53.7%, multiplicity-adjusted p = 0.046), but not in the RIPC group compared with the control group (43.0% vs. 53.7%, multiplicity-adjusted p = 0.245). The adjusted odds ratios (95% confidence interval) for pMI in the RIPC and nicorandil groups versus the control group were 0.63 (0.34 to 1.16) and 0.51 (0.27 to 0.96), respectively. CONCLUSION Intravenous nicorandil significantly reduces pMI following PCI in a subgroup of older patients with stable CAD. Phase 3 trials are required to validate our results. TRIAL REGISTRATION UMIN Clinical Trials Registry UMIN000005607.
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Comparative studies on the hypolipidemic, antioxidant and hepatoprotective activities of catechin-enriched green and oolong tea in a double-blind clinical trial.
Venkatakrishnan, K, Chiu, HF, Cheng, JC, Chang, YH, Lu, YY, Han, YC, Shen, YC, Tsai, KS, Wang, CK
Food & function. 2018;(2):1205-1213
Abstract
This study aimed to compare the beneficial effect of catechin-enriched green tea and oolong tea on mildly hypercholesterolemic subjects. Sixty mildly hypercholesterolemic subjects (180-220 mg dL-1) were enrolled and divided into three groups as catechin-enriched green tea (CEGT), catechin-enriched oolong tea (CEOT) or placebo. The subjects were instructed to drink 2 × 300 mL of CEGT (780.6 mg of catechin), CEOT (640.4 mg of catechin) or placebo beverage for 12 weeks. Drinking CEGT and CEOT significantly decreased (p < 0.05) the body weight, fat, and BMI, lipid peroxidation as well as lipid profile (TC, LDL-c, HDL-c, and TG). Also, intervention with CEGT and CEOT significantly improved (p < 0.05) the oxidative indices (TEAC and GSH) and antioxidant enzymes (SOD, CAT, GPx, and GR). Moreover, ultrasound examination endorsed the hepatoprotective activity of CEGT and CEOT by reverting mild fatty liver to the normal hepatic condition because of antioxidant and hypolipidemic activities. To summarize, both CEGT and CEOT showed similar antioxidant and hepatoprotective activities. However, CEOT displayed superior lipid-lowering activity compared to CEGT or placebo, and hence it could be used to amend the wellness condition of mildly hypercholesterolemic subjects.
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[Role of NF-κB in the protective effects of L-carnitine against oxidative injury in hepatocytes].
Li, J, Li, N, Dong, X, Yang, J, Luan, H
Wei sheng yan jiu = Journal of hygiene research. 2017;(4):533-537
Abstract
OBJECTIVE To investigate whether the protective effects of L-carnitine( LC) against hydrogen peroxide( H_2O_2)-induced injury in hepatocytes were related to nuclear factor-kappa B( NF-κB). METHODS CCK-8 and lactate dehydrogenase( LDH)methods were used to detect the influences of NF-κB inhibitors on the cell damage induced by H_2O_2. The effects of LC on the NF-κB expressions in H_2O_2-treated HL7702 cells were determined by Western blot. The translocation of NF-κB was observed by immunofluorescence staining. Electrophoretic mobility shift assay( EMSA) was used to evaluate NF-κB-DNA binding activities. RESULTS Compared with H_2O_2 group, NF-κB inhibitor groups showed increased cell activities and decreased LDH release( P < 0. 05, P < 0. 01). Western blot and immunofluorescence staining both demonstrated that the nucleus NF-κB expressions elevated in H_2O_2 group and LC had inhibitory effect on them( P < 0. 01). LC also inhibited H_2O_2-induced increase of NF-κB-DNA binding activity inHL7702 cells. CONCLUSION LC protects against H_2O_2-induced injury in HL7702 cells by inhibiting NF-κB activities.
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Zinc Protects Oxidative Stress-Induced RPE Death by Reducing Mitochondrial Damage and Preventing Lysosome Rupture.
Rajapakse, D, Curtis, T, Chen, M, Xu, H
Oxidative medicine and cellular longevity. 2017;:6926485
Abstract
Zinc deficiency is known to increase the risk of the development of age-related macular degeneration (AMD), although the underlying mechanism remains poorly defined. In this study, we investigated the effect of zinc on retinal pigment epithelium (RPE) survival and function under oxidative conditions. Zinc level was 5.4 μM in normal culture conditions (DMEM/F12 with 10% FCS) and 1.5 μM in serum-free medium (DMEM/F12). Under serum-free culture conditions, the treatment of RPE cells with oxidized photoreceptor outer segment (oxPOS) significantly increased intracellular ROS production, reduced ATP production, and promoted RPE death compared to oxPOS-treated RPE under normal culture condition. Serum deprivation also reduced RPE phagocytosis of oxPOS and exacerbated oxidative insult-induced cathepsin B release from lysosome, an indicator of lysosome rupture. The addition of zinc in the serum-free culture system dose dependently reduced ROS production, recovered ATP production, and reduced oxidative stress- (oxPOS- or 4-HNE) induced cell death. Zinc supplementation also reduced oxidative stress-mediated cathepsin B release in RPE cells. Our results suggest that zinc deficiency sensitizes RPE cells to oxidative damage, and zinc supplementation protects RPE cells from oxidative stress-induced death by improving mitochondrial function and preventing lysosome rupture.