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1.
Probucol Protects Neuronal Cells Against Peroxide-Induced Damage and Directly Activates Glutathione Peroxidase-1.
Santos, DB, Colle, D, Moreira, ELG, Santos, AA, Hort, MA, Santos, K, Oses, JP, Razzera, G, Farina, M
Molecular neurobiology. 2020;(8):3245-3257
Abstract
Experimental evidence has shown that probucol, a hypocholesterolemic agent, is also able to increase glutathione peroxidase (GPx) activity. However, there is a lack of knowledge about the mechanism(s) involved in this event. In this study, in vitro experiments with purified GPx1 from bovine erythrocytes and cultured SH-SY5Y neuroblastoma cells, as well as in silico studies with GPx1, were performed in order to elucidate mechanisms mediating the stimulatory effect of probucol on GPx activity and to investigate the relevance of this event in terms of susceptibility against peroxide-induced cytotoxicity. In vitro experiments with purified GPx1 showed a direct stimulatory effect of probucol on the activity of GPx1, which was related to an increase in Vmax with no changes in KM. Probucol also increased GPx activity in cultured SH-SY5Y neuroblastoma cells, while the levels of GPx1 expression were not changed, corroborating the results found with the purified enzyme. In addition, probucol rendered SH-SY5Y cells more resistant to hydroperoxide-induced cytotoxicity, and this event was abolished in GPx1 knocked-down cells. In silico studies with GPx1 pointed to a potential binding site for probucol at the close vicinity of the GSH pocket. Collectively, the results presented herein indicate that GPx1 plays a central role in the probucol-induced protective effects against peroxide toxicity. This highlights a novel target (GPx1) and a new mechanism of action (direct activation) for an "old drug." The relevance of such results for in vivo conditions deserves further investigation.
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Silymarin and Cancer: A Dual Strategy in Both in Chemoprevention and Chemosensitivity.
Delmas, D, Xiao, J, Vejux, A, Aires, V
Molecules (Basel, Switzerland). 2020;(9)
Abstract
Silymarin extracted from milk thistle consisting of flavonolignan silybin has shown chemopreventive and chemosensitizing activity against various cancers. The present review summarizes the current knowledge on the potential targets of silymarin against various cancers. Silymarin may play on the system of xenobiotics, metabolizing enzymes (phase I and phase II) to protect normal cells against various toxic molecules or to protect against deleterious effects of chemotherapeutic agents on normal cells. Furthermore, silymarin and its main bioactive compounds inhibit organic anion transporters (OAT) and ATP-binding cassettes (ABC) transporters, thus contributing to counteracting potential chemoresistance. Silymarin and its derivatives play a double role, namely, limiting the progression of cancer cells through different phases of the cycle-thus forcing them to evolve towards a process of cell death-and accumulating cancer cells in a phase of the cell cycle-thus making it possible to target a greater number of tumor cells with a specific anticancer agent. Silymarin exerts a chemopreventive effect by inducing intrinsic and extrinsic pathways and reactivating cell death pathways by modulation of the ratio of proapoptotic/antiapoptotic proteins and synergizing with agonists of death domains receptors. In summary, we highlight how silymarin may act as a chemopreventive agent and a chemosensitizer through multiple pathways.
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The Role of Glycosaminoglycans in Protection from Neonatal Necrotizing Enterocolitis: A Narrative Review.
Burge, K, Bergner, E, Gunasekaran, A, Eckert, J, Chaaban, H
Nutrients. 2020;(2)
Abstract
Necrotizing enterocolitis, a potentially fatal intestinal inflammatory disorder affecting primarily premature infants, is a significant cause of morbidity and mortality in neonates. While the etiology of the disease is, as yet, unknown, a number of risk factors for the development of necrotizing enterocolitis have been identified. One such risk factor, formula feeding, has been shown to contribute to both increased incidence and severity of the disease. The protective influences afforded by breastfeeding are likely attributable to the unique composition of human milk, an extremely potent, biologically active fluid. This review brings together knowledge on the pathogenesis of necrotizing enterocolitis and current thinking on the instrumental role of one of the more prominent classes of bioactive components in human breast milk, glycosaminoglycans.
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Additively protective effects of vitamin D and calcium against colorectal adenoma incidence, malignant transformation and progression: A systematic review and meta-analysis.
Huang, D, Lei, S, Wu, Y, Weng, M, Zhou, Y, Xu, J, Xia, D, Xu, E, Lai, M, Zhang, H
Clinical nutrition (Edinburgh, Scotland). 2020;(8):2525-2538
Abstract
BACKGROUND Colorectal cancer (CRC) exhibits a linear progression from normal colonic epithelium, adenoma initiation, carcinoma transformation and even to metastasis. Diet changes might influence carcinogenesis and prognosis. We aimed to determine the effects of vitamin D and calcium on colorectal adenoma incidence, malignancy development and prognosis. METHODS Systematic literature searches (PubMed, Embase, and Cochrane Library databases) and hand searches were performed by September 30, 2019. A random-effects model was adopted to pool relative ratios (RRs) for colorectal tumour incidence or hazard ratios (HRs) for CRC mortality. Stratified analyses were performed by gender, tumour location, calcium intake level and ethnic group. RESULTS Total 854,195 cases from 166 studies were included. The colorectal adenoma incidence was inversely correlated with the circulating 25-hydroxyvitamin D [25(OH)D] level (RR: 0.80, 95% CI: 0.71-0.89), vitamin D intake (RR: 0.87, 95% CI: 0.82-0.92) and calcium intake (RR: 0.86, 95% CI: 0.81-0.91). The CRC incidence was decreased by circulating 25(OH)D (RR: 0.67, 95% CI: 0.59-0.77), vitamin D intake (RR: 0.85, 95% CI: 0.78-0.93) and calcium intake (RR: 0.75, 95% CI: 0.70-0.79). High-level circulating 25(OH)D triggered better overall survival (HR: 0.67, 95% CI: 0.57-0.79) and CRC-specific survival (HR: 0.63, 95% CI: 0.53-0.74). Stratified analyses showed that vitamin D and calcium significantly suppressed colorectal tumour incidence among women. Left-sided CRC risk was reversely related to circulating 25(OH)D (RR: 0.60, 95% CI: 0.41-0.88) and vitamin D intake (RR: 0.73, 95% CI: 0.57-0.93). Circulating 25(OH)D decreased colorectal adenoma (RR: 0.63, 95% CI: 0.48-0.82) and CRC (RR: 0.69, 95% CI: 0.56-0.86) risk in populations with higher calcium intake. European and American populations benefited more from vitamin D intake against colorectal tumour. A significant dose-response relationship was observed between intake of vitamin D or calcium and colorectal tumour incidence. CONCLUSIONS Vitamin D and calcium play additively chemopreventive roles in colorectal adenoma incidence, malignant transformation and progression, especially for women and left-sided CRC patients.
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The potential protective roles of zinc, selenium and glutathione on hypoxia-induced TRPM2 channel activation in transfected HEK293 cells.
Duzgun Ergun, D, Dursun, S, Pastaci Ozsobaci, N, Hatırnaz Ng, O, Naziroglu, M, Ozcelik, D
Journal of receptor and signal transduction research. 2020;(6):521-530
Abstract
Hypoxia induces cell death through excessive production of reactive oxygen species (ROS) and calcium (Ca2+) influx in cells and TRPM2 cation channel is activated by oxidative stress. Zinc (Zn), selenium (Se), and glutathione (GSH) have antioxidant properties in several cells and hypoxia-induced TRPM2 channel activity, ROS and cell death may be inhibited by the Zn, Se, and GSH treatments. We investigated effects of Zn, Se, and GSH on lipid peroxidation (LPO), cell cytotoxicity and death through inhibition of TRPM2 channel activity in transfected HEK293 cells exposed to hypoxia defined as oxygen deficiency.We induced four groups as normoxia 30 and 60 min evaluated as control groups, hypoxia 30 and 60 min in the HEK293 cells. The cells were separately pre-incubated with extracellular Zn (100 µM), Se (150 nM) and GSH (5 mM). Cytotoxicity was evaluated by lactate dehydrogenase (LDH) release and the LDH and LPO levels were significantly higher in the hypoxia-30 and 60 min-exposed cells according to normoxia 30 and 60 min groups. Furthermore, we found that the LPO and LDH were decreased in the hypoxia-exposed cells after being treated with Zn, Se, and GSH according to the hypoxia groups. Compared to the normoxia groups, the current densities of TRPM2 channel were increased in the hypoxia-exposed cells by the hypoxia applications, while the same values were decreased in the treatment of Zn, Se, and GSH according to hypoxia group. In conclusion, hypoxia-induced TRPM2 channel activity, ROS and cell death were recovered by the Se, Zn and GSH treatments.
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Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study.
Meador, KJ, Pennell, PB, May, RC, Brown, CA, Baker, G, Bromley, R, Loring, DW, Cohen, MJ, ,
Neurology. 2020;(7):e729-e740
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Abstract
OBJECTIVE Emerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. METHODS The NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age). RESULTS Periconceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function-Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age. CONCLUSIONS Use of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development. CLINICALTRIALSGOV IDENTIFIER NCT00021866.
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Uraemic toxin-induced inflammation and oxidative stress in human endothelial cells: protective effect of polyphenol-rich extract from açaí.
Monteiro, EB, Soares, EDR, Trindade, PL, de Bem, GF, Resende, AC, Passos, MMCDF, Soulage, CO, Daleprane, JB
Experimental physiology. 2020;(3):542-551
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Abstract
NEW FINDINGS What is the central question of this study? Does a polyphenol-rich extract from açaí have a potential role in preventing uraemic toxin-induced endothelial cell dysfunction? What is the main finding and its importance? Polyphenols from açaí prevented cell death, restored migratory capacity, protected from inflammation and contributed to the restoration of the antioxidant response in endothelial cells exposed to uraemic toxins. The protective role of açaí against toxic effects exerted by uraemic toxins presents a potential new therapeutic target in endothelial cells. ABSTRACT In chronic kidney disease (CKD), progressive loss of kidney function results in the accumulation of protein-bound uraemic toxins such as p-cresyl sulfate (pCS) and indoxyl sulfate (IS). Among strategies to ameliorate the harmful actions of uraemic toxins, phenolic compounds have been extensively studied. The main goal of this work was to evaluate the antioxidant and anti-inflammatory actions of phenolic-rich açaí seed extract (ASE) in response to endothelial dysfunction induced by IS and pCS, in human umbilical vein endothelial cells (HUVECs). Cells were treated with ASE (10 µg ml-1 ) in the presence or absence of IS (61 µg ml-1 ) and pCS (40 µg ml-1 ). Cell viability, cell death, cell migratory capacity and inflammatory biomarker expression were evaluated. Cellular antioxidant response was measured through the activity and expression of antioxidant enzymes, and oxidative damage was evaluated. IS and pCS lowered cell viability, triggered cell death and lowered the migratory capacity in endothelial cells (P < 0.05). ASE prevented cell death and restored the migratory capacity in cells exposed to IS. Both toxins up-regulated pro-inflammatory cytokine expression, and ASE was able to beneficially counteract this effect. Tumour necrosis factor-α secretion was greater in uraemic toxin-treated cells and ASE reversed this phenomenon in cells treated with both toxins concomitantly (P < 0.05). With regard to the antioxidant response, superoxide dismutase expression was strikingly lower in cells treated with both toxins, and ASE inhibited this harmful effect (P < 0.05). From the results, we conclude that ASE exerted protective effects on inflammation and oxidative stress caused by uraemic toxins (particularly by IS) in human endothelial cells.
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Predictive Factors for Efficacy of AST-120 Treatment in Diabetic Nephropathy: a Prospective Single-Arm, Open-Label, Multi-Center Study.
Hwang, YC, Kim, SW, Hur, KY, Cha, BS, Kim, IJ, Park, TS, Baik, SH, Yoon, KH, Lee, KW, Lee, IK, et al
Journal of Korean medical science. 2019;(15):e117
Abstract
BACKGROUND Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μol/L to 1.91 ± 0.72 μol/L; P = 0.002) but not in the non-responder group. CONCLUSION The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.
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Adequate nephroprotection reduces renal complications after hyperthermic intrathoracic chemotherapy.
Markowiak, T, Kerner, N, Neu, R, Potzger, T, Großer, C, Zeman, F, Hofmann, HS, Ried, M
Journal of surgical oncology. 2019;(7):1220-1226
Abstract
BACKGROUND AND OBJECTIVES Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern. METHODS This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018. RESULTS A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m2 BSA n = 36; 175 mg/m2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%). CONCLUSIONS Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies.
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Meta-analysis on allopurinol preventive intervention on contrast-induced acute kidney injury with random controlled trials: PRISMA.
Ma, G, Wang, G, Xiao, D, Teng, W, Hui, X, Ma, G
Medicine. 2019;(25):e15962
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Abstract
OBJECTIVES The objective of this meta-analysis on randomized controlled trials is to evaluate whether the administration of allopurinol with or without hydration will reduce contrast-induced acute kidney injury (CI-AKI) in patients undergoing contrast exposure. BACKGROUND The efficacy of allopurinol in the prevention of CI-AKI after cardiac catheterization and percutaneous coronary intervention (PCI) is significantly related to the heterogeneous results. METHODS Two investigators independently searched MEDLINE, EMBASE, the Cochrane Controlled Trials Registry, the China Wanfang Data, the China Biological Medicine Database and the China National Knowledge Infrastructure (CNKI) databases for randomized controlled trials (RCTs) comparing allopurinol with placebo or no allopurinol for the prevention of CI-AKI in patients from their inception to July 31, 2018. The primary outcome was the incidence of CI-AKI, and the secondary outcomes were the differences of serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), and estimated glomerular filtration rate (eGFR) levels between groups after contrast media exposure. We used fixed-effects or random-effects models according to I statistics. The meta-analytic procedures were completed by Review Manager, version 5.3. ACHIEVEMENTS Eight random controlled trials with 1141 patients were included for this analysis. Compared with the control, allopurinol was associated with a reduced risk of CI-AKI (Relatives Risk (RR) 0.39, 95% confidence interval [CI] 0.20,0.74, P = .004) and only a intend for decrease a post-procedure uric acid levels compared with the controlled ones at 48 hours (standardized mean difference (SMD) -0.72, 95% CI -1.44, 0.01, P = .05). But the difference of post-procedure uric acid levels was not statistically significant in allopurinol groups compared with controlled groups. There were lower post-procedure Scr and BUN levels in allopurinol groups than those in controlled groups (SMD -0.50, 95% CI -0.79,-0.21, P = .0009; SMD -0.40, 95% CI -0.60,-0.20, P < .0001;respectively). There were higher post-procedure eGFR levels in allopurinol groups than those in controlled groups (SMD 0.65, 95% CI 0.48, 0.83, P < .0001). CONCLUSION The main findings of this meta-analysis are focus on allopurinol may cause reduces in the incidence of CI-AKI in patients undergoing interventional coronary procedures. Further researches are still required for confirmation.