scholarly journals Renoprotective Effects of a New Free Radical Scavenger, XH-003, against Cisplatin-Induced Nephrotoxicity

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Ya-Hong Liu ◽  
Kui Li ◽  
Hong-Qi Tian
Keyword(s):  
Side Effects ◽  
Organic Cation Transporter ◽  
Renal Tissue ◽  
Free Radical Scavenger ◽  
Mechanistic Study ◽  
Radical Scavenger ◽  
Protective Agent ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway

Acute renal injury has an incidence of 25%–30% in patients with tumors who are treated with cisplatin and in patients for whom no specific drugs are available for treatment. Amifostine is the only FDA-approved chemoprotective drug; however, its clinical application is limited because of side effects. The small-molecule antioxidant XH-003, an acute radiation syndrome- (ARS-) protective drug independently developed in our laboratory, with 100% intellectual property rights, overcomes the side effects of amifostine but retains its high efficacy. In this study, XH-003 showed a chemoprotective effect similar to that of amifostine. A mechanistic study showed that XH-003 could significantly reduce cisplatin-induced increases in serum creatinine and urea nitrogen, increase the activity of antioxidant enzymes (SOD, CAT, and GSH-Px), reduce oxidative stress and tissue inflammation, and alleviate renal tissue damage by blocking the activity of the mitochondrial apoptosis pathway. Most importantly, XH-003 could reduce the accumulation of cisplatin in renal tissue by regulating the expression of proteins involved in cisplatin uptake and excretion, such as organic cation transporter 2 and MRP2. Moreover, in an in vivo xenotransplantation model, XH-003 did not interfere with the antitumor effect of cisplatin. These data provide strong evidence that the ARS-protective agent has a great potential for protecting against chemotherapy-induced toxicity. Thus, XH-003 can be considered in antitumor therapy.

scholarly journals New Tetrahydroacridine Hybrids with Dichlorobenzoic Acid Moiety Demonstrating Multifunctional Potential for the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 21 (11) ◽  
pp. 3765
Author(s):  
Kamila Czarnecka ◽  
Małgorzata Girek ◽  
Przemysław Wójtowicz ◽  
Paweł Kręcisz ◽  
Robert Skibiński ◽  
...  
Keyword(s):  
Active Compound ◽  
Inhibitory Activity ◽  
Docking Study ◽  
Free Radical Scavenger ◽  
Neuroprotective Activity ◽  
Radical Scavenger ◽  
Catalytic Active Site ◽  
Aβ Aggregation ◽  
Ic50 Values

A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver–Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).

scholarly journals Streptozotocin Inhibits Electrophysiological Determinants of Excitatory and Inhibitory Synaptic Transmission in CA1 Pyramidal Neurons of Rat Hippocampal Slices: Reduction of These Effects by Edaravone

2016 ◽  
Vol 40 (6) ◽  
pp. 1274-1288 ◽  
Author(s):  
Ting Ju ◽  
Yuru Li ◽  
Xiaoran Wang ◽  
Lifeng Xiao ◽  
Li Jiang ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Paired Pulse ◽  
Ca1 Pyramidal Neurons ◽  
Postsynaptic Currents ◽  
Pulse Ratio ◽  
Synaptic Mechanisms

Background: Streptozotocin (STZ) has served as an agent to generate an Alzheimer's disease (AD) model in rats, while edaravone (EDA), a novel free radical scavenger, has recently emerged as an effective treatment for use in vivo and vitro AD models. However, to date, these beneficial effects of EDA have only been clearly demonstrated within STZ-induced animal models of AD and in cell models of AD. A better understanding of the mechanisms of EDA may provide the opportunity for their clinical application in the treatment of AD. Therefore, the purpose of this study was to investigate the underlying mechanisms of STZ and EDA as assessed upon electrophysiological alterations in CA1 pyramidal neurons of rat hippocampal slices. Methods: Through measures of evoked excitatory postsynaptic currents (eEPSCs), AMPAR-mediated eEPSCs (eEPSCsAMPA), evoked inhibitory postsynaptic currents (eIPSCs), evoked excitatory postsynaptic current paired pulse ratio (eEPSC PPR) and evoked inhibitory postsynaptic current paired pulse ratio (eIPSC PPR), it was possible to investigate mechanisms as related to the neurotoxicity of STZ and reductions in these effects by EDA. Results: Our results showed that STZ (1000 µM) significantly inhibited peak amplitudes of eEPSCs, eEPSCsAMPA and eIPSCs, while EDA (1000 µM) attenuated these STZ-induced changes at holding potentials ranging from -60mV to +40 mV for EPSCs and -60mV to +20 mV for IPSCs. Our work also indicated that mean eEPSC PPR were substantially altered by STZ, effects which were partially restored by EDA. In contrast, no significant effects upon eIPSC PPR were obtained in response to STZ and EDA. Conclusion: Our data suggest that STZ inhibits glutamatergic transmission involving pre-synaptic mechanisms and AMPAR, and that STZ inhibits GABAergic transmission by post-synaptic mechanisms within CA1 pyramidal neurons. These effects are attenuated by EDA.

scholarly journals Hydroxyl radical induced structural changes of collagen

2007 ◽  
Vol 21 (2) ◽  
pp. 91-103 ◽  
Author(s):  
Helan Xiao ◽  
Guoping Cai ◽  
Mingyao Liu
Keyword(s):  
Free Radical ◽  
Hydroxyl Radicals ◽  
Structural Changes ◽  
Type I Collagen ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Type I ◽  
Dependent Manner ◽  
First Time

Extracellular matrix (ECM) plays an important role in cell differentiation, growth, migration and apoptosis. Collagen is the most abundant protein familyin vivo, but its function has still not been clearly defined yet. Reactive oxygen species (ROS) have a central role in oxidative cell stress. Electron spin resonance (ESR) spectroscopy indicates that type I collagen could uniquely scavenge hydroxyl radicals in dose- and time-dependent manner; whereas BSA and gelatin (a denatured collagen) have no such an effect. However, the mechanism by which type I collagen scavenges hydroxyl radicals is different from that of GSH, a well-known free radical scavenger. Using a new method, two-dimensional FTIR correlation analysis, for the first time, we show that the order of functional group changes of type I collagen in this process is amide I earlier than amide II than amide III than –CH– thanν(C=O). The results indicates that the structure of the main chain of collagen changed first, followed by more residue groupν(C=O) exposed to hydroxyl radicals. The reaction with the carbonyl group in collagen causes the hydroxyl free radicals to be scavenged. Therefore, ECM can effectively scavenge ROS under normal physiological conditions. When the proteins of ECM were denatured in the same way as gelatin, they lost their function as a free radical scavenger. All of these results provide new insight into therapy or prevention of oxidative stress, apoptosis and ageing.

scholarly journals Effect of Trigonella Foenum against Ethylene Diamine Tetra Acetic Acid induced Nephrotoxicity in Male Albino Rats

2020 ◽  
Vol 1 (1) ◽  
pp. 32-43
Author(s):  
A I Barakat ◽  
EH Radwan
Keyword(s):  
Creatinine Clearance ◽  
Aqueous Extract ◽  
Renal Damage ◽  
Kidney Tissue ◽  
Free Radical Scavenger ◽  
Albino Rats ◽  
Radical Scavenger ◽  
Protective Agent ◽  
Protective Effects ◽  
Oxidative Stress Biomarkers

Background Nephrotoxicity is a complication due to the effect of some toxic chemicals on kidney. Current study planned to screen the effect of Trigonella foenumaqueous seeds extracts on EDTA induced nephrotoxicity. Trigonella foenum known for its various medicinal properties is also a natural antioxidant and a free radical scavenger with no documented evidence as a nephron-protective agent. Objective To investigate the protective effects of aqueous seed extracts of Trigonella foenum. Material and Methods The present study was used 40 male albino rats (Rattus albinus) with weight of (150 ± 10) g with divided into four groups: control gp; EDTA gp (95 mg/kg); Trigonella foenum gp (500 mg/kg) and EDTA + Trigonella f oenum gp by gastric tube daily for 4 weeks. Blood urea, creatinine, GFR, creatinine clearance, MDA and GPx analyses and microscopic examination of kidney were performed. Results In the present study, Blood samples were taken from all groups and concentration of serum urea, creatinine, GFR, Creatinine clearance, MDA and GPx were determined. Histopathological observations were observed in kidney tissue. Data were analyzed using analysis of variance (ANOVA). EDTA induced an increase in urea and creatinine as well as there was a decrease in the concentration of GFR and creatinine clearance. The level of MDA was increase while the concentration of GPx was decrease in the serum of EDTA group. The aqueous extracts of Trigonella seeds significantly prevented renal damage by normalizing increased levels of renal markers. The correction of oxidative stress biomarkers was consistent with amelioration of the histopathological changes induced by EDTA. Hence, it is suggested that ameliorative effect of aqueous extract of Trigonella foenumagainst EDTA induced nephrotoxicity. Conclusion The present data suggest that aqueous extract of Trigonella foenum exhibits reno-protective effect in EDTA induced renal damage.

Ceria-Zirconia Antioxidant Nanoparticles Attenuate Hypoxia-Induced Acute Kidney Injury by Restoring Autophagy Flux and Alleviating Mitochondrial Damage

2020 ◽  
Vol 16 (7) ◽  
pp. 1144-1159
Author(s):  
Sang-Eun Hong ◽  
Jong Hun An ◽  
Seong-Lan Yu ◽  
Jaeku Kang ◽  
Chang Gyo Park ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Free Radical ◽  
Antioxidant Activities ◽  
Kidney Injury ◽  
Mitochondrial Damage ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Autophagy Flux ◽  
Novel Approach

Oxidative stress is one of the principal causes of hypoxia-induced kidney injury. The ceria nanoparticle (CNP) is known to exhibit free radical scavenger and catalytic activities. When zirconia is attached to CNPs (CZNPs), the ceria atom tends to remain in a Ce3+ form and its efficacy as a free radical scavenger thus increases. We determined the effectiveness of CNP and CZNP antioxidant activities against hypoxia-induced acute kidney injury (AKI) and observed that these nanoparticles suppress the apoptosis of hypoxic HK-2 cells by restoring autophagy flux and alleviating mitochondrial damage. In vivo experiments revealed that CZNPs effectively attenuate hypoxia-induced AKI by preserving renal structures and glomerulus function. These nanoparticles can successfully diffuse into HK-2 cells and effectively counteract reactive oxygen species (ROS) to block hypoxia-induced AKI. This suggests that these particles represent a novel approach to controlling this condition.

scholarly journals Camalexin Induces Apoptosis via the ROS-ER Stress-Mitochondrial Apoptosis Pathway in AML Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Yang Yang ◽  
Gang Wang ◽  
Wenjun Wu ◽  
Shunnan Yao ◽  
Xiaoyan Han ◽  
...  
Keyword(s):  
Er Stress ◽  
Plant Pathogens ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Mitochondrial Apoptosis ◽  
Antitumor Effects ◽  
Sod Activity ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway

Camalexin is a phytoalexin that accumulates in various cruciferous plants upon exposure to environmental stress and plant pathogens. It was shown that camalexin has potent antitumor properties, but its underlying mechanisms are still elusive. In the present study, we evaluated the effects of camalexin on human leukemic cells and normal polymorph nuclear cells. CCK-8 assay was used to determine cell viability after camalexin treatment. Apoptosis, intracellular reactive oxygen species (ROS) levels, and loss of mitochondrial membrane potential (MMP) were measured by flow cytometry. The activity of SOD, catalase, and ratio of GSH/GSSG were assayed. ER stress and apoptotic signaling pathway was examined by Western blot. Xenograft mice were used to verify the effect of camalexin in vivo. Our results indicated that camalexin inhibited viability of leukemic but not normal polymorph nuclear cells. Furthermore, camalexin induces apoptosis via the mitochondrial pathway in a caspase-dependent manner. We also observed ER stress is located upstream of apoptosis induced by camalexin. Besides, ROS levels, SOD activity, CAT activity, and GSSG levels were significantly enhanced while the GSH level was decreased after treatment of camalexin. In addition, the generation of ROS is critical for the ER stress and apoptosis induced by camalexin. Finally, administration of camalexin suppresses xenograft tumor graft growth without obvious toxicity. Taken together, this study indicates that camalexin exerts antitumor effects against leukemia cells via the ROS-ER stress-mitochondrial apoptosis pathway.

scholarly journals Myricitrin Protects against Doxorubicin-Induced Cardiotoxicity by Counteracting Oxidative Stress and Inhibiting Mitochondrial Apoptosis via ERK/P53 Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Jing Sun ◽  
Guibo Sun ◽  
Xiaolan Cui ◽  
Xiangbao Meng ◽  
Meng Qin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Damage ◽  
Mitochondrial Apoptosis ◽  
Mechanism Study ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Myocardial Apoptosis ◽  
Underlying Mechanisms

Doxorubicin (Dox) is one of the most effective and widely used anthracycline antineoplastic antibiotics. Unfortunately, the use of Dox is limited by its cumulative and dose-dependent cardiac toxicity. Myricitrin, a natural flavonoid which is isolated from the ground bark ofMyrica rubra, has recently been found to have a strong antioxidative effect. This study aimed to evaluate the possible protective effect of myricitrin against Dox-induced cardiotoxicity and the underlying mechanisms. An in vivo investigation in SD rats demonstrated that myricitrin significantly reduced the Dox-induced myocardial damage, as indicated by the decreases in the cardiac index, amelioration of heart pathological injuries, and decreases in the serum cardiac enzyme levels. In addition, in vitro studies showed that myricitrin effectively reduced the Dox-induced cell toxicity. Further study showed that myricitrin exerted its function by counteracting oxidative stress and increasing the activities of antioxidant enzymes. Moreover, myricitrin suppressed the myocardial apoptosis induced by Dox, as indicated by decreases in the activation of caspase-3 and the numbers of TUNEL-positive cells, maintenance of the mitochondrial membrane potential, and increase in the Bcl-2/Bax ratio. Further mechanism study revealed that myricitrin-induced suppression of myocardial apoptosis relied on the ERK/p53-mediated mitochondrial apoptosis pathway.

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