scholarly journals Silymarin Dehydroflavonolignans Chelate Zinc and Partially Inhibit Alcohol Dehydrogenase

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4238
Author(s):  
Václav Tvrdý ◽  
Marcel Hrubša ◽  
Eduard Jirkovský ◽  
David Biedermann ◽  
Michal Kutý ◽  
...  
Keyword(s):  
Alcohol Dehydrogenase ◽  
Glutamate Dehydrogenase ◽  
Liver Damage ◽  
Chelating Agent ◽  
Dependent Manner ◽  
Zinc Ions ◽  
Protective Effects ◽  
Concentration Dependent Manner ◽  
In Silico Docking ◽  
Chelating Activity

Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against Amanita phalloides intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may influence alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3-dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase.

Properties of neuroprotective cell-permeant Ca2+ chelators: effects on [Ca2+]i and glutamate neurotoxicity in vitro

1994 ◽  
Vol 72 (4) ◽  
pp. 1973-1992 ◽  
Author(s):  
M. Tymianski ◽  
M. P. Charlton ◽  
P. L. Carlen ◽  
C. H. Tator
Keyword(s):  
Time Course ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tetraacetic Acid ◽  
Acetoxymethyl Ester ◽  
Neuroprotective Effects ◽  
Concentration Dependent Manner ◽  
Fura 2 ◽  
Glutamate Neurotoxicity

1. Cell-permeant Ca2+ chelators such as 1,2-bis-(2-amino-phenoxy)ethane- N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) protect neurons against excitotoxic and ischemic neuronal injury in vitro and in vivo. Here we provide the first steps toward characterizing the mechanisms by which these agents produce their neuroprotective effects. 2. Cultured mouse spinal neurons were simultaneously loaded with the Ca2+ indicator fura-2 and with one of three permeant chelators derived from the fast Ca2+ buffer BAPTA, or with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid acetoxymethyl ester (EGTA-AM). Adding these chelators did not interfere with the fluorescence spectrum of fura-2 and had no effect on baseline [Ca2+]i. 3. The neurons were challenged with 250 microM L-glutamate for 50 min, producing a marked transient [Ca2+]i increase followed by a decay of [Ca2+]i to a lower “plateau.” About 80% of control neurons succumbed to this excitotoxic insult. Neurons that survived adjusted their plateau [Ca2+]i to lower levels than those that succumbed. 4. Neurons that were pretreated with permeant Ca2+ chelators became more resistant to these neurotoxic challenges. 5. We examined whether this reduction in glutamate neurotoxicity could be related to the given buffer's known Ca2+ affinity (Kd), its Ca2+ binding kinetics, and its ability to attenuate glutamate-induced [Ca2+]i increases. 6. Pretreatment of neurons with BAPTA analogues having Kds ranging from 100 to 3,600 microM 1) attenuated the amplitude and 2) lengthened the time constant describing the rise and decay of the glutamate-evoked [Ca2+]i transient. The magnitude of these effects paralleled the affinity of the chelator for Ca2+. 7. BAPTA-AM and its analogues dramatically attenuated the early neurotoxicity of glutamate, reducing cell deaths by up to 80%. However, in contrast with the graded effects of chelators having different Ca2+ affinities on Ca2+ transients, all BAPTA analogues were equally protective. These protective effects did not relate to the chelators' Ca2+ affinity within a Kd range of 100 nM (for BAPTA) to 3,600 nM (for 5,5'-dibromo BAPTA). 8. BAPTA-AM protected neurons in a concentration-dependent manner with 50% protection obtained with 10 microM, a concentration having no effect on the [Ca2+]i transient amplitude. 9. EGTA, a slow Ca2+ buffer with a similar Ca2+ affinity to BAPTA produced the same effects as BAPTA on [Ca2+]i transient kinetics. However, it was far less protective than BAPTA. 10. The time course of early glutamate neurotoxicity was altered by the BAPTA analogues, but not EGTA. BAPTA analogues caused a small increase in cell deaths in the first minutes of each experiment, followed by relative sparing from further neurodegeneration. 11. The ability of low Ca2+ affinity chelators such as 5,5'-dibromo BAPTA to protect neurons without markedly attenuating measured [Ca2+]i increases conflicts with the hypothesis that global elevations in [Ca2+]i are responsible for triggering neurotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Vascular Protective Effects of Xanthotoxin and Its Action Mechanism in Rat Aorta and Human Vascular Endothelial Cells

2020 ◽  
Vol 57 (6) ◽  
pp. 313-324
Author(s):  
Li-Hua Cao ◽  
Ho Sub Lee ◽  
Zhe-Shan Quan ◽  
Yun Jung Lee ◽  
Yu Jin
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Neuroprotective Effect ◽  
Intercellular Adhesion Molecule ◽  
Dependent Manner ◽  
Protective Effects ◽  
Concentration Dependent Manner

<b><i>Objective:</i></b> Xanthotoxin (XAT) is a linear furanocoumarin mainly extracted from the plants <i>Ammi majus</i> L. XAT has been reported the apoptosis of tumor cells, anti-convulsant, neuroprotective effect, antioxidative activity, and vasorelaxant effects. This study aimed to investigate the vascular protective effects and underlying molecular mechanisms of XAT. <b><i>Methods:</i></b> XAT’s activity was studied in rat thoracic aortas, isolated with aortic rings, and human umbilical vein endothelial cells (HUVECs). <b><i>Results:</i></b> XAT induced endothelium-dependent vasodilation in a concentration-dependent manner in the isolated rat thoracic aortas. Removal of endothelium or pretreatment of aortic rings with L-NAME, 1<i>H</i>-[1,2,4]-oxadiazolo-[4,3-<i>a</i>]-quinoxalin-1-one, and wortmannin significantly inhibited XAT-induced relaxation. In addition, treatment with thapsigargin, 2-aminoethyl diphenylborinate, Gd<sup>3+</sup>, and 4-aminopyridine markedly attenuated the XAT-induced vasorelaxation. XAT increased nitric oxide production and Akt- endothelial NOS (eNOS) phosphorylation in HUVECs. Moreover, XAT attenuated the expression of TNF-α-induced cell adhesion molecules such as intercellular adhesion molecule, vascular cell adhesion molecule-1, and E-selectin. However, this effect was attenuated by the eNOS inhibitors L-NAME and asymmetric dimethylarginine. <b><i>Conclusions:</i></b> This study suggests that XAT induces vasorelaxation through the Akt-eNOS-cGMP pathway by activating the K<sub>V</sub> channel and inhibiting the L-type Ca<sup>2+</sup> channel. Furthermore, XAT exerts an inhibitory effect on vascular inflammation, which is correlated with the observed vascular protective effects.

Cu2+-induced modification of the kinetics of Aβ(1-42) channels

2003 ◽  
Vol 285 (4) ◽  
pp. C873-C880 ◽  
Author(s):  
Randa Bahadi ◽  
Peter V. Farrelly ◽  
Bronwyn L. Kenna ◽  
Cyril C. Curtain ◽  
Colin L. Masters ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Chelating Agent ◽  
Common Mechanism ◽  
Amyloid Β Peptide ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Channel Inhibition ◽  
Low Concentrations ◽  
Redox Agents ◽  
In Cis

We found that the amyloid β peptide Aβ(1-42) is capable of interacting with membrane and forming heterogeneous ion channels in the absence of any added Cu2+ or biological redox agents that have been reported to mediate Aβ(1-42) toxicity. The Aβ(1-42)-formed cation channel was inhibited by Cu2+ in cis solution ([Cu2+] cis) in a voltage- and concentration-dependent manner between 0 and 250 μM. The [Cu2+] cis-induced channel inhibition is fully reversible at low concentrations between 50 and 100 μM [Cu2+] cis and partially reversible at 250 μM [Cu2+] cis. The inhibitory effects of [Cu2+] cis between 50 and 250 μM on the channel could not be reversed with addition of Cu2+-chelating agent clioquinol (CQ) at concentrations between 64 and 384 μM applied to the cis chamber. The effects of 200-250 μM [Cu2+] cis on the burst and intraburst kinetic parameters were not fully reversible with either wash or 128 μM [CQ] cis. The kinetic analysis of the data indicate that Cu2+-induced inhibition was mediated via both desensitization and an open channel block mechanism and that Cu2+ binds to the histidine residues located at the mouth of the channel. It is proposed that the Cu2+-binding site of the Aβ(1-42)-formed channels is modulated with Cu2+ in a similar way to those of channels formed with the prion protein fragment PrP(106-126), suggesting a possible common mechanism for Cu2+ modulation of Aβ and PrP channel proteins linked to neurodegenerative diseases.

Protective Effects on Mitochondria and Anti-Aging Activity of Polysaccharides from Cultivated Fruiting Bodies of Cordyceps militaris

2010 ◽  
Vol 38 (06) ◽  
pp. 1093-1106 ◽  
Author(s):  
Xing-Tai Li ◽  
Hong-Cheng Li ◽  
Chun-Bin Li ◽  
De-Qiang Dou ◽  
Ming-Bo Gao
Keyword(s):  
Hydroxyl Radicals ◽  
Cordyceps Militaris ◽  
Mitochondrial Swelling ◽  
Dependent Manner ◽  
Protective Effects ◽  
Fruiting Bodies ◽  
Concentration Dependent Manner ◽  
Mitochondrial Injury

Cordyceps militaris (L.) Link is an entomopathogenic fungus parasitic to Lepidoptera larvae, and is widely used as a folk tonic or invigorant for longevity in China. Although C. militaris has been used in traditional Chinese medicine for millennia, there is still a lack convincing evidence for its anti-aging activities. This study was performed to investigate the effects of polysaccharides from cultivated fruiting bodies of C. militaris (CMP) on mitochondrial injury, antioxidation and anti-aging activity. Fruiting bodies of C. militaris were cultivated artificially under optimized conditions. The spectrophotometric method was used to measure thiobarbituric acid reactive substances (TBARS), mitochondrial swelling, and activities of scavenging superoxide anions in vitro. D-galactose (100 mg/kg/day) was injected subcutaneously into back of the neck of mice for 7 weeks to induce an aging model. The effects of CMP on the activities of catalase (CAT), surperoxide dismutase (SOD), glutathione peroxidase (GPx) and anti-hydroxyl radicals were assayed in vivo using commercial monitoring kits. The results showed that CMP could inhibit mitochondrial injury and swelling induced by Fe2+ -L-Cysteine in a concentration- dependent manner and it also had a significant superoxide anion scavenging effect. Moreover, the activities of CAT, SOD, GPx and anti-hydroxyl radicals in mice liver were increased significantly by CMP. These results indicate that CMP protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting mitochondrial swelling, and increasing the activities of antioxidases. Therefore, CMP may have pharmaceutical values for mitochondrial protection and anti-aging. CMP was the major bioactive component in C. militaris.

scholarly journals Antioxidant activity of pineal methoxyindoles on hepatocyte plasmatic membrane

2019 ◽  
Vol 2 (1) ◽  
pp. 161-174
Author(s):  
Marcos C Reyes-Gonzales ◽  
Eduardo Esteban-Zubero ◽  
Laura López-Pingarrón ◽  
María Soledad Soria ◽  
Desiree Pereboom ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Membrane ◽  
Membrane Fluidity ◽  
Membrane Lipid ◽  
Hydroxyl Group ◽  
Dependent Manner ◽  
Protective Effects ◽  
Concentration Dependent Manner ◽  
Plasmatic Membrane ◽  
Membrane Rigidity

Antioxidant effect of several pineal derived molecules has been well documented. Here, the protective effects of 5-methoxytryptophol (5-MTOH) and 5-methoxyindol-3-acetic acid (5-MIAA) on hepatic cell membrane lipid peroxidation and cell membrane rigidity induced by FeCl3 plus ascorbic acid have been systemically investigated. The membrane fluidity was evaluated by fluorescence spectroscopy, malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) concentrations and carbonyl groups of protein were measured as the parameters of lipid and protein damage, respectively. Results showed that oxidative stress increased membrane rigidity, MDA and 4-HDA concentrations as well as carbonyl content in a concentration-dependent manner. 5-MTOH, but not 5-MIAA, significantly attenuated these oxidative indecies. In absence of oxidative stress, none of these methoxyindoleamines modified the content of MDA, 4-HDA or carbonylation. However 5-MIAA at its highest concentration slightly modified membrane fluidity. The results suggest that structural modification of C3 in the methoxyindoleamine, that is, the carboxyl group replaced by hydroxyl group in this site could improve the ability of 5-methoxyindoleamine derivatives to preserve membrane fluidity of cells which are under oxidative stress. 

scholarly journals Condensin II plays an essential role in reversible assembly of mitotic chromosomes in situ

2017 ◽  
Vol 28 (21) ◽  
pp. 2875-2886 ◽  
Author(s):  
Takao Ono ◽  
Chiyomi Sakamoto ◽  
Mitsuyoshi Nakao ◽  
Noriko Saitoh ◽  
Tatsuya Hirano
Keyword(s):  
Mitotic Chromosome ◽  
Learning Algorithm ◽  
Chelating Agent ◽  
Point Of View ◽  
Dependent Manner ◽  
Mitotic Chromosomes ◽  
Concentration Dependent Manner ◽  
Tightly Coupled ◽  
Hypotonic Buffer

Condensins I and II are multisubunit complexes that play a central role in mitotic chromosome assembly. Although both complexes become concentrated along the axial region of each chromatid by metaphase, it remains unclear exactly how such axes might assemble and contribute to chromosome shaping. To address these questions from a physico-chemical point of view, we have established a set of two-step protocols for inducing reversible assembly of chromosome structure in situ, namely within a whole cell. In this assay, mitotic chromosomes are first expanded in a hypotonic buffer containing a Mg2+-chelating agent and then converted into different shapes in a NaCl concentration-dependent manner. Both chromatin and condensin-positive chromosome axes are converted into near-original shapes at 100 mM NaCl. This assay combined with small interfering RNA depletion demonstrates that the recovery of chromatin shapes and the reorganization of axes are highly sensitive to depletion of condensin II but less sensitive to depletion of condensin I or topoisomerase IIα. Furthermore, quantitative morphological analyses using the machine-learning algorithm wndchrm support the notion that chromosome shaping is tightly coupled to the reorganization of condensin II-based axes. We propose that condensin II makes a primary contribution to mitotic chromosome architecture and maintenance in human cells.

scholarly journals Pyocyanin induces NK92 cell apoptosis via mitochondrial damage and elevated intracellular Ca2+

2018 ◽  
Vol 25 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Ting Li ◽  
Xiaoyuan Huang ◽  
Zhechen Yuan ◽  
Linfang Wang ◽  
Miaobo Chen ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Damage ◽  
Chelating Agent ◽  
Mitochondrial Damage ◽  
Ros Generation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Induced Apoptosis

Pseudomonas aeruginosa-derived pigment pyocyanin (PCN) has been proved to induce cell apoptosis mediated by the generation of reactive oxygen species (ROS), which has been studied mainly in epithelial cells and neutrophils. However, we previously found that the PCN-producing strain PA14 induces cell apoptosis in human NK cell line NK92 more effectively than in PCN-deficient strain PA14-phZ1/2 via a yet undetermined mechanism. In the current study, we found that PCN-induced NK92 cell apoptosis occurs through mitochondrial damage despite inhibiting intracellular ROS generation. Intracellular Ca2+ ([Ca2+]i) and Bcl-2 family proteins act as important “priming signals” for apoptosis. PCN treatment increased [Ca2+]i in NK92 cells more than twofold after 2 h stimulation, whereas the Ca2+-chelating agent ethylene glycol tetra-acetic acid (EGTA) inhibited apoptosis. PCN triggered the activation of Bim, Bid, Bik, Bak, and phospho-Bad in NK92 cells in a concentration-dependent manner, but these pro-apoptotic Bcl-2 family proteins were not inhibited by EGTA. In this study, we describe the function of PCN in NK92 cells and identify mitochondrial damage as the mechanism underlying the apoptosis. [Ca2+]i and pro-apoptotic Bcl-2 family proteins are novel targets for PCN-induced apoptosis. Clarification of the cytotoxic diversity of PCN provides a new therapeutic target for defense from P. aeruginosa-induced immune cell damage.

scholarly journals Protective Effects of Aqueous Extracts of Flos lonicerae Japonicae against Hydroquinone-Induced Toxicity in Hepatic L02 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yanfang Gao ◽  
Huanwen Tang ◽  
Liang Xiong ◽  
Lijun Zou ◽  
Wenjuan Dai ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Viability ◽  
Dependent Manner ◽  
Aqueous Extracts ◽  
Protective Effects ◽  
Concentration Dependent Manner ◽  
Flos Lonicerae ◽  
L02 Cells ◽  
Flos Lonicerae Japonicae

Hydroquinone (HQ) is widely used in food stuffs and is an occupational and environmental pollutant. Although the hepatotoxicity of HQ has been demonstrated both in vitro and in vivo, the prevention of HQ-induced hepatotoxicity has yet to be elucidated. In this study, we focused on the intervention effect of aqueous extracts of Flos lonicerae Japonicae (FLJ) on HQ-induced cytotoxicity. We demonstrated that HQ reduced cell viability in a concentration-dependent manner by administering 160 μmol/L HQ for 12 h as the positive control of cytotoxicity. The aqueous FLJ extracts significantly increased cell viability and decreased LDH release, ALT, and AST in a concentration-dependent manner compared with the corresponding HQ-treated groups in hepatic L02 cells. This result indicated that aqueous FLJ extracts could protect the cytotoxicity induced by HQ. HQ increased intracellular MDA and LPO and decreased the activities of GSH, GSH-Px, and SOD in hepatic L02 cells. In addition, aqueous FLJ extracts significantly suppressed HQ-stimulated oxidative damage. Moreover, HQ promoted DNA double-strand breaks (DSBs) and the level of 8-hydroxy-2′-deoxyguanosine and apoptosis. However, aqueous FLJ extracts reversed HQ-induced DNA damage and apoptosis in a concentration-dependent manner. Overall, our results demonstrated that the toxicity of HQ was mediated by intracellular oxidative stress, which activated DNA damage and apoptosis. The findings also proved that aqueous FLJ extracts exerted protective effects against HQ-induced cytotoxicity in hepatic L02 cells.

scholarly journals Atheroprotective action of a modified organoselenium compound: in vitro evidence

2016 ◽  
Vol 88 (3 suppl) ◽  
pp. 1953-1965 ◽  
Author(s):  
JADE DE OLIVEIRA ◽  
MARCOS R. STRALIOTTO ◽  
GIANNI MANCINI ◽  
CLAUDIA P. FIGUEIREDO ◽  
ANTÔNIO L. BRAGA ◽  
...  
Keyword(s):  
Foam Cell ◽  
Oxidized Ldl ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Protective Effects ◽  
Organoselenium Compound ◽  
Organoselenium Compounds ◽  
Concentration Dependent Manner

ABSTRACT Oxidation of low-density lipoprotein (LDL) has been strongly suggested to play a significant role in the pathogenesis of atherosclerosis. Thus, reducing LDL oxidation is a potential approach to decrease the risk of the atherosclerosis. Organoselenium compounds have demonstrated promising atheroprotective properties in experimental models. Herein, we tested the in vitro atheroprotective capability of a modified organoselenium compound, Compound HBD, in protecting isolated LDL from oxidation as well as foam cells formation. Moreover, the glutathione peroxidase (GPx)-like activity of Compound HBD was analyzed in order to explore the mechanisms related to the above-mentioned protective effects. The Compound HBD in a concentration-dependent manner reduced the Cu2+-induced formation of conjugated dienes. The protein portion from LDL were also protected from Cu2+-induced oxidation. Furthermore, the Compound HBD efficiently decreased the foam cell formation in J774 macrophage cells exposed to oxidized LDL. We found that the atheroprotective effects of this compound can be, at least in part, related to its GPx-like activity. Our findings demonstrated an impressive effect of Compound HBD against LDL-induced toxicity, a further in vivo study to investigate in more detail the antioxidant and antiatherogenic effects of this compound could be considered.

Modifications of cellular responses to lysophosphatidic acid and platelet-activating factor by plasma gelsolin

2007 ◽  
Vol 292 (4) ◽  
pp. C1323-C1330 ◽  
Author(s):  
Teresia M. Osborn ◽  
Claes Dahlgren ◽  
John H. Hartwig ◽  
Thomas P. Stossel
Keyword(s):  
Platelet Activating Factor ◽  
Protective Role ◽  
Actin Binding ◽  
Dependent Manner ◽  
Protective Effects ◽  
Concentration Dependent Manner ◽  
Blood Concentrations ◽  
Plasma Gelsolin

Gelsolin is a highly conserved intracellular actin-binding protein with an extracellular isoform, plasma gelsolin (pGSN). Blood concentrations of pGSN decrease in response to diverse tissue injuries. Depletion of pGSN to critical levels precedes and often predicts complications of injuries such as lung permeability changes and death. Administration of recombinant pGSN ameliorates such complications and reduces mortality in animal models. One proposed mechanism for pGSN's protective effects is that it inhibits inflammatory mediators generated during primary injuries, since pGSN binds bioactive mediators, including lysophospatidic acid (LPA) and endotoxin in vitro. However, no direct evidence in support of this hypothesis has been available. Here we show that recombinant pGSN modestly inhibited LPA-induced P-selectin upregulation by human platelets in the presence of albumin ( P < 0.0001). However, physiologically relevant pGSN concentrations inhibit platelet-activating factor (PAF)-mediated P-selectin expression by up to 77% ( P < 0.0001). pGSN also markedly inhibited PAF-induced superoxide anion (O2−) production of human peripheral neutrophils (PMN) in a concentration-dependent manner ( P < 0.0001). A phospholipid-binding peptide derived from pGSN (QRLFQVKGRR) also inhibited PAF-mediated O2− generation ( P = 0.024). Therefore, pGSN interferes with PAF- and LPA-induced cellular activation in vitro, suggesting a mechanism for the protective role of pGSN in vivo.

Sign in / Sign up

Export Citation Format

Share Document