scholarly journals Blockade of Cyclophilin D Attenuates Oxidative Stress-Induced Cell Death in Human Dental Pulp Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Shengbin Huang ◽  
Bingbing Zheng ◽  
Xing Jin ◽  
Qihao Yu ◽  
Xiaorong Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Dental Pulp ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Dependent Manner ◽  
Dental Pulp Cells ◽  
Cyclophilin D ◽  
Pulp Cells

Pathological stimuli, such as bacterial activity, dental bleaching, and nonpolymerized resin monomers, can cause death of dental pulp cells (DPCs) through oxidative stress- (OS-) induced mitochondrial dysfunction. However, the crucial molecular mechanisms that mediate such a phenomenon remain largely unknown. OS is characterized by the overproduction of reactive oxygen species (ROS), e.g., H2O2, O2−, and ⋅OH. Mitochondria are a major source of ROS and the principal attack target of ROS. Cyclophilin D (CypD), as the only crucial protein for mitochondrial permeability transition pore (mPTP) induction, facilitates the opening of mPTP and causes mitochondrial dysfunction, leading to cell death. In the present study, we hypothesized that CypD-mediated mitochondrial molecular pathways were closely involved in the process of OS-induced death of human DPCs (HDPCs). We tested the phenotypic and molecular changes of HDPCs in a well-established OS model—H2O2 treatment. We showed that H2O2 dramatically reduced the viability and increased the death of HDPCs in a time- and dose-dependent manner by performing MTT, flow cytometry, and TUNEL assays and quantifying the expression changes of Bax and Bcl-2 proteins. H2O2 also induced mitochondrial dysfunction, as reflected by the increased mitochondrial ROS, reduced ATP production, and activation of mPTP (decreased mitochondrial membrane potential and enhanced intracellular Ca2+ level). An antioxidant (N-acetyl-L-cysteine) effectively preserved mitochondrial function and significantly attenuated H2O2-induced cytotoxicity and death. Moreover, H2O2 treatment markedly upregulated the CypD protein level in HDPCs. Notably, genetic or pharmacological blockade of CypD significantly attenuated H2O2-induced mitochondrial dysfunction and cell death. These findings provided novel insights into the role of a CypD-dependent mitochondrial pathway in the H2O2-induced death in HDPCs, indicating that CypD may be a potential therapeutic target to prevent OS-mediated injury in dental pulp.

Specific parameters of infrared LED irradiation promote the inhibition of oxidative stress in dental pulp cells

2021 ◽  
pp. 105273
Author(s):  
Jéssica F.S. Bonvicini ◽  
Gabriela L. de Souza ◽  
Fernanda G. Basso ◽  
Carlos A. de Souza Costa ◽  
Camilla C.G. Moura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dental Pulp ◽  
Dental Pulp Cells ◽  
Pulp Cells ◽  
Led Irradiation

scholarly journals The novel cyclophilin-D-interacting protein FASTKD1 protects cells against oxidative stress-induced cell death

2019 ◽  
Vol 317 (3) ◽  
pp. C584-C599
Author(s):  
Kurt D. Marshall ◽  
Paula J. Klutho ◽  
Lihui Song ◽  
Maike Krenz ◽  
Christopher P. Baines
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Kinase Domain ◽  
Protective Role ◽  
Mitochondrial Morphology ◽  
Cyclophilin D ◽  
Interacting Protein ◽  
Mitochondrial Homeostasis

Opening of the mitochondrial permeability transition (MPT) pore leads to necrotic cell death. Excluding cyclophilin D (CypD), the makeup of the MPT pore remains conjecture. The purpose of these experiments was to identify novel MPT modulators by analyzing proteins that associate with CypD. We identified Fas-activated serine/threonine phosphoprotein kinase domain-containing protein 1 (FASTKD1) as a novel CypD interactor. Overexpression of FASTKD1 protected mouse embryonic fibroblasts (MEFs) against oxidative stress-induced reactive oxygen species (ROS) production and cell death, whereas depletion of FASTKD1 sensitized them. However, manipulation of FASTKD1 levels had no effect on MPT responsiveness, Ca2+-induced cell death, or antioxidant capacity. Moreover, elevated FASTKD1 levels still protected against oxidative stress in CypD-deficient MEFs. FASTKD1 overexpression decreased Complex-I-dependent respiration and ΔΨm in MEFs, effects that were abrogated in CypD-null cells. Additionally, overexpression of FASTKD1 in MEFs induced mitochondrial fragmentation independent of CypD, activation of Drp1, and inhibition of autophagy/mitophagy, whereas knockdown of FASTKD1 had the opposite effect. Manipulation of FASTKD1 expression also modified oxidative stress-induced caspase-3 cleavage yet did not alter apoptotic death. Finally, the effects of FASTKD1 overexpression on oxidative stress-induced cell death and mitochondrial morphology were recapitulated in cultured cardiac myocytes. Together, these data indicate that FASTKD1 supports mitochondrial homeostasis and plays a critical protective role against oxidant-induced death.

Infrared LED irradiation photobiomodulation of oxidative stress in human dental pulp cells

2013 ◽  
Vol 47 (8) ◽  
pp. 747-755 ◽  
Author(s):  
L. A. Montoro ◽  
A. P. S. Turrioni ◽  
F. G. Basso ◽  
C. A. de Souza Costa ◽  
J. Hebling
Keyword(s):  
Oxidative Stress ◽  
Dental Pulp ◽  
Dental Pulp Cells ◽  
Human Dental Pulp Cells ◽  
Human Dental Pulp ◽  
Pulp Cells ◽  
Led Irradiation

N-acetyl Cysteine (NAC)-assisted Detoxification of PMMA Resin

2008 ◽  
Vol 87 (4) ◽  
pp. 372-377 ◽  
Author(s):  
M. Yamada ◽  
N. Kojima ◽  
A. Paranjpe ◽  
W. Att ◽  
H. Aita ◽  
...  
Keyword(s):  
Dental Pulp ◽  
Significant Degree ◽  
Cell Phenotype ◽  
Dependent Manner ◽  
Dental Pulp Cells ◽  
Concentration Dependent Manner ◽  
Pulp Cells ◽  
Acetyl Cysteine ◽  
Dentin Sialoprotein ◽  
Pmma Resin

Despite its proven cytotoxicity, poly-methyl methacrylate (PMMA) resin is one of the most frequently and extensively used materials in dental practice. This study hypothesized that an anti-oxidant amino acid, N-acetyl cysteine (NAC), has the potential to detoxify this material. Ten percent of the rat dental pulp cells were viable when cultured on the PMMA resin for 24 hours, while over 70% of the cells were viable on the NAC-added resin. Nearly all suppressed alkaline phosphatase activity, matrix mineralizing capability, and odontoblastic gene expression, such as dentin sialoprotein, on the untreated control resin was recovered by NAC in a concentration-dependent manner. A Ca/P ratio of 1.65 was found in the extracellular matrix of cultures on NAC-added resin, while that in the untreated resin culture was 0.70. The addition of NAC to PMMA resin significantly ameliorated its cytotoxicity to the dental pulp cells and restored their odontoblast-like cell phenotype to a biologically significant degree.

scholarly journals Oxidative stress alters mitochondrial bioenergetics and modifies pancreatic cell death independently of cyclophilin D, resulting in an apoptosis-to-necrosis shift

2018 ◽  
Vol 293 (21) ◽  
pp. 8032-8047 ◽  
Author(s):  
Jane A. Armstrong ◽  
Nicole J. Cash ◽  
Yulin Ouyang ◽  
Jack C. Morton ◽  
Michael Chvanov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Acinar Cell ◽  
Pancreatic Acinar Cell ◽  
Atp Depletion ◽  
Mitochondrial Bioenergetics ◽  
Dependent Manner ◽  
Cyclophilin D ◽  
Respiratory Capacity ◽  
Atp Turnover

Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+-dependent formation of the mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), the formation of which causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP formation and is elevated in clinical AP, but how reactive oxygen species influence cell death is unclear. Here, we assessed potential MPTP involvement in oxidant-induced effects on pancreatic acinar cell bioenergetics and fate. H2O2 application promoted acinar cell apoptosis at low concentrations (1–10 μm), whereas higher levels (0.5–1 mm) elicited rapid necrosis. H2O2 also decreased the mitochondrial NADH/FAD+ redox ratio and ΔΨm in a concentration-dependent manner (10 μm to 1 mm H2O2), with maximal effects at 500 μm H2O2. H2O2 decreased the basal O2 consumption rate of acinar cells, with no alteration of ATP turnover at <50 μm H2O2. However, higher H2O2 levels (≥50 μm) diminished spare respiratory capacity and ATP turnover, and bioenergetic collapse, ATP depletion, and cell death ensued. Menadione exerted detrimental bioenergetic effects similar to those of H2O2, which were inhibited by the antioxidant N-acetylcysteine. Oxidant-induced bioenergetic changes, loss of ΔΨm, and cell death were not ameliorated by genetic deletion of CypD or by its acute inhibition with cyclosporine A. These results indicate that oxidative stress alters mitochondrial bioenergetics and modifies pancreatic acinar cell death. A shift from apoptosis to necrosis appears to be associated with decreased mitochondrial spare respiratory capacity and ATP production, effects that are independent of CypD-sensitive MPTP formation.

Abstract 1783: Pro-Apoptotic Bnip3 Mediates Permeabilization of Mitochondria and Release of Cytocrome c via a Novel Mechanism

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Melissa N Quinsay ◽  
Shivaji Rikka ◽  
M Richard Sayen ◽  
Jeffery D Molkentin ◽  
Roberta A Gottlieb ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Matrix Protein ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Heart Association ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Cyclophilin D ◽  
The Matrix

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. The pro-apoptotic Bcl-2 proteins mediate mitochondrial dysfunction independent of the mitochondrial permeability transition pore (mPTP). However, Bnip3 has been reported to mediate cell death via the mPTP. In this study, we investigated the mechanism(s) by which Bnip3 causes mitochondrial dysfunction. Using a mitochondrial swelling assay to assess pore opening, we found that addition of 200 microM Ca2+ to mitochondria isolated from rat hearts induced rapid swelling of mitochondria and release of cytochrome c (cyto c). Bnip3 also induced mitochondrial swelling and cyto c release, but always at a slower rate and to a greater degree, suggesting that Bnip3 mediates swelling via a different mechanism. Cyclosporin A (CsA), an inhibitor of mPTP opening, prevented Ca2+-induced swelling and cyto c release, but had no effect on Bnip3. Another BH3-only protein, tBid, caused release of cyto c but failed to induce swelling of mitochondria. Interestingly, Bnip3, but not Ca2+ and tBid, induced release of the matrix protein MnSOD. Cyclophilin D (cycD) is an essential component of the mPTP and heart mitochondria isolated from cycD−/− mice were resistant to Ca2+-, but not to Bnip3-induced swelling and cyto c release. Also, tBid caused cyto c release without mitochondrial swelling in the absence of cycD. To further explore the mPTP as a downstream effector of Bnip3-mediated cell death, we assessed cell death in mouse embryonic fibroblasts (MEFs) isolated from wild type (wt) and cycD−/− mice. Infection with an adenovirus expressing Bnip3 caused significant cell death in wt (52.8±1.8%) and cycD−/− (61.8±6.1%) MEFs as measured by LDH release. In addition, both Bnip3 and opening of the mPTP have been reported to initiate upregulation of autophagy. Monitoring of GFP-LC3 incorporation into autophagosomes by fluorescence microscopy revealed that Bnip3 infection induced autophagy in wt (86.5±6.6%) and cycD−/− (96.4±1.4%) MEFs (n=3, p<0.05). Thus, these studies suggest that Bnip3 mediates permeabilization of the inner and outer mitochondrial membranes via a novel mechanism that is different from other BH3-only proteins. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2–AMPK–PGC1α signaling pathway

2019 ◽  
Vol 97 (4) ◽  
pp. 397-405 ◽  
Author(s):  
Bing Liu ◽  
Jiangbo Jin ◽  
Ziyu Zhang ◽  
Li Zuo ◽  
Meixiu Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Antitumor Activity ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathway ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Tricarboxylic Acid Cycle ◽  
Dependent Manner ◽  
Promising Therapeutic Approach

Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon, exhibits broad-spectrum antitumor activity via different molecular mechanisms. In this study, we investigated the effect of shikonin on mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanisms underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1α pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2–AMPK–PGC1α signaling pathway and provide a promising therapeutic approach for the treatment of HCC.

scholarly journals Elucidation of Molecular Mechanisms of Streptozotocin-Induced Oxidative Stress, Apoptosis, and Mitochondrial Dysfunction in Rin-5F Pancreatic β-Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Arwa M. T. Al Nahdi ◽  
Annie John ◽  
Haider Raza
Keyword(s):  
Oxidative Stress ◽  
Type 1 Diabetes ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Pancreatic Beta Cell ◽  
Dependent Manner ◽  
Respiratory Enzymes ◽  
Altered Expression ◽  
Pancreatic Cancer Cells

Streptozotocin is a pancreatic beta-cell-specific cytotoxin and is widely used to induce experimental type 1 diabetes in rodent models. The precise molecular mechanism of STZ cytotoxicity is however not clear. Studies have suggested that STZ is preferably absorbed by insulin-secreting β-cells and induces cytotoxicity by producing reactive oxygen species/reactive nitrogen species (ROS/RNS). In the present study, we have investigated the mechanism of cytotoxicity of STZ in insulin-secreting pancreatic cancer cells (Rin-5F) at different doses and time intervals. Cell viability, apoptosis, oxidative stress, and mitochondrial bioenergetics were studied. Our results showed that STZ induces alterations in glutathione homeostasis and inhibited the activities of the respiratory enzymes, resulting in inhibition of ATP synthesis. Apoptosis was observed in a dose- and time-dependent manner. Western blot analysis has also confirmed altered expression of oxidative stress markers (e.g., NOS and Nrf2), cell signaling kinases, apoptotic protein-like caspase-3, PARP, and mitochondrial specific proteins. These results suggest that STZ-induced cytotoxicity in pancreatic cells is mediated by an increase in oxidative stress, alterations in cellular metabolism, and mitochondrial dysfunction. This study may be significant in better understanding the mechanism of STZ-induced β-cell toxicity/resistance and the etiology of type 1 diabetes induction.

scholarly journals Inhibition of Carrageenin-induced Dental Inflammatory Responses Owing to Decreasing TRPV1 Activity by Dexmedetomidine

2019 ◽  
Author(s):  
Gang Lu ◽  
Guanhua Zhu ◽  
Maohua Xu ◽  
Xinggao Ping ◽  
Qingfeng Xiao
Keyword(s):  
Dental Pulp ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Dental Pulp Cells ◽  
Defensive Role ◽  
Pulp Inflammation ◽  
Human Dental Pulp ◽  
Pulp Cells

Abstract Background : Dexmedetomidine (Dex) is a highly selective agonist of the α2 adrenergic receptor and a common sedative; however, its anti-inflammatory effect has been studied. In this study, the inhibitory effect of Dex on inflammation in dental pulp cells was assessed. To solve this problem, the effect of Dex on inflammation induced by carrageenan (Car) in human dental pulp cells (hDPCs) was studied. Car incubation induced a robust inflammatory response in the hDPCs as well as activation of PKA–STAT3 and PKC–nuclear factor kappa B (NFκB) signaling pathways. Results : Dex could reduce the expression of inflammatory cytokines in a dose-dependent manner. Meanwhile, the phosphorylation of PKA, PKC, STAT3, and NFκB as well as the nuclear accumulation of STAT3 and NFκB were significantly increased in Dex-treated Car-induced hDPCs. Western blotting results also showed that the phosphorylation level of transient receptor potential cation channel subfamily V member 1 (TRPV1) was downregulated owing to Dex treatment. Further, we found that the administration of the TRPV1 agonist capsaicin (Cap) reversed the effects of Dex on proinflammatory cytokines; however, the expression and activation of PKA–STAT3 and PKC–NFκB signals were not altered owing to Cap administration. Conclusions : These results indicate that Dex exerts a defensive role in dental pulp inflammation by regulating the TRPV1 channel and can be used as a potential target for human dental pulp inflammation intervention.

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