scholarly journals Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Yunhe Zhao ◽  
Jiao Li ◽  
Wei Guo ◽  
Houxuan Li ◽  
Lang Lei
Keyword(s):  
Cell Death ◽  
Periodontal Ligament ◽  
Iron Homeostasis ◽  
Glutathione Depletion ◽  
Periodontal Pocket ◽  
Periodontal Ligament Fibroblasts ◽  
Periodontal Tissues ◽  
Regulated Cell Death ◽  
Long Term Treatment

Abstract Loss of periodontal ligament fibroblasts (PDLFs) is one critical issue for regenerating lost periodontal tissues. A wide variety of regulated cell death pathways, such as apoptosis, pyroptosis, and necroptosis have been proposed in the periodontitis development. The aim of the present study was to explore whether long-term periodontitis-level butyrate may trigger ferroptosis, a newly characterized iron-dependent regulated cell death in PDLFs. Here, we showed that long-term treatment of butyrate, an important short-chain fatty acid in the periodontal pocket, induces the cargo receptor nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis in PDLFs. Butyrate-induced iron accumulation, reactive oxygen species (ROS) generation, glutathione depletion and lipid peroxidation in PDLFs, and the butyrate-induced ferroptosis can be blocked by the lipid peroxide scavenger ferrostatin-1. The NCOA4-mediated ferritinophagy is dependent on p38/hypoxia inducible factor-1α (HIF-1α) pathway activation as well as Bromodomain-containing protein (BRD) 4 and cyclin-dependent kinase 9 (CDK9) coordination. These lines of evidence provide a new mechanistic insight into the mechanism of loss of PDLFs during periodontitis development, showing that periodontitis-level butyrate disrupted iron homeostasis by activation of NCOA4-mediated ferritinophagy, leading to ferroptosis in PDLFs.

scholarly journals Short- and long-term treatment with TNF-α inhibits the induction of osteoblastic differentiation in cyclic tensile-stretched periodontal ligament fibroblasts

2020 ◽  
Vol 42 (4) ◽  
pp. 396-406
Author(s):  
Adamantia Papadopoulou ◽  
Aurelie Cantele ◽  
Despina Koletsi ◽  
Theodore Eliades ◽  
Dimitris Kletsas
Keyword(s):  
Periodontal Ligament ◽  
Osteoblastic Differentiation ◽  
Marker Genes ◽  
Periodontal Ligament Fibroblasts ◽  
Alizarin Red ◽  
Differentiation Potential ◽  
Tnf Α ◽  
Long Term Treatment ◽  
Short And Long Term

Summary Background Cyclic tensile stretching (CTS) induces osteoblastic differentiation of periodontal ligament fibroblasts (PDLF). On the other hand, increased concentrations of tumour necrosis factor-α (TNF-α) are found in inflammatory conditions, leading to periodontal disease and tooth loss. Accordingly, our aim was to investigate the short- and long-term effect of TNF-α on the response of human PDLF to CTS and its implication on osteoblastic differentiation. Methods PDLF were either pre-incubated for 4 hours or were repeatedly exposed to TNF-α for up to 50 days and then subjected to CTS. Gene expression was determined by quantitative real-time polymerase chain reaction. Activation of mitogen-activated protein kinase (MAPK) was monitored by western analysis and cell proliferation by bromodeoxyuridine incorporation. Intracellular reactive oxygen species were determined by the 2´, 7´-dichlorofluorescein-diacetate assay and osteoblastic differentiation by Alizarin Red-S staining after an osteo-inductive period of 21 days. Results CTS of PDLF induced an immediate upregulation of the c-fos transcription factor and, further downstream the overexpression of alkaline phosphatase and osteopontin, two major osteoblast marker genes. A 4-hour pre-incubation with TNF-α repressed these effects. Similarly, long-term propagation of PDLF along with TNF-α diminished their osteoblastic differentiation capacity and suppressed cells’ CTS-elicited responses. The observed phenomena were not linked with TNF-α-induced premature senescence or oxidative stress. While CTS induced the activation of MAPKs, involved in mechanotransduction, TNF-α treatment provoked a small delay in the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. Conclusion Increased concentrations of TNF-α, such as those recorded in many inflammatory diseases, suppress PDLF’s immediate responses to mechanical forces compromising their osteoblastic differentiation potential, possibly leading to tissue’s impaired homeostasis.

scholarly journals In Vitro Compression Model for Orthodontic Tooth Movement Modulates Human Periodontal Ligament Fibroblast Proliferation, Apoptosis and Cell Cycle

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 932
Author(s):  
Julia Brockhaus ◽  
Rogerio B. Craveiro ◽  
Irma Azraq ◽  
Christian Niederau ◽  
Sarah K. Schröder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Periodontal Ligament ◽  
Environmental Changes ◽  
Tooth Movement ◽  
Orthodontic Tooth Movement ◽  
Compressive Force ◽  
Periodontal Ligament Fibroblasts ◽  
Human Periodontal Ligament Fibroblasts

Human Periodontal Ligament Fibroblasts (hPDLF), as part of the periodontal apparatus, modulate inflammation, regeneration and bone remodeling. Interferences are clinically manifested as attachment loss, tooth loosening and root resorption. During orthodontic tooth movement (OTM), remodeling and adaptation of the periodontium is required in order to enable tooth movement. hPDLF involvement in the early phase-OTM compression side was investigated for a 72-h period through a well-studied in vitro model. Changes in the morphology, cell proliferation and cell death were analyzed. Specific markers of the cell cycle were investigated by RT-qPCR and Western blot. The study showed that the morphology of hPDLF changes towards more unstructured, unsorted filaments under mechanical compression. The total cell numbers were significantly reduced with a higher cell death rate over the whole observation period. hPDLF started to recover to pretreatment conditions after 48 h. Furthermore, key molecules involved in the cell cycle were significantly reduced under compressive force at the gene expression and protein levels. These findings revealed important information for a better understanding of the preservation and remodeling processes within the periodontium through Periodontal Ligament Fibroblasts during orthodontic tooth movement. OTM initially decelerates the hPDLF cell cycle and proliferation. After adapting to environmental changes, human Periodontal Ligament Fibroblasts can regain homeostasis of the periodontium, affecting its reorganization.

scholarly journals Ferrous-glutathione coupling mediates ferroptosis and frailty in Caenorhabditis elegans

2019 ◽  
Author(s):  
Nicole L. Jenkins ◽  
Simon A. James ◽  
Agus Salim ◽  
Fransisca Sumardy ◽  
Terence P. Speed ◽  
...  
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Ferrous Iron ◽  
Somatic Tissue ◽  
Glutathione Depletion ◽  
Death Process ◽  
C Elegans ◽  
Regulated Cell Death ◽  
Age Related ◽  
Ageing Rate

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis1, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in the Caenorhabditis elegans model of ageing2. Here we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan in C. elegans. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant ageing rate. Because excess age-related iron elevation in somatic tissue, particularly in brain3–5, is thought to contribute to degenerative disease6, 7, our data indicate that post-developmental interventions to limit ferroptosis may promote healthy ageing.

scholarly journals LPS fromP. gingivalisand Hypoxia Increases Oxidative Stress in Periodontal Ligament Fibroblasts and Contributes to Periodontitis

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
L. Gölz ◽  
S. Memmert ◽  
B. Rath-Deschner ◽  
A. Jäger ◽  
T. Appel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Periodontal Ligament ◽  
Inflammatory Diseases ◽  
Periodontal Pathogen ◽  
Oral Diseases ◽  
Redox Systems ◽  
Periodontal Ligament Fibroblasts ◽  
Prolonged Incubation ◽  
Periodontal Tissues ◽  
Pdl Cells

Oxidative stress is characterized by an accumulation of reactive oxygen species (ROS) and plays a key role in the progression of inflammatory diseases. We hypothesize that hypoxic and inflammatory events induce oxidative stress in the periodontal ligament (PDL) by activating NOX4. Human primary PDL fibroblasts were stimulated with lipopolysaccharide fromPorphyromonas gingivalis(LPS-PG), a periodontal pathogen bacterium under normoxic and hypoxic conditions. By quantitative PCR, immunoblot, immunostaining, and a specific ROS assay we determined the amount of NOX4, ROS, and several redox systems. Healthy and inflamed periodontal tissues were collected to evaluate NOX4 and redox systems by immunohistochemistry. We found significantly increased NOX4 levels after hypoxic or inflammatory stimulation in PDL cells (P<0.001) which was even more pronounced after combination of the stimuli. This was accompanied by a significant upregulation of ROS and catalase (P<0.001). However, prolonged incubation with both stimuli induced a reduction of catalase indicating a collapse of the protective machinery favoring ROS increase and the progression of inflammatory oral diseases. Analysis of inflamed tissues confirmed our hypothesis. In conclusion, we demonstrated that the interplay of NOX4 and redox systems is crucial for ROS formation which plays a pivotal role during oral diseases.

Abstract 2741: S-Nitrosoglutathione Increases Benefit of Motor Exercise on Functional Recovery and Stimulates Neurorepair Mechanisms Following Experimental Stroke in Rats

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Mushfiquddin Khan ◽  
Harutoshi Sakakima ◽  
Tajinder S Dhammu ◽  
Shunmugavel Anandakumar ◽  
Inderjit Singh ◽  
...  
Keyword(s):  
Cell Death ◽  
Functional Recovery ◽  
Neurotrophic Factors ◽  
Neuronal Cell ◽  
Male Rats ◽  
Experimental Stroke ◽  
Protective Agent ◽  
Neurobehavioral Function ◽  
Long Term Treatment

Background: Stroke is the leading cause of long-term physical disability and life-long neurologic deficits. The disability stems from acute neurovascular injury and injury-induced compromised neuroplasticity. This neuroplasticity can be restored by stimulating neurotrophic factors via two possible modalities: rehabilitation activity and neurorepair therapy. Improvement of neurologic function has been achieved following brain trauma by the neurovascular protective agent S-nitrosoglutathione (GSNO). Therefore, we investigated whether GSNO stimulates the expression neurotrophic factors and enhances the benefits of motor exercise, leading to functional recovery in a rat model of experimental stroke. Methods: Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) for 60 min followed by reperfusion in adult male rats. Injured animals were either treated with vehicle (IR group), GSNO (0.25 mg/kg, GSNO group) or underwent rotarod exercise (EX group). In the third treatment group, GSNO was combined with rotarod exercise (GSNO+EX group). The groups were compared in terms of brain infarction, neurological score, motor function, cell death, tissue structure, and the expression of the neurotrophic factors BDNF, TrKB, and myelin. Results: All three treated groups (GSNO, EX and GSNO+EX) showed reduced infarction, improved motor and neurological functions, and decreased apoptotic neuronal cell death compared to the IR group. However, the combination group GSNO+EX showed a trend toward greater recovery than the GSNO or EX group alone. All the three treated groups also showed enhanced expression of neurotrophic factors and improved tissue histology. A delayed intervention (24 h after IR) by GSNO also aided the functional recovery. Furthermore, the protective effect of GSNO and exercise was blunted in another set of animals by an inhibition of AKT activity using the PI3 kinase inhibitor LY 294002 compound. Conclusion: GSNO, like exercise, aids recovery of functions in a long-term treatment by stimulating the expression of neurotrophic factors, reducing infarctions, and decreasing cell death. A combination of exercise and GSNO shows a greater degree of improvement in neurobehavioral function. Clinical relevance of the therapy is supported by an improved functional recovery even when GSNO was administered 24 h following IR. Mechanistically, the improvements by GSNO and exercise are dependent, at least in part, on AKT activity.

scholarly journals Long-Term Treatment of Anterior Pituitary Cells with Nitric Oxide Induces Programmed Cell Death

Endocrinology ◽  
2004 ◽  
Vol 145 (4) ◽  
pp. 2064-2070 ◽  
Author(s):  
Miguel Omar Velardez ◽  
Ariel Hernán Poliandri ◽  
Jimena Paula Cabilla ◽  
Cristian Carlos Armando Bodo ◽  
Leticia Inés Machiavelli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Anterior Pituitary ◽  
Term Treatment ◽  
Pituitary Cells ◽  
Anterior Pituitary Cells ◽  
Long Term Treatment

scholarly journals Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Nicole L Jenkins ◽  
Simon A James ◽  
Agus Salim ◽  
Fransisca Sumardy ◽  
Terence P Speed ◽  
...  
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Ferrous Iron ◽  
Healthy Aging ◽  
Somatic Tissue ◽  
Glutathione Depletion ◽  
Death Process ◽  
Regulated Cell Death ◽  
Age Related ◽  
Cell Death Process

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

scholarly journals Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Yi Luo ◽  
Xu Gao ◽  
Luetao Zou ◽  
Miao Lei ◽  
Junming Feng ◽  
...  
Keyword(s):  
Cell Death ◽  
Glutathione Depletion ◽  
Ros Generation ◽  
Mitochondrial Morphology ◽  
Iron Level ◽  
Intracellular Iron ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Regulated Cell Death

Ferroptosis is a new form of regulated cell death, which is mediated by intracellular iron. Although it is reported that bavachin has antitumour effects on several tumour cells and prompts the reactive oxygen species (ROS) generation, it is unclear whether ferroptosis can be induced by bavachin in osteosarcoma (OS) cells. In this study, we found that bavachin inhibits the viability of MG63 and HOS OS cell lines along with an increase in the ferrous iron level, ROS accumulation, malondialdehyde overexpression, and glutathione depletion. Moreover, iron chelators (deferoxamine), antioxidants (Vit E), and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) reverse bavachin-induced cell death. Bavachin also altered the mitochondrial morphology of OS cells, leading to smaller mitochondria, higher density of the mitochondrial membrane, and reduced mitochondrial cristae. Further investigation showed that bavachin upregulated the expression of transferrin receptor, divalent metal transporter-1, and P53, along with downregulating the expression of ferritin light chain, ferritin heavy chain, p-STAT3 (705), SLC7A11, and glutathione peroxidase-4 in OS cells. More importantly, STAT3 overexpression, SLC7A11 overexpression, and pretreatment with pifithrin-α (P53 inhibitor) rescued OS cell ferroptosis induced by bavachin. The results show that bavachin induces ferroptosis via the STAT3/P53/SLC7A11 axis in OS cells.

scholarly journals Long-Term Treatment of HIV-Infected MT-4 Cells in Culture with HIV Proteinase Inhibitor RO 31-8959 Leads to Complete Cure of Infection

1994 ◽  
Vol 5 (4) ◽  
pp. 236-242 ◽  
Author(s):  
H. Nitschko ◽  
H. Lindhofer ◽  
H. Schätzl ◽  
J. Eberle ◽  
G. Deby ◽  
...  
Keyword(s):  
Cell Culture ◽  
Cell Death ◽  
Hiv Infection ◽  
Proteinase Inhibitor ◽  
Proteinase Inhibitors ◽  
Antiviral Effect ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Drug Removal

An HIV-infected cell culture was treated with the specific HIV proteinase inhibitor Ro 31-8959 for three months to analyse the antiviral effect and possible cytotoxicity of the drug in long-term treatment. The drug was added 1 h after HIV infection with 0.002 m.o.i. and maintained for 87 days in the cell culture. There was no detectable cell death nor any evidence of HIV production in this time. Cells were proven to be initially infected, since premature drug removal led to a re-emergence of infectious HIV and cell death. However, after 87 days of treatment the drug could be removed safely and HIV was cleared demonstrably from the culture. These data suggest that long-term dosage may be advantageous to the clinical treatment of HIV infection by HIV proteinase inhibitors.

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