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International Journal of Molecular... Mar 2022With the increase in life expectancy and consequent aging of the world's population, the prevalence of many neurodegenerative diseases is increasing, without concomitant...
With the increase in life expectancy and consequent aging of the world's population, the prevalence of many neurodegenerative diseases is increasing, without concomitant improvement in diagnostics and therapeutics. These diseases share neuropathological hallmarks, including mitochondrial dysfunction. In fact, as mitochondrial alterations appear prior to neuronal cell death at an early phase of a disease's onset, the study and modulation of mitochondrial alterations have emerged as promising strategies to predict and prevent neurotoxicity and neuronal cell death before the onset of cell viability alterations. In this work, differentiated SH-SY5Y cells were treated with the mitochondrial-targeted neurotoxicants 6-hydroxydopamine and rotenone. These compounds were used at different concentrations and for different time points to understand the similarities and differences in their mechanisms of action. To accomplish this, data on mitochondrial parameters were acquired and analyzed using unsupervised (hierarchical clustering) and supervised (decision tree) machine learning methods. Both biochemical and computational analyses resulted in an evident distinction between the neurotoxic effects of 6-hydroxydopamine and rotenone, specifically for the highest concentrations of both compounds.
Topics: Apoptosis; Cell Death; Cell Line, Tumor; Cell Survival; Humans; Neuroprotective Agents; Neurotoxicity Syndromes; Oxidopamine; Rotenone
PubMed: 35328430
DOI: 10.3390/ijms23063009 -
Molecular Psychiatry Apr 2023Bipolar-disorder's pathophysiology and the mechanism by which medications exert their beneficial effect is yet unknown, but others' and our data implicate patients'...
Does treatment with autophagy-enhancers and/or ROS-scavengers alleviate behavioral and neurochemical consequences of low-dose rotenone-induced mild mitochondrial dysfunction in mice?
Bipolar-disorder's pathophysiology and the mechanism by which medications exert their beneficial effect is yet unknown, but others' and our data implicate patients' brain mitochondrial-dysfunction and its amendment by mood-stabilizers. We recently designed a novel mouse bipolar-disorder-like model using chronic administration of a low-dose of the oxidative-phosphorylation complex I inhibitor, rotenone. Four and eight weeks rotenone treatment induced manic- and depressive-like behavior, respectively, accompanied by mood-related neurochemical changes. Here we aimed to investigate whether each of the autophagy-enhancers lithium (a mood-stabilizer), trehalose and resveratrol and/or each of the reactive oxygen species (ROS)-scavengers, resveratrol and N-acetylcystein and/or the combinations lithium+resveratrol or trehalose+N-acetylcystein, can ameliorate behavioral and neurochemical consequences of neuronal mild mitochondrial-dysfunction. We observed that lithium, trehalose and N-acetylcystein reversed rotenone-induced manic-like behavior as well as deviations in protein levels of mitochondrial complexes and the autophagy marker LC3-II. This raises the possibility that mild mitochondrial-dysfunction accompanied by impaired autophagy and a very mild increase in ROS levels are related to predisposition to manic-like behavior. On the other hand, although, as expected, most of the drugs tested eliminated the eight weeks rotenone-induced increase in protein levels of all hippocampal mitochondrial complexes, only lithium ubiquitously ameliorated the depressive-like behaviors. We cautiously deduce that aberrant autophagy and/or elevated ROS levels are not involved in predisposition to the depressive phase of bipolar-like behavior. Rather, that amending the depressive-like characteristics requires different mitochondria-related interventions. The latter might be antagonizing N-methyl-D-aspartate receptors (NMDARs), thus protecting from disruption of mitochondrial calcium homeostasis and its detrimental consequences. In conclusion, our findings suggest that by-and-large, among the autophagy-enhancers and ROS-scavengers tested, lithium is the most effective in counteracting rotenone-induced changes. Trehalose and N-acetylcystein may also be effective in attenuating manic-like behavior.
Topics: Animals; Mice; Lithium; Reactive Oxygen Species; Resveratrol; Rotenone; Trehalose; Autophagy; Brain Diseases; Mitochondria
PubMed: 36690794
DOI: 10.1038/s41380-023-01955-x -
Biochimica Et Biophysica Acta.... Mar 2023Rotenone has widespread beneficial effects in agriculture, fisheries and animal husbandries; however prolonged exposure causes a detrimental effect on the health of...
Rotenone has widespread beneficial effects in agriculture, fisheries and animal husbandries; however prolonged exposure causes a detrimental effect on the health of personnel working in such industries. Rotenone during its extraction, formulation or usage may cross the blood brain barrier leading to neurodegeneration and the development of Parkinson's disease like symptoms. It is a known inhibitor of the mitochondrial ETC complex I and responsible for impairing the OXPHOS system. Our study showed that rotenone exposure results in an increased production of ROS and decreased ATP level along with a conspicuous loss of mitochondrial membrane potential in N2A cells. The transcription and expression pattern of cofilin, a key component of actin cytoskeleton, was also altered after rotenone exposure; leading to the actin cytoskeleton degradation. We further observed an increased expression, as well as activity of matrix metalloproteinase9 (MMP9) in rotenone exposed N2A cells; suggesting the involvement of inflammation upon rotenone exposure. Simultaneously, an opposite pattern was noticed for the tissue inhibitors of metalloproteinases-1 (TIMP-1) protein, which is a known modulator of MMP9 activity. Additionally, the localization of MMP9 along with alpha-synuclein, UCHL1 and cofilin suggested their close proximity and cross interaction upon rotenone treatment. Furthermore, we observed significant increase in the level of TNF-α upon rotenone exposure along with the phosphorylation of RIPK1, RIPK3 and MLKL that has been identified as the necroptosis markers leading to programmed necroptotic death.
Topics: Animals; Rotenone; Protein Kinases; Necroptosis; Matrix Metalloproteinase 9; Cytoskeleton
PubMed: 36581087
DOI: 10.1016/j.bbamcr.2022.119417 -
Free Radical Biology & Medicine Mar 2024Peripheral autonomic nervous system (P-ANS) dysfunction is a critical non-motor phenotype of Parkinson's disease (PD). The majority of PD cases are sporadic and lack...
Peripheral autonomic nervous system (P-ANS) dysfunction is a critical non-motor phenotype of Parkinson's disease (PD). The majority of PD cases are sporadic and lack identified PD-associated genes involved. Epidemiological and animal model studies suggest an association with pesticides and other environmental toxins. However, the cellular mechanisms underlying toxin induced P-ANS dysfunctions remain unclear. Here, we mapped the global transcriptome changes in human induced pluripotent stem cell (iPSC) derived P-ANS sympathetic neurons during inhibition of the mitochondrial respiratory chain by the PD-related pesticide, rotenone. We revealed distinct transcriptome profiles between acute and chronic exposure to rotenone. In the acute stage, there was a down regulation of specific cation channel genes, known to mediate electrophysiological activity, while in the chronic stage, the human P-ANS neurons exhibited dysregulation of anti-apoptotic and Golgi apparatus-related pathways. Moreover, we identified the sodium voltage-gated channel subunit SCN3A/Nav1.3 as a potential biomarker in human P-ANS neurons associated with PD. Our analysis of the rotenone-altered coding and non-coding transcriptome of human P-ANS neurons may thus provide insight into the pathological signaling events in the sympathetic neurons during PD progression.
Topics: Animals; Humans; Parkinson Disease; Rotenone; Induced Pluripotent Stem Cells; Neurons; Phenotype
PubMed: 38246514
DOI: 10.1016/j.freeradbiomed.2024.01.016 -
Free Radical Biology & Medicine May 2008Tight regulation of intracellular iron levels in response to mitochondrial dysfunction is an important mechanism that prevents oxidative stress, thereby limiting...
Tight regulation of intracellular iron levels in response to mitochondrial dysfunction is an important mechanism that prevents oxidative stress, thereby limiting cellular damage. Here, we describe a cytoprotective response involving transcriptional activation of the ferritin H gene in response to the mitochondrial complex I inhibitor and neurotoxic compound rotenone. Rotenone exposure increased ferritin H mRNA and protein synthesis in NIH3T3 fibroblasts and SH-SY5Y neuroblastoma cells. Transient transfection of a ferritin H promoter-luciferase reporter into NIH3T3 cells showed that ferritin H was transcriptionally activated by rotenone through an antioxidant-responsive element (ARE). Chromatin immunoprecipitation assays showed that rotenone treatment enhanced binding of Nrf2 and JunD transcription factors to the ARE. In addition, rotenone induced production of reactive oxygen species (ROS), and pretreatment with N-acetylcysteine abrogated ferritin H mRNA induction by rotenone, suggesting that this response is oxidative stress-mediated. Furthermore, reduced ferritin H expression by siRNA sensitized cells to rotenone-induced apoptosis with increased ROS production and annexin V-positive cells. Taken together, these results suggest that ferritin H transcription is activated by rotenone via an oxidative stress-mediated pathway leading to ARE activation and may be critically important to protect cells from mitochondrial dysfunction and oxidative stress.
Topics: Animals; Antioxidants; Apoferritins; Cell Line, Tumor; Gene Expression Regulation; Humans; Mice; Mitochondria; Models, Biological; NF-E2-Related Factor 2; NIH 3T3 Cells; Oxidative Stress; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-jun; Rotenone; Uncoupling Agents
PubMed: 18325346
DOI: 10.1016/j.freeradbiomed.2008.01.031 -
Chemosphere Feb 2022Rotenone is a pesticide commonly used to eradicate Northern Pike (Esox lucius), an invasive species, in Southcentral Alaska. The present work incorporates a field...
Rotenone is a pesticide commonly used to eradicate Northern Pike (Esox lucius), an invasive species, in Southcentral Alaska. The present work incorporates a field investigation of rotenone attenuation in eight lakes of the Kenai Peninsula, following a CFT Legumine® treatment in October 2018 and a laboratory simulation to determine persistence under light/dark and sterile/nonsterile conditions representative of Southcentral Alaskan winters. In the field, rotenone degraded within <60 days of application in all lakes, while rotenolone, the primary product of rotenone degradation, persisted for up to <280 days post-treatment at two locations. Prolonged rotenolone attenuation was most likely caused by short days and ice cover between October and April. This hypothesis was supported by a laboratory simulation which revealed photolysis as the dominant process driving the overall degradation of rotenone and that microbial degradation will significantly contribute in the absence of sunlight under simulated "winter" conditions of 4 °C. Degradation model fit comparisons (pseudo-first order, multi-parameter linear, and gamma) indicate the most accurate prediction occurred when modeling all eight lakes grouped together in a single dataset, combined and treated with pseudo-first order model kinetics, based on Akaike information criteria (AIC) scores.
Topics: Alaska; Laboratories; Lakes; Pesticides; Rotenone
PubMed: 34626650
DOI: 10.1016/j.chemosphere.2021.132478 -
Clinical and Experimental Pharmacology... Aug 2020Rotenone, a toxic rotenoid compound, has anti-tumour effects on several cancers. This study aims to clarify the effect of rotenone on the proliferation, apoptosis,...
Rotenone, a toxic rotenoid compound, has anti-tumour effects on several cancers. This study aims to clarify the effect of rotenone on the proliferation, apoptosis, invasion and migration of colon cancer cells and tumourigenesis in nude mice. The present results show that rotenone significantly inhibited the proliferation, promoted the apoptosis, and suppressed the invasion and migration of colon cancer cells in a dose-dependent manner. Rotenone inhibited PI3K/AKT pathway in LoVo and SW480 cells in a dose-dependent manner. In addition, rotenone regulated the proliferation, apoptosis, invasion, migration and EMT of LoVo and SW480 cells through PI3K/AKT pathway. In colon cancer xenograft mice, rotenone inhibited tumour volume and weight in nude mice, inhibited PI3K/AKT pathway and EMT in vivo. Therefore, rotenone inhibited the proliferation, invasion and migration, promoted the apoptosis of colon cancer cells through PI3K/AKT pathway in vitro, and suppressed the tumourigenesis in nude mice in vivo.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; Epithelial-Mesenchymal Transition; Humans; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rotenone; Xenograft Model Antitumor Assays
PubMed: 32282954
DOI: 10.1111/1440-1681.13320 -
Frontiers in Bioscience (Landmark... Nov 2023Neurodegenerative diseases, including age-related macular degeneration (AMD), may be linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. We...
BACKGROUND
Neurodegenerative diseases, including age-related macular degeneration (AMD), may be linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. We examined whether Pigment epithelium-derived factor (PEDF) could prevent changes in the structure and function of these organelles by accelerating by rotenone (ROT), a mitochondrial inhibitor, in human retinal pigment epithelium (RPE) cells of chronological age.
METHODS
RPE cells from 9-20, 50-55, 60-70, and >70-year-old donors were isolated, grown as primary cultures, harvested, and treated with ROT and PEDF for electron microscope (EM), western blot analysis, and polymerase chain reaction (PCR). Reactive oxygen species (ROS) and cytoplasmic calcium [Ca2+]c and mitochondrial calcium [Ca2+]m levels were measured by flow cytometry using 2',7'-dichlorodihydrofluorescin diacetate (H2-DCF-DA), fluo-3/AM, and Rhod-2/AM, and ATP levels were measured using a luciferin/luciferase-based assay. Mitochondrial membrane potential (ΔΨm) was detected using 5,5',6,6'-tetrachloro1,1',3,3'-tetraethylbenzimid azolocarbocyanine iodide (JC-1), and susceptibility of the cells to ROT toxicity and PEDF-protective effect was determined by propidium iodide (PI) staining and lactate dehydrogenase (LDH) assay. The expression of ER stress-related genes was detected using real-time (RT)-PCR.
RESULTS
We observed decay in the mitochondria of aged RPE cells, including matrix abnormalities, elongation, loss of cristae, and disruption of membrane integrity after ROT treatment. We also observed lower [Ca2+]c, higher ROS and [Ca2+]m levels, decreased ΔΨm after ROT treatment, and greater susceptibility to ROT toxicity in aged RPE cells. PEDF can protect the cristae and integrity of the mitochondrial membrane, increase ATP levels and ΔΨm, and lower ROS, [Ca2+]c, and [Ca2+]m in aged RPE cells induced by ROT. In addition, there was an increase in RDH expression in RPE cells with increasing age after PEDF treatment. Similarly, PEDF decreased the expression of ROT-induced ER stress-related genes.
CONCLUSIONS
Our study provides evidence that PEDF can reduce bioenergetic deficiencies, mitochondrial decay, and ER stress in aging RPE, a condition that may trigger the onset of retinal diseases such as AMD.
Topics: Humans; Aged; Reactive Oxygen Species; Rotenone; Calcium; Cells, Cultured; Mitochondria; Adenosine Triphosphate; Oxidative Stress
PubMed: 38062839
DOI: 10.31083/j.fbl2811319 -
Brain Research Bulletin Sep 2023Young onset Parkinson disease (YOPD) accounts for about 10% of PD patients, with the onset of symptoms between the ages of 21 and 40. At this age, the probability of...
BACKGROUND
Young onset Parkinson disease (YOPD) accounts for about 10% of PD patients, with the onset of symptoms between the ages of 21 and 40. At this age, the probability of pregnancy is high and there is a concern that the disease affects the fetuses. Therefore, in the present study, the effects of rotenone-induced PD on female mice as well as their fetuses and curcumin supplementation on the cerebral tissue of both female mice and their resulted fetuses were studied.
METHODS
The rotenone was injected subcutaneously to induce PD model of female mice. The different concentrations of curcumin were administrated every day i.p. for 3 weeks and the rotarod test was done on day 1 and 19. Cell viability was measured by MTT test and apoptosis and necrosis of cells were evaluate using flow cytometry technique. After primer design, the expressions of bax, bcl-2, miR-211 and circRNA 0001518 genes were measured using RT-PCR technique.
RESULTS
Curcumin administration were improved cerebral cell viability of both female PD mice and resulted fetuses by preventing cell apoptosis and necrosis. bax, miR-211 and circRNA 0001518 were downregulated and bcl-2 overexpressed in cerebral neurons of PD mice and their fetuses.
CONCLUSION
PD induction in mice affects their fetal brain, and curcumin can partially reduce the negative effects of PD on fetal brain cells by overexpressing bcl-2 and decreasing bax expression genes.
Topics: Mice; Female; Animals; Pregnancy; Parkinson Disease; Curcumin; Neuroprotective Agents; Rotenone; bcl-2-Associated X Protein; RNA, Circular; Apoptosis; Proto-Oncogene Proteins c-bcl-2; Necrosis; MicroRNAs
PubMed: 37543296
DOI: 10.1016/j.brainresbull.2023.110726 -
CNS Neuroscience & Therapeutics Aug 2023The etiology of Parkinson's disease (PD) is still unknown. Until now, oxidative stress and neuroinflammation play a crucial role in the pathogenesis of PD. However, the...
INTRODUCTION
The etiology of Parkinson's disease (PD) is still unknown. Until now, oxidative stress and neuroinflammation play a crucial role in the pathogenesis of PD. However, the specific synergistic role of oxidative stress and neuroinflammation in the occurrence and development of PD remains unclear.
METHODS
The changes in motor behavior, dopamine (DA) neurons quantification and their mitochondrial respiratory chain, glial cells activation and secreted cytokines, Nrf2 signaling pathway, and redox balance in the brain of rats were evaluated.
RESULTS
Lipopolysaccharide (LPS)-induced neuroinflammation and rotenone (ROT)-induced oxidative stress synergistically aggravated motor dysfunction, DA neuron damage, activation of glial cells, and release of related mediators, activation of Nrf2 signaling and destruction of oxidative balance. In addition, further studies indicated that after ROT-induced oxidative stress caused direct damage to DA neurons, LPS-induced inflammatory effects had stronger promoting neurotoxic effects on the above aspects.
CONCLUSIONS
Neuroinflammation and oxidative stress synergistically aggravated DA neuronal loss. Furtherly, oxidative stress followed by neuroinflammation caused more DA neuronal loss than neuroinflammation followed by oxidative stress.
Topics: Rats; Animals; Rotenone; Lipopolysaccharides; Dopamine; Neuroinflammatory Diseases; NF-E2-Related Factor 2; Parkinson Disease; Oxidative Stress; Dopaminergic Neurons
PubMed: 36942519
DOI: 10.1111/cns.14180