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Journal of Translational Medicine May 2024As a key factor in determining testis size and sperm number, sertoli cells (SCs) play a crucial role in male infertility. Heat stress (HS) reduces SCs counts, negatively...
As a key factor in determining testis size and sperm number, sertoli cells (SCs) play a crucial role in male infertility. Heat stress (HS) reduces SCs counts, negatively impacting nutrient transport and supply to germ cells, and leading to spermatogenesis failure in humans and animals. However, how HS affects the number of SCs remains unclear. We hypothesized that changes in SC metabolism contribute to the adverse effects of HS. In this study, we first observed an upregulation of arachidonic acid (AA), an unsaturated fatty acid after HS exposure by LC-MS/MS metabolome detection. By increasing ROS levels, expression of KEAP1 and NRF2 proteins as well as LC3 and LAMP2, 100 µM AA induced autophagy in SCs by activating oxidative stress (OS). We observed adverse effects of AA on mitochondria under HS with a decrease of mitochondrial number and an increase of mitochondrial membrane potential (MMP). We also found that AA alternated the oxygen transport and absorption function of mitochondria by increasing glycolysis flux and decreasing oxygen consumption rate as well as the expression of mitochondrial electron transport chain (ETC) proteins Complex I, II, V. However, pretreatment with 5 mM NAC (ROS inhibitor) and 2 µM Rotenone (mitochondrial ETC inhibitor) reversed the autophagy induced by AA. In summary, AA modulates autophagy in SCs during HS by disrupting mitochondrial ETC function, inferring that the release of AA is a switch-like response, and providing insight into the underlying mechanism of high temperatures causing male infertility.
Topics: Male; Sertoli Cells; Autophagy; Animals; Mitochondria; Heat-Shock Response; Arachidonic Acid; Up-Regulation; Electron Transport; Membrane Potential, Mitochondrial; Oxidative Stress; Reactive Oxygen Species
PubMed: 38797842
DOI: 10.1186/s12967-024-05182-y -
Life (Basel, Switzerland) May 2024The aquatic environment encompasses a wide variety of pollutants, from plastics to drug residues, pesticides, food compounds, and other food by-products, and improper... (Review)
Review
The aquatic environment encompasses a wide variety of pollutants, from plastics to drug residues, pesticides, food compounds, and other food by-products, and improper disposal of waste is the main cause of the accumulation of toxic substances in water. Monitoring, assessing, and attempting to control the effects of contaminants in the aquatic environment are necessary and essential to protect the environment and thus human and animal health, and the study of aquatic ecotoxicology has become topical. In this respect, zebrafish are used as model organisms to study the bioaccumulation, toxicity, and influence of environmental pollutants due to their structural, functional, and material advantages. There are many similarities between the metabolism and physiological structures of zebrafish and humans, and the nervous system structure, blood-brain barrier function, and social behavior of zebrafish are characteristics that make them an ideal animal model for studying neurotoxicity. The aim of the study was to highlight the neurotoxicity of nanoplastics, microplastics, fipronil, deltamethrin, and rotenone and to highlight the main behavioral, histological, and oxidative status changes produced in zebrafish exposed to them.
PubMed: 38792660
DOI: 10.3390/life14050640 -
Brain Sciences May 2024Rotenone is a pesticide used in research for its ability to induce changes similar, in vivo and in vitro, to those observed in Parkinson's disease (PD). This includes a...
Rotenone is a pesticide used in research for its ability to induce changes similar, in vivo and in vitro, to those observed in Parkinson's disease (PD). This includes a selective death of dopaminergic neurons in the substantia nigra. Nonetheless, the precise mechanism through which rotenone modifies structure and function of neurons remains unclear. The PC12 cells closely resemble dopamine terminal neurons. This makes it a preferred model for studying the morphology of central dopamine neurons and predicting neurotoxicity. In this paper, we investigated the effects of 0.5 µM rotenone for 24-48 h on PC12 cell viability and ultrastructure (TEM), trying to identify primary and more evident alterations that can be related to neuronal damages similar to that seen in animal PD models. Cell viability decreased after 24 h rotenone treatment, with a further decrease after 48 h. Ultrastructural changes included vacuolar degeneration, mitochondrial mild swelling, decrease in the number of neuropeptide granules, and the loss of cell-to-cell adhesion. These findings are in agreement with previous research suggesting that rotenone, by inhibiting energy production and increasing ROS generation, is responsible for significant alterations of the ultrastructure and cell death of PC12 cells. Our data confirm the link between rotenone exposure, neuronal damage, and changes in dopamine metabolism, suggesting its role in the pathogenesis of PD.
PubMed: 38790454
DOI: 10.3390/brainsci14050476 -
Cells May 2024Parkinson's disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also...
Parkinson's disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder.
Topics: Animals; Disease Models, Animal; Mice; Parkinson Disease; Rotenone; Mice, Inbred C57BL; Male; Peripheral Nervous System Diseases; Corpus Striatum; Dopamine
PubMed: 38786023
DOI: 10.3390/cells13100799 -
BMC Pharmacology & Toxicology May 2024The specific mechanism by which rotenone impacts thoracic aortic autophagy and apoptosis is unknown. We aimed to investigate the regulatory effects of rotenone on...
BACKGROUND
The specific mechanism by which rotenone impacts thoracic aortic autophagy and apoptosis is unknown. We aimed to investigate the regulatory effects of rotenone on autophagy and apoptosis in rat thoracic aortic endothelial cells (RTAEC) via activation of the LKB1-AMPK-ULK1 signaling pathway and to elucidate the molecular mechanisms of rotenone on autophagy and apoptosis in vascular endothelial cells.
METHODS
In vivo, 60 male SD rats were randomly selected and divided into 5 groups: control (Con), DMSO, 1, 2, and 4 mg/kg groups, respectively. After 28 days of treatment, histopathological and ultrastructural changes in each group were observed using HE and transmission electron microscopy; Autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related proteins were detected by Western blot; Apoptosis levels in the thoracic aorta were detected by TUNEL. In vitro, RTAEC were cultured and divided into control (Con), DMSO, 20, 100, 500, and 1000 nM groups. After 24 h of intervention, autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related factors were detected by Western blot and qRT-PCR; Flow cytometry to detect apoptosis levels; Autophagy was inhibited with 3-MA and CQ to detect apoptosis levels, and changes in autophagy, apoptosis, and downstream factors were detected by the AMPK inhibitor CC intervention.
RESULTS
Gavage in SD rats for 28 days, some degree of damage was observed in the thoracic aorta and heart of the rotenone group, as well as the appearance of autophagic vesicles was observed in the thoracic aorta. TUNEL analysis revealed higher apoptosis in the rotenone group's thoracic aorta; RTAEC cultured in vitro, after 24 h of rotenone intervention, showed increased ROS production and significantly decreased ATP production. The flow cytometry data suggested an increase in the number of apoptotic RTAEC. The thoracic aorta and RTAEC in the rotenone group displayed elevated levels of autophagy and apoptosis, and the LKB1-AMPK-ULK1 pathway proteins were activated and expressed at higher levels. Apoptosis and autophagy were both suppressed by the autophagy inhibitors 3-MA and CQ. The AMPK inhibitor CC reduced autophagy and apoptosis in RTAEC and suppressed the production of the AMPK downstream factors ULK1 and P-ULK1.
CONCLUSIONS
Rotenone may promote autophagy in the thoracic aorta and RTAEC by activating the LKB1-AMPK-ULK1 signaling pathway, thereby inducing apoptosis.
Topics: Animals; Rotenone; Autophagy; Autophagy-Related Protein-1 Homolog; Male; Apoptosis; Signal Transduction; Rats, Sprague-Dawley; AMP-Activated Protein Kinases; Endothelial Cells; Aorta, Thoracic; Protein Serine-Threonine Kinases; Rats; AMP-Activated Protein Kinase Kinases; Cells, Cultured; Intracellular Signaling Peptides and Proteins
PubMed: 38783387
DOI: 10.1186/s40360-024-00755-5 -
European Review For Medical and... May 2024Malvidin is a natural, biologically active polyphenol found in several fruits. It exhibits several therapeutic benefits; however, limited studies are available on its...
OBJECTIVE
Malvidin is a natural, biologically active polyphenol found in several fruits. It exhibits several therapeutic benefits; however, limited studies are available on its effects on neurodegenerative clinical conditions, including Parkinson's disease. The study aimed to investigate the therapeutic properties of malvidin on rotenone-triggered Parkinson's disease in an animal model.
MATERIALS AND METHODS
To determine the effects of malvidin, rotenone (1.5 mg/kg) was injected subcutaneously into Wistar rats for 21 days, followed by a dose of malvidin (200 and 100 mg/kg). Behavioral tests were performed on the experimental animals before sacrifice. On the 22nd day of the experiment, biochemical tests were performed, including superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and catalase (CAT). The activity of neurotransmitters and their metabolites, including acetylcholine (ACh), acetylcholinesterase (AChE), dopamine (DA), norepinephrine (NE), serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) along with neuroinflammatory markers including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor- α (TNF-α), and nuclear factor erythroid 2-related factor 2 (Nrf-2) were estimated. Moreover, the level of the apoptotic marker, caspase-3, was also estimated. In addition, molecular docking was performed.
RESULTS
The administration of rotenone resulted in oxidative stress, cholinergic imbalances, dopaminergic alternations, and increased expression of inflammatory compounds. The docking analysis revealed that malvidin displayed a favorable binding affinity for AChE, showcasing a binding energy of -9.329 Kcal/mol.
CONCLUSIONS
The investigation concludes that malvidin exhibits neuroprotective effects due to its curative effects against inflammation and oxidative stress. These findings suggest that malvidin possesses therapeutic potential against rotenone-triggered behavioral, oxidative, and inflammatory abnormalities in rodents.
Topics: Animals; Rotenone; Molecular Docking Simulation; Rats, Wistar; Rats; NF-E2-Related Factor 2; Caspase 3; Tumor Necrosis Factor-alpha; Male; Oxidative Stress; Neuroprotective Agents; Behavior, Animal; Disease Models, Animal
PubMed: 38766791
DOI: 10.26355/eurrev_202405_36179 -
Neurotherapeutics : the Journal of the... May 2024Constipation symptoms of Parkinson's disease (PD) seriously reduce the quality of life of patients and aggravate the development of the disease, but current treatment...
Electroacupuncture improves gastrointestinal motility through a central-cholinergic pathway-mediated GDNF releasing from intestinal glial cells to protect intestinal neurons in Parkinson's disease rats.
Constipation symptoms of Parkinson's disease (PD) seriously reduce the quality of life of patients and aggravate the development of the disease, but current treatment options still cannot alleviate the progress of constipation. Electroacupuncture (EA) is a new method for the treatment of constipation, which can effectively treat the symptoms of constipation in PD patients. However, the specific regulatory mechanisms of EA in the treatment of constipation symptoms in PD remain unclear. The aim of this study is to investigate the therapeutic effect of EA on PD constipation rats and its regulatory mechanism. A rotenone (ROT)-induced gastrointestinal motility disorder model was used to simulate the pathological process of constipation in PD. The results showed that EA could effectively promote gastrointestinal peristalsis, reduce α-synuclein accumulation in substantia nigra and colon and colonic injury in rats after ROT administration. Mechanistically, EA activation of the central-cholinergic pathway increases acetylcholine release in the colon. At the same time, EA up-regulated the co-expression of enteric glial cells (EGCs) and α7 nicotinic acetylcholine receptor (α7nAChR). EA increased the expression of choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and tyrosine hydroxylase (TH) in the colon of PD rats. Further mechanistic studies showed that EA increased the expression of glial cell-derived neurotrophic factor (GDNF), GFRa1 and p-AKT in colon tissues. The present study confirmed that EA upregulates α7nAChR through a central-cholinergic mechanism to promote GDNF release from EGCs, thereby protecting intestinal neurons and thereby improving gastrointestinal motility.
PubMed: 38744625
DOI: 10.1016/j.neurot.2024.e00369 -
Frontiers in Molecular Neuroscience 2024Parkinson's disease (PD), ranking as the second most prevalent neurodegenerative disorder globally, presents a pressing need for innovative animal models to deepen our...
Parkinson's disease (PD), ranking as the second most prevalent neurodegenerative disorder globally, presents a pressing need for innovative animal models to deepen our understanding of its pathophysiology and explore potential therapeutic interventions. The development of such animal models plays a pivotal role in unraveling the complexities of PD and investigating promising treatment avenues. In this study, we employed transcriptome sequencing on BmN cells treated with 1 μg/ml rotenone, aiming to elucidate the underlying toxicological mechanisms. The investigation brought to light a significant reduction in mitochondrial membrane potential induced by rotenone, subsequently triggering mitophagy. Notably, the PTEN induced putative kinase 1 (PINK1)/Parkin pathway emerged as a key player in the cascade leading to rotenone-induced mitophagy. Furthermore, our exploration extended to silkworms exposed to 50 μg/ml rotenone, revealing distinctive motor dysfunction as well as inhibition of gene expression. These observed effects not only contribute valuable insights into the impact and intricate mechanisms of rotenone exposure on mitophagy but also provide robust scientific evidence supporting the utilization of rotenone in establishing a PD model in the silkworm. This comprehensive investigation not only enriches our understanding of the toxicological pathways triggered by rotenone but also highlights the potential of silkworms as a valuable model organism for PD research.
PubMed: 38706874
DOI: 10.3389/fnmol.2024.1359294 -
Neurobiology of Disease Jun 2024Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that...
Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.
Topics: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Animals; Reactive Oxygen Species; Rats; Trichloroethylene; Mitochondria; Rotenone; Parkinson Disease; Paraquat; Dopaminergic Neurons; Oxidative Stress; Humans; Environmental Pollutants; Rats, Sprague-Dawley
PubMed: 38705492
DOI: 10.1016/j.nbd.2024.106522 -
Frontiers in Neurology 2024Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Olfactory dysfunction (OD) is an important nonmotor feature of...
BACKGROUND
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Olfactory dysfunction (OD) is an important nonmotor feature of PD. Dl-3-n-Butylphthalide (NBP) is a synthetic compound isolated from seeds. The present study was conducted to investigate the effect of NBP on olfaction in rotenone-induced Parkinson's rats to explore the mechanism and pathway of OD in PD.
METHODS
The PD model was established using rotenone-induced SD rats, divided into blank control, model, and treatment groups. A sham group was also established, with 10 rats in each group. The treatment group was given NBP (1 mg/kg, 10 mg/kg, and 100 mg/kg, dissolved in soybean oil) intragastrically for 28 days. Meanwhile, the control group rats were given intra-gastrically soybean oil. After behavioral testing, all rats were executed, and brain tissue was obtained. Proteomics and Proteomic quantification techniques (prm) quantification were used to detect proteomic changes in rat brain tissues.
RESULTS
Compared with the control group, the model group showed significant differences in behavioral tests, and this difference was reduced after treatment. Proteomics results showed that after treatment with high-dose NBP, there were 42 differentially expressed proteins compared with the model group. Additionally, the olfactory marker (P08523) showed a significant upregulation difference. We then selected 22 target proteins for PRM quantification and quantified 17 of them. Among them, the olfactory marker protein was at least twofold upregulated in the RTH group compared to the model group.
PubMed: 38685946
DOI: 10.3389/fneur.2024.1367973