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ContextRotenone is a toxic chemical found in various plants, including some used as food. Rotenone poisoning can be fatal and there is no antidote. Mechanistically, rotenone inhibits mitochondrial complex I, leading to reduced ATP production, compensatory glycolytic upregulation and secondary lactate production, and oxidative stress. Our literature review examined acute rotenone poisoning in humans, including exposure scenarios, clinical presentations, and treatments.MethodsWe searched five databases for relevant literature from database inception through the search date: July 12, 2022, pairing controlled vocabulary and keywords for "rotenone" with terms relating to human exposures and outcomes, such as "ingestion," "exposure," and "poisoning." We included all peer-reviewed reports found using the search terms where the full English text was available. Data abstracted included the number, age, weight, and sex of the exposed person(s), country where exposure happened, exposure scenario, ingestion context, estimated dose, clinical features, whether hospitalization occurred, treatments, and outcomes.ResultsAfter removing non-qualifying sources from 2,631 publications, we identified 11 case reports describing 18 victims, 15 of whom were hospitalized and five died. Most cases occurred in private quarters where victims unknowingly consumed rotenone-containing plants. Vomiting and metabolic acidosis occurred most commonly. Some patients exhibited impaired cardiopulmonary function. Supportive treatment addressed symptoms and included gastric lavage and/or activated charcoal to remove rotenone from the stomach, vasopressors for hypotension, mechanical ventilation for respiratory insufficiency, and sodium bicarbonate for acidosis. Some patients received N-acetylcysteine to counter oxidative stress.ConclusionsRotenone poisoning, though rare, can be fatal. Exposure prevention is impractical since rotenone is found in some plants used as food or pesticides. Cases may be under-diagnosed because symptoms are non-specific and under-reported in English-language journals since most cases occurred in non-English speaking countries. Treatments are supportive. Exploring antioxidant therapy in animal models of rotenone poisoning may be indicated considering rotenone's mechanism of toxicity.

BACKGROUND: Studies have found that nicotine can activate the dopamine system, slowing the progression of Parkinson’s disease, but the specific mechanism is still unclear. Research on the neuroprotective mechanism of nicotine in animal models of Parkinson’s disease is lacking. OBJECTIVE: To investigate the neuroprotective effect of nicotine on rotenone-induced Parkinson’s disease in mice. METHODS: Twenty-eight C57BL/6 mice were randomly divided into vehicle group, rotenone group, autophagy agonist group and nicotine group, with seven mice in each group. Dopaminergic nerve damage was induced by rotenone in C57BL/6 mice, and the autophagy agonist (rapamycin) or nicotine was given before modeling. The spatial exploration function of the mice was observed by open field test. Western blot and Q-PCR were used to detect the expression of α-synuclein, autophagy related factors Beclin-1 and P62, and apoptosis-related factors Bax, Bcl-2 and Cleaved-caspase3 in the nigra of each group. The deposition of mitochondria, autophagosomes and lipofuscin in nigra cells were observed by transmission electron microscopy. The survival of neurons was observed by Nissl staining. The expression of tyrosine hydroxylase was observed by immunofluorescence and immunohistochemical staining. RESULTS AND CONCLUSION: The open field test showed that the distance, average speed and time of movement were reduced in the rotenone group compared with the solvent group. Compared with the rotenone group, the exercise distance, average speed and exercise time of mice were increased in the nicotine group and autophagy agonist group (P < 0.05). The results of immunofluorescence and immunohistochemistry showed that the mean fluorescence intensity and mean absorbance value of tyrosine hydroxylase in the rotenone group decreased compared with that in the solvent group. Compared with the rotenone group, the mean fluorescence intensity and mean absorbance value of tyrosine hydroxylase were increased in the nicotine group and autophagy agonist group. Western blot and Q-PCR results showed that compared with the solvent group, the expressions of α-synuclein and P62 in the rotenone group were increased, while Beclin-1 expression was decreased (P < 0.05); compared with the rotenone group, the expression of α-synuclein and P62 decreased in the nicotine group and autophagy agonist group, and the expression of Beclin-1 increased (P < 0.05). Compared with the solvent group, the expressions of Bax and Cleaved caspase3 were increased and Bcl-2 expression was decreased in the rotenone group (P < 0.05); compared with the rothenone group, the expressions of Bax and Cleaved-caspase3 were decreased and the expression of Bcl-2 was increased in the nicotine and autophagy agonist groups (P < 0.05). To conclude, nicotine may have a dopaminergic neuroprotective effect on rotenone-induced Parkinson’s disease mouse models by improving autophagy dysfunction and reducing apoptosis. [ABSTRACT FROM AUTHOR]

The behavioral and functional states preceding the onset of specific parkinsonian symptoms were studied at an early (presymptomatic) stage of hemi-parkinsonian syndrome development in rodents and monkeys. The consecutive steps of neuropathological traits development—cognitive impairments developing from weeks 1–2 of rotenone exposure, minor motor impairments on weeks 3–4 before the development of pronounced motor dysfunction, and some biochemical indicators—were studied using the model of hemi-parkinsonian syndrome in rodents induced by chronic administration of low doses of rotenone toxin. The characteristics of visually guided saccades (VGS) while an instrumental conditioning task performing were studied using the model of hemi-parkinsonian syndrome in nonhuman primates (Macaca mulatta) chronically treated with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin. As MPTP syndrome progresses, an increase in the latencies of VGS and a decline in their accuracy with the retention of an instrumental conditioning performance have been shown. The negative behavioral effects in rodents and primates and biochemical effects in rodents manifested at the presymptomatic stage of the disease, suggest to consider them as early markers of a hemi-parkinsonian syndrome. [ABSTRACT FROM AUTHOR]

Parkinsonism is an age-related neurodegenerative illness that affects motor coordination leading to loss of dopaminergic neurons. Many medications are used for the treatment of Parkinson's disease but are only symptomatic and have a limited effect on the progression of this ailment. Therefore, bioactive compounds which derived from plants have been examined for their ability to improve the neuronal damage and cell death happened in parkinsonian patients. In this study the iridoids-rich fraction isolated from Pentas lanceolata (PIRF) leaves was investigated for its phytoconstituents. Seven iridoids (1–7) and one flavonol diglycoside (8) were isolated, and their chemical structures were achieved by 1H and 13C nuclear magnetic resonance and ESI–MS spectral data. Compound 1 (6β,7β-epoxy-8-epi-splendoside) and 5 (gaertneroside) were isolated for the first time from Pentas genus as well as compound 8 (kaempferol-3-O-robinobioside). The current study aims to investigate the possible anti-parkinsonian effect of PIRF using a rotenone model of Parkinsonism in mice. Behavioural tests (wirehanging, stair and wooden-walking tests) were done to examine the motor coordination in mice after treatment. Biochemical and histopathological examinations for brain striatum in different groups were also evaluated. Results revealed that rotenone-treated mice had poor motor functions described by depletion of dopamine and Ach levels, a significant increase in proinflammatory cytokines, IL-1B, TNF-α and Mcp-1 and oxidative biomarkers with subsequent reduction in antioxidant mediators. Disorganization of striatum, degenerated neurocytes, slight vacuolation, shrunken neurons with pyknotic nuclei and apoptotic cells are displayed by histopathological examinations. Treatment with PIRF ameliorates the neurodegeneration-induced by rotenone in the brain of mice. The anti-parkinsonian effect of PIRF could be attributed to their bioactive constituents of iridoids. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common motor neurodegenerative disease that still lacks effective therapeutic options. Previous studies have reported that lactoferrin exhibited neuroprotective effects in cellular and animal models of PD, typically induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) synthetic toxin. However, the neuroprotective capacity of lactoferrin in the rotenone-induced cellular model of PD remains relatively less established. Unlike MPTP/MPP+, rotenone is a naturally occurring environmental toxin known to induce chronic toxicity and increase the risk of PD in humans. In this study, we constructed a cellular model of PD by differentiating SH-SY5Y neuroblastoma cells with retinoic acid into mature dopaminergic neurons with increased β-tubulin III and tyrosine hydroxylase expression, followed by 24 h of rotenone exposure. Using this cellular model of PD, we showed that lactoferrin (1–10 µg/ml) pre-treatment for 48 h decreased loss of cell viability, mitochondrial membrane potential impairment, reactive oxygen species generation and pro-apoptotic activities (pan-caspase activation and nuclear condensation) in cells exposed to rotenone (1 and 5 µM) using biochemical assays, Hoechst 33342 staining and immunocytochemical techniques. We further demonstrated that 48 h of lactoferrin (10 µg/ml) pre-treatment decreased Bax:Bcl2 ratio and p42/44 mitogen-activated protein kinase expression but increased pAkt expression in 5 µM rotenone-exposed cells. Our study demonstrates that lactoferrin neuroprotective capacity is present in the rotenone-induced cellular model of PD, further supporting lactoferrin as a potential PD therapeutic that warrants further studies. [ABSTRACT FROM AUTHOR]

Mitochondrial abnormalities underscore a variety of neurologic injuries and diseases and are well-studied in adult populations. Clinical studies identify critical roles of mitochondria in a wide range of developmental brain injuries, but models that capture mitochondrial abnormalities in systems representative of the neonatal brain environment are lacking. Here, we develop an organotypic whole-hemisphere (OWH) brain slice model of mitochondrial dysfunction in the neonatal brain. We extended the utility of complex I inhibitor rotenone (ROT), canonically used in models of adult neurodegenerative diseases, to inflict mitochondrial damage in OWH slices from term-equivalent rats. We quantified whole-slice health over 6 days of exposure for a range of doses represented in ROT literature. We identified 50 nM ROT as a suitable exposure level for OWH slices to inflict injury without compromising viability. At the selected exposure level, we confirmed exposure- and time-dependent mitochondrial responses showing differences in mitochondrial fluorescence and nuclear localization using MitoTracker imaging in live OWH slices and dysregulated mitochondrial markers via RT-qPCR screening. We leveraged the regional structures present in OWH slices to quantify cell density and cell death in the cortex and the midbrain regions, observing higher susceptibilities to damage in the midbrain as a function of exposure and culture time. We supplemented these findings with analysis of microglia and mature neurons showing time-, region-, and exposure-dependent differences in microglial responses. We demonstrated changes in tissue microstructure as a function of region, culture time, and exposure level using live-video epifluorescence microscopy of extracellularly diffusing nanoparticle probes in live OWH slices. Our results highlight severity-, time-, and region-dependent responses and establish a complimentary model system of mitochondrial abnormalities for high-throughput or live-tissue experimental needs. [ABSTRACT FROM AUTHOR]

Simple Summary: Parkinson's disease (PD) is one of the most common chronic, degenerative brain diseases worldwide. Patients are diagnosed on the basis of slowness of movement and/or tremor and/or stiffness. However, many symptoms that are not movement related are now well recognized. Patients show changes in skin sensation, and the vast majority of patients show loss of sensory neurites, which enable sensation in skin. These changes in skin sensation occur prior to diagnosis; however, sensory issues may also be exacerbated by levodopa, an important drug used in the treatment of PD. Undoubtedly, levodopa is critical for the treatment of PD, but at high doses, it has repeatedly been shown to impair sensation in PD patients. Here, we show for the first time that high-dose levodopa impairs function of sensory neurons. Importantly, we also show for the first time that lysosomes, a critical organelle involved in recycling, are impaired by levodopa concentrations observed in patients. These data are important given the well-known lysosomal dysfunction observed in PD. Our data shed light on how levodopa, the most important drug in the treatment of PD, may contribute to sensory deficits in PD. Parkinson's disease (PD) is the second-most common neurodegenerative disease worldwide. Patients are diagnosed based upon movement disorders, including bradykinesia, tremor and stiffness of movement. However, non-motor signs, including constipation, rapid eye movement sleep behavior disorder, smell deficits and pain are well recognized. Peripheral neuropathy is also increasingly recognized, as the vast majority of patients show reduced intraepidermal nerve fibers, and sensory nerve conduction and sensory function is also impaired. Many case studies in the literature show that high-dose levodopa may induce or exacerbate neuropathy in PD, which is thought to involve levodopa's metabolism to homocysteine. Here, we treated primary cultures of dorsal root ganglia and a sensory neuronal cell line with levodopa to examine effects on cell morphology, mitochondrial content and physiology, and lysosomal function. High-dose levodopa reduced mitochondrial membrane potential. At concentrations observed in the patient, levodopa enhanced immunoreactivity to beta III tubulin. Critically, levodopa reduced lysosomal content and also reduced the proportion of lysosomes that were acidic, thereby impairing their function, whereas homocysteine tended to increase lysosome content. Levodopa is a critically important drug for the treatment of PD. However, our data suggest that at concentrations observed in the patient, it has deleterious effects on sensory neurons that are not related to homocysteine. [ABSTRACT FROM AUTHOR]

Epidemiological studies have revealed a potent association between chronic exposure to rotenone, a commonly used pesticide, in individuals and the incidence of Parkinson's disease (PD). We previously identified the contribution of the activation of microglial NADPH oxidase (NOX2) in rotenone-induced neurotoxicity. However, the regulation of NOX2 activation remains unexplored. Integrins are known to be bidirectionally regulated in the plasma membrane through the inside-out and outside-in signaling. CD11b is the α-chain of integrin macrophage antigen complex-1. This study aimed to investigate whether CD11b mediates rotenone-induced NOX2 activation. We observed that rotenone exposure increased NOX2 activation in BV2 microglia, which was associated with elevated CD11b expression. Silencing CD11b significantly reduced rotenone-induced ROS production and p47 phox phosphorylation, a key step for NOX2 activation. Furthermore, the Src-FAK-PKB and Syk-Vav1-Rac1 signaling pathways downstream of CD11b were found to be essential for CD11b-mediated NOX2 activation in rotenone-intoxicated microglia. Interestingly, we also found that inhibition of NOX2 decreased rotenone-induced CD11b expression, indicating a crosstalk between CD11b and NOX2. Subsequently, the inhibition of the CD11b-NOX2 axis suppressed rotenone-induced microglial activation and exosome release. Furthermore, inhibiting exosome synthesis in microglia blocked rotenone-induced gene expression of proinflammatory factors and related neurotoxicity. Finally, blocking the CD11b-NOX2 axis and exosome synthesis or endocytosis mitigated microglial activation and dopaminergic neurodegeneration in rotenone-intoxicated midbrain primary cultures. Our findings highlight the crucial involvement of the CD11b-NOX2 axis in rotenone-induced inflammation and neurotoxicity, offering fresh perspectives on the underlying mechanisms of pesticide-induced neuronal damage. [Display omitted] • The silence of CD11b attenuates rotenone-induced NOX2 activation. • The Src-FAK-PKB and Syk-Vav1-Rac1 signaling pathways underlie CD11b-mediated NOX2 activation. • NOX2 activation regulates CD11b expression via NF-κB pathway. • Blocking CD11b-NOX2 axis prevents rotenone-induced microglial exosome release and related neurotoxicity. [ABSTRACT FROM AUTHOR]

Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson's disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression (p < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex (p < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression. [ABSTRACT FROM AUTHOR]

Background/Objectives: 6-Shogaol is a comparatively innovative anti-Parkinson's remedy with antioxidant and anti-inflammatory characteristics. This investigation intended to determine the role of 6-shogaol in the Parkinson's disease (PD) paradigm in rotenone-induced rats. Methods: Thirty male Wistar rats (10–12 weeks old; 180 ± 20 g) were divided into five groups. Animals with rotenone-induced experimental PD were subsequently treated with 6-shogaol-10 at 20 mg/kg for 28 days. After the experimental duration, behavioural investigations were performed, i.e., open field test, forced swim test, rotarod test, and catalepsy test. Biochemical assessments like AChE, GSH, CAT, SOD, MDA, nitrite, ceruloplasmin, proinflammatory markers such as IL-1β, NF-κB, TNF-α, and catecholamines markers (DA, GABA, and MAO-B) were determined. The docking procedure was conducted using the AutoDock Vina docking protocol. Furthermore, histopathology was performed. Results: Rotenone significantly increased the level of MAO-B, oxidative, nitrative, and pro-inflammatory markers. However, there was a decline in ceruloplasmin, dopamine, and endogenous antioxidants. Treatment with 6-shogaol (10 and 20 mg/kg) considerably sustained the elevation of oxidative stress and inflammatory indicators and decreased AChE activity and dopamine levels. In the histology of the brain, 6-shogaol improved the neuronal structure and reduced the degeneration of neurons. Based on the binding energy values, compound 6-shogaol demonstrates a favourable binding affinity to AChE, MAO-B, DA, and GABA with respective binding energies of −8.214, −8.133, −7.396 and −6.189 kcal/mol. Conclusions: In this study, 6-shogaol exhibited neuroprotective properties against PD, which could be employed as a prospective medication for PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) affects movement; however, most patients with PD also develop nonmotor symptoms, such as hyposmia, sleep disorder, and depression. Dopamine levels in the brain have a critical influence on movement control, but other neurotransmitters are also involved in the progression of PD. This study analyzed the fluctuation of neurotransmitters in PC12 cells during neurogenesis and neurodegeneration by performing mass spectrometry. We found that the dopaminergic metabolism pathway of PC12 cells developed vigorously during the neuron differentiation process and that the neurotransmitters were metabolized into 3-methoxytyramine, which was released from the cells. The regulation of the intracellular and extracellular concentrations of adenosine indicated that adenine nucleotides were actively utilized in neural differentiation. Moreover, we exposed the differentiated PC12 cells to rotenone, which is a suitable material for modeling PD. The cells exposed to rotenone in the early stage of differentiation exhibited stimulated serotoninergic metabolism, and the contents of the serotoninergic neurotransmitters returned to their normal levels in the late stage of differentiation. Interestingly, the nondifferentiated cells can resist the toxicant rotenone and produce normal dopaminergic metabolites. However, when differentiated neuron cells were exposed to rotenone, they were seriously damaged, leading to a failure to produce dopaminergic neurotransmitters. In the low-dosage damage process, the amino acids that functioned as dopaminergic pathway precursors could not be absorbed by the cells, and dopamine and L-dopa were secreted and unable to be reuptaken to trigger the cell damage. [ABSTRACT FROM AUTHOR]

Background and Objectives: Parkinson's disease (PD) is a pathological state characterized by a combined set of abnormal movements including slow motion, resting tremors, profound stiffness of skeletal muscles, or obvious abnormalities in posture and gait, together with significant behavioral changes. Until now, no single therapeutic modality was able to provide a complete cure for PD. This work was a trial to assess the immunomodulatory effects of canagliflozin with or without levodopa/carbidopa on rotenone-induced parkinsonism in Balb/c mice. Materials and Methods: In a mouse model of PD, the effect of canagliflozin with or without levodopa/carbidopa was assessed at the behavioral, biochemical, and histopathological levels. Results: The combination of levodopa/carbidopa and canagliflozin significantly mitigated the changes induced by rotenone administration regarding the behavioral tests, striatal dopamine, antioxidant status, Nrf2 content, SIRT–1/PPAR–gamma axis, RAGE/HMGB1/NF-κB signaling, and mitochondrial dysfunction; abrogated the neuroinflammatory responses, and alleviated the histomorphologic changes induced by rotenone administration relative to the groups that received either levodopa/carbidopa or canagliflozin alone. Conclusions: Canagliflozin may represent a new adjuvant therapeutic agent that may add value to the combatting effects of levodopa/carbidopa against the pathological effects of PD. [ABSTRACT FROM AUTHOR]

Degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain are the main pathological changes in Parkinson's disease (PD); however, the mechanism underlying the selective vulnerability of specific neuronal populations in PD remains unclear. Here, we used single-cell RNA sequencing to identify seven cell clusters, including oligodendrocytes, neurons, astrocytes, oligodendrocyte progenitor cells, microglia, synapse-rich cells (SRCs), and endothelial cells, in the substantia nigra of a rotenone-induced rat model of PD based on marker genes and functional definitions. We found that SRCs were a previously unidentified cell subtype, and the tight interactions between SRCs and other cell populations can be improved by icaritin, which is a flavonoid extracted from Epimedium sagittatum Maxim. and exerts anti-neuroinflammatory, antioxidant, and immune-improving effects in PD. We also demonstrated that icaritin bound with transcription factors of SRCs, and icaritin application modulated synaptic characterization of SRCs, neuroinflammation, oxidative stress, and survival of dopaminergic neurons, and improved abnormal energy metabolism, amino acid metabolism, and phospholipase D metabolism of astrocytes in the substantia nigra of rats with PD. Moreover, icaritin supplementation also promotes the recovery of the physiological homeostasis of the other cell clusters to delay the pathogenesis of PD. These data uncovered previously unknown cellular diversity in a rat model of Parkinson's disease and provide insights into the promising therapeutic potential of icaritin in PD. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is the second leading neurodegenerative disease after Alzheimer’s disease. Mucuna pruriens (L.) DC. (MP) is a plant that contains Levodopa (L-DOPA) and has been known to improve the symptoms of PD. In this preliminary study, we investigated the anti-parkinsonian potential of MP to compare the effects of L-DOPA. We first developed an in vivo model of the PD in C57BL/6 male mice using rotenone. A total of twelve mice were used for this experiment. Nine mice were injected with rotenone (28 mg/kg) daily for 28 days. The mice experiments were performed to validate the effectiveness of MP to treat PD. Synthetic L-DOPA in a ratio of 1:20 with MP was used as MP contains 5% L-DOPA by weight in it. MP and L-DOPA were injected for 19 days on a daily basis. Cognitive function was evaluated using beam balance and olfactory tests. Serum analysis was performed using serum enzyme-linked immunosorbent assay (ELISA) analysis test. IL-12, IL-6, and TGF-β 1 were evaluated to validate the PD inducement and treatment. The levels of IL-12, IL-6, and TGF-β1 (p < 0.0001) in the PD mice group were significantly higher than those in the control group. The PD mice also showed higher latencies in beam balance and olfactory tests (p < 0.0001) compared to the control group. Both MP and L-DOPA-treated groups showed alleviation in latencies in beam balance and olfactory tests and decreased neuroinflammation in ELISA analysis (p < 0.001). The results treated by MP and L-DOPA showed insignificant differences in their values (p > 0.05). This proved that the MP and L-DOPA had similar effects in improving the symptoms of PD when used in the ratio of 1:20. Furthermore, both MP and L-DOPA reduced the level of IL-6 and TGF-β1 in this study. It may be inferred that a reduction in the level of IL-6 and TGF-β1 eventually leads to a reduction in the Th17 cells. The pathogenic Th17 is thought to be present in virtually all chronic inflammatory disorders. This can be an interesting area of research in further understanding the immunological effect of MP in ameliorating PD symptoms.

Objective: To investigate the neuroprotective effect of C-phycocyanin in a mouse model of rotenone-induced Parkinson’s disease. Methods: C-phycocyanin (50 mg/kg, i.p., daily) was administered to rotenone (30 mg/kg, p.o., daily) treated mice for 28 days. Behavioral studies (Y-maze, rotarod, round beam walk, and wire-hang tests) were carried out to assess neurobehavioral deficits. Glutathione and malondialdehyde were determined in both serum and striatal tissue. Molecular proteins (AKT, AMPK, NF-κB, BDNF, and alpha-synuclein) in the striatum were estimated using ELISA. Histopathological analyses (hematoxylin and eosin stainning as well as Nissl staining) were carried out to assess structural abnormalities in the striatum. Results: C-phycocyanin significantly increased BDNF levels and decreased alpha-synuclein levels. It also slightly upregulated AMPK and AKT levels without significant difference compared with the rotenone group. Additionally, rotenone-induced elevated oxidative stress and structural abnormalities in the striatum were markedly mitigated by C-phycocyanin. Conclusions: C-phycocyanin might have potential neuroprotective effects against Parkinson’s disease. Further studies are warranted to verify its efficacy and to understand the molecular mechanisms behind the neuroprotective effects of C-phycocyanin in Parkinson’s disease.

Abstract As an important pest on winter wheat, Rhopalosiphum padi (L.) causes damage to the wheat yield by sucking plant nutrients, transmitting plant viruses and producing mildew. R. padi has been reported to develop resistance to pyrethroids and neonicotinoids. To explore potential alternative approaches for R. padi control, the activity of 10 botanical insecticides was evaluated. Results suggested that the toxicity of rotenone and pyrethrins to R. padi were the highest and near to the commonly used chemical insecticides. When exposed to the low-lethal concentrations (LC10, LC30) of rotenone or pyrethrins for 24 h, the lifespan and fecundity of adults in F0 generation decreased significantly compared to control. The negative effect could also be observed in the F1 generation, including the decreased average offspring, longevity of adult, and prolonged nymph period. The population parameters in F1 generation of R. padi were also inhibited by exposing to the low-lethal concentrations of rotenone or pyrethrins, including the decreased net reproductive rate, intrinsic rate of natural increase, finite rate of population increase, and gross reproduction rate. Co-toxocity factor results showed that mixtures of rotenone and thiamethoxam, pyrethrins and thiamethoxam showed synergistic effect. Our work suggested that rotenone and pyrethrins showed negative effect on the population growth under low-lethal concentrations. They are suitable for R. padi control as foliar spraying without causing population resurgence.

In the present study, we aimed to establish and characterize a mature cortical spheroid model system for Kleefstra syndrome (KS) using patient-derived iPSC. We identified key differences in the growth behavior of KS spheroids determined by reduced proliferation marked by low Ki67 and high E-cadherin expression. Conversely, in the spheroid-based neurite outgrowth assay KS outperformed the control neurite outgrowth due to higher BDNF expression. KS spheroids were highly enriched in VGLUT1/2-expressing glutamatergic and ChAT-expressing cholinergic neurons, while TH-positive catecholamine neurons were significantly underrepresented. Furthermore, high NMDAR1 expression was also detected in the KS spheroid, similarly to other patients-derived neuronal cultures, denoting high NMDAR1 expression as a general, KS-specific marker. Control and KS neuronal progenitors and neurospheres were exposed to different toxicants (paraquat, rotenone, bardoxolone, and doxorubicin), and dose-response curves were assessed after acute exposure. Differentiation stage and compound-specific differences were detected with KS neurospheres being the most sensitive to paraquat. Altogether this study describes a robust 3D model system expressing the disease-specific markers and recapitulating the characteristic pathophysiological traits. This platform is suitable for testing developing brain-adverse environmental effects interactions, drug development, and screening towards individual therapeutic strategies. [ABSTRACT FROM AUTHOR]

Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise. [ABSTRACT FROM AUTHOR]

Under regulations such as REACH, testing of novel and established compounds for their (neuro)toxic potential is a legal requirement in many countries. These are largely based on animal-, cost-, and time-intensive in vivo models, not in line with the 3 Rs' principle of animal experimentation. Thus, the development of alternative test methods has also received increasing attention in neurotoxicology. Such methods focus either on physiological alterations in brain development and neuronal pathways or on behavioral changes. An example of a behavioral developmental neurotoxicity (DNT) assay is the zebrafish (Danio rerio) embryo coiling assay, which quantifies effects of compounds on the development of spontaneous movement of zebrafish embryos. While the importance of embryo-to-embryo contact prior to hatching in response to environmental contaminants or natural threats has been documented for many other clutch-laying fish species, little is known about the relevance of intra-clutch contacts for zebrafish. Here, the model neurotoxin rotenone was used to assess the effect of grouped versus separate rearing of the embryos on the expression of the coiling behavior. Some group-reared embryos reacted with hyperactivity to the exposure, to an extent that could not be recorded effectively with the utilized software. Separately reared embryos showed reduced activity, compared with group-reared individuals when assessing. However, even the control group embryos of the separately reared cohort showed reduced activity, compared with group-reared controls. Rotenone could thus be confirmed to induce neurotoxic effects in zebrafish embryos, yet modifying one parameter in an otherwise well-established neurotoxicity assay such as the coiling assay may lead to changes in behavior influenced by the proximity between individual embryos. This indicates a complex dependence of the outcome of behavior assays on a multitude of environmental parameters. [ABSTRACT FROM AUTHOR]

Perilla seed oil, derived from a regional plant native to northern Thailand, undergoes cold‐pressing to analyze its bioactive components, notably alpha‐linolenic acid (ALA). ALA, constituting approximately 61% of the oil, serves as a precursor for therapeutic omega‐3 fatty acids, EPA and DHA, with neurodegenerative disease benefits and anti‐inflammatory responses. This study administered different concentrations of perilla seed oil to male C57BL/6 mice, categorized as low dose (LP 5% w/w), middle dose (MP 10% w/w), and high dose (HP 20% w/w), along with a fish oil (FP 10% w/w) diet. An experimental group received soybean oil (5% w/w). Over 42 days, these diets were administered while inducing Parkinson's disease (PD) with rotenone injections. Mice on a high perilla seed oil dose exhibited decreased Cox‐2 expression in the colon, suppressed Iba‐1 microglia activation, reduced alpha‐synuclein accumulation in the colon and hippocampus, prevented dopaminergic cell death in the substantia nigra, and improved motor and non‐motor symptoms. Mice on a middle dose showed maintenance of diverse gut microbiota, with an increased abundance of short‐chain fatty acid (SCFA)‐producing bacteria (Bifidobacteria, Lactobacillus, and Faecalibacteria). A reduction in bacteria correlated with PD (Turicibacter, Ruminococcus, and Akkermansia) was observed. Results suggest the potential therapeutic efficacy of high perilla seed oil doses in mitigating both intestinal and neurological aspects linked to the gut–brain axis in PD. [ABSTRACT FROM AUTHOR]

Rotenone is a mitochondrial complex I inhibitor that causes retinal degeneration. A study of a rat model of rotenone-induced retinal degeneration suggested that this model is caused by indirect postsynaptic N-methyl-D-aspartate (NMDA) stimulation triggered by oxidative stress-mediated presynaptic intracellular calcium signaling. To elucidate the mechanisms by which rotenone causes axonal degeneration, we investigated morphological changes in optic nerves and the change in retinal ganglion cell (RGC) number in rats. Optic nerves and retinas were collected 3 and 7 days after the intravitreal injection of rotenone. The cross-sections of the optic nerves were subjected to a morphological analysis with axon quantification. The axons and somas of RGCs were analyzed immunohistochemically in retinal flatmounts. In the optic nerve, rotenone induced axonal swelling and degeneration with the incidence of reactive gliosis. Rotenone also significantly reduced axon numbers in the optic nerve. Furthermore, rotenone caused axonal thinning, fragmentation, and beading in RGCs on flatmounts and decreased the number of RGC soma. In conclusion, the intravitreal injection of rotenone in rats induced morphological abnormities with a reduced number of optic nerve axons and RGC axons when the RGC somas were degenerated. These findings help elucidate the pathogenesis of optic neuropathy induced by mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Targeted delivery of α-synuclein using AAV vectors has over the two decades since its introduction developed into a versatile tool for modeling different aspects of synucleinopathy, mimicking those seen in Parkinson's disease and related Lewy body disorders. The viral vector approach to disease modeling is attractive in that the expression of α-synuclein, wild-type or mutated, can be confined to defined anatomical structures and targeted to selected cell populations using either cell-type specific promoter constructs or different natural or engineered AAV serotypes. AAV-α-synuclein was initially used to model progressive α-synuclein pathology in nigral dopamine neurons, and, like the standard 6-OHDA model, it has most commonly been applied unilaterally, using the non-injected side as a reference and control. In recent years, however, the AAV-α-synuclein model has become more widely used to induce Parkinson-like synuclein pathology in other relevant neuronal systems, such as the brainstem noradrenergic and serotonergic neurons, the vagal motor neurons, as well as in oligodendrocytes, the prime target relevant to the pathology seen in multiple system atrophy. The purpose of this review is to give an overview of the progress made in the use of the AAV-α-synuclein model over the last two decades and summarize the state-of-the art in the use of the AAV-α-synuclein model for disease modeling in rats and mice. Plain Language Summary: Misfolding of the neuronal protein α-synuclein is central to the cellular processes that underlie the development of Parkinson's disease and related disorders, such as dementia with Lewy bodies and multiple system atrophy. Targeted delivery of α-synuclein using adeno-associated virus, AAV, has become a standard tool to model the disease process in animals. This AAV-α-synuclein model of Parkinson's disease was introduced two decades ago and over the ensuing decades it has become a widely used standard tool for experimental studies in animals. The usefulness of the AAV-α-synuclein model is largely due to its flexibility and versatility as an experimental tool. In this review the authors summarize the state-of-the art in this field and review the range of applications that has been developed using AAV-α-synuclein alone, in single hit models, or in combinations with other interacting risk factors, in double hit models. [ABSTRACT FROM AUTHOR]

Owing to its ability to separate substances with a broad scope of polarities, exploring the three‐phase solvent systems (TPSSs) with high‐speed countercurrent chromatography is a topic of interest in separation science, and their retention volumes should be more concerned. This study primarily investigates the behavior of retention volumes while examining the isolation abilities of the TPSS in the technique above. We took standard compounds, including sophoricoside, Sudan red 7B, and rotenone, which have a broad range of polarity, for investigation in this study and separated them using different four‐liquid TPSSs made up of water, acetonitrile, methyl acetate, and n‐hexane (WAMH). Our findings show that the retention volumes gradually alter in response to changes in phase polarity within the proposed solvent systems. With TPSSs, we preliminarily studied compound isolation and the promising formula of their retention volumes. The proposed solvent systems WAMH in different ratios showed high correlations and adjusted correlation coefficients above 0.9978 and 0.9913 for the actual and calculated retention volumes. This study will be particularly beneficial for researchers focusing on countercurrent chromatography with TPSSs, as it offers valuable time‐saving insights. [ABSTRACT FROM AUTHOR]

Rabbit fish (Siganus vermiculatus) is one of the biological resources in the sea that is widely consumed by the people in Maluku. Rabbit fish are caught during low tide with nets or by using natural resources to poison the fish, such as tuba root (Derris elliptica), which contains rotenone to make fish easy to catch. This study aimed to determining the concentration of tuba root extract that was effective against damage to the liver tissue of rabbit fish. Rabbit fish and tuba root were collected from Oma Village, Haruku Island, Central Maluku District, Maluku Province. In the study, a laboratory experiment was conducted in which the tuba root was treated with doses of 0.1 g, 0.3 g, 0.5 g and 1 g with an exposure time of 18 to 24 hours. Data were analyzed using two-way analysis of variance (ANOVA) followed by Duncan's post-hoc test. As a result, the lowest level of liver damage in rabbit fish was observed at a dose of 0.1 g, with a total damage of 7 ± 0.00 and 8.5 ± 0.71. Conversely, the highest level of liver damage was observed at a dose of 1 g, with a total damage of 14 ± 0.00 and 15 ± 0.00. The results of the post hoc test showed a subset value of 0.1 g dose (7.75), 0.3 g dose (9.25), 0.5 g dose (12.00), and 1 g dose (14.50). This research indicates that administering tuba root to rabbit fish can result in damage to the liver's structure. The severity of this damage is contingent upon the dose administered, whereas exposure duration does not affect the level of damage to fish organs. [ABSTRACT FROM AUTHOR]

Vector-borne diseases in humans occur through snails, mosquitoes, fleas, ticks, lice, sandflies, and tsetse flies infected with microbes. These comprise over 17% of all infectious diseases and significantly contribute to the burden of disease and economy. Mosquito-borne diseases account for nearly 700 million new cases and over a million deaths on an annual basis. The purpose of this review is to offer a critical analysis of mosquito repellent properties of different plants' essential oils (pyrethrin, menthol, nicotine and rotenone) and adverse effects of synthetic repellents on different organs of animals, their mode of action, pharmacological properties, and traditional applications. DEET inhibits odorant receptors. Nicotine competitively binds with ACh receptors. Organophosphate and carbamate prevent the removal of Ach from AChE, thymol blocks the GABA-gated chloride channel, rotenone blocks the electron transport chain, and azadirachtin interferes with the synthesis of ecdysteroid and juvenile hormone. Resistance against these can be gained by mutations in some genes like kdr mutation, Ace-1R gene mutation and Rdl mutation. This review focuses on the potential of plant-based mosquito repellents as a replacement for chemical-based repellents and highlights their modes of action and relatively less or no side effects in preventing mosquito-related diseases. [ABSTRACT FROM AUTHOR]

Apart from dopaminergic neurotoxicity, exposure to rotenone, a commonly used insecticide in agriculture, also adversely affects hippocampal and cortical neurons, resulting in cognitive impairments in mice. We recently established a role of microglia-mediated neuroinflammation in rotenone-elicited deficits of cognition, yet the mechanisms remain elusive. Here, we investigated the involvement of NADPH oxidase 2 (NOX2) catalytic subunit gp91phox in rotenone-induced cognitive deficits and the associated mechanisms. Our study demonstrated that rotenone exposure elevated expression of gp91phox and phosphorylation of the NOX2 cytosolic subunit p47phox, along with NADPH depletion in the hippocampus and cortex of mice, indicating NOX2 activation. Specific knockdown of gp91phox in microglia via adeno-associated virus delivery resulted in reduced microglial activation, proinflammatory gene expression and improved learning and memory capacity in rotenone-intoxicated mice. Genetic deletion of gp91phox also reversed rotenone-elicited cognitive dysfunction in mice. Furthermore, microglial gp91phox knockdown attenuated neuronal damage and synaptic loss in mice. This intervention also suppressed iron accumulation, disruption of iron-metabolism proteins and iron-dependent lipid peroxidation and restored the balance of ferroptosis-related parameters, including GPX4, SLC711, PTGS2 , and ACSL4 in rotenone-lesioned mice. Intriguingly, pharmacological inhibition of ferroptosis with liproxstatin-1 conferred protection against rotenone-induced neurodegeneration and cognitive dysfunction in mice. In summary, our findings underscored the contribution of microglial gp91phox-dependent neuroinflammation and ferroptosis to learning and memory dysfunction in rotenone-lesioned mice. These results provided valuable insights into the pathogenesis of cognitive deficits associated with pesticide-induced Parkinsonism, suggesting potential therapeutic avenues for intervention. [Display omitted] • The expression of microglial gp91phox is elevated in rotenone-intoxicated mice. • Microglial gp91phox knockdown attenuates rotenone-induced neuroinflammation. • Microglial gp91phox knockdown ameliorates rotenone-induced ferroptosis. • Inhibition of ferroptosis recovers the cognitive function of rotenone-intoxicated mice. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a second most common neurodegenerative disorder characterized by the selective and progressive degeneration of dopaminergic neurons in substantia nigra pars compacta. Rotenone is a neurotoxin which selectively degenerate dopaminergic neurons in striatum, leading to cause PD like symptoms. Rotenone was administered at a dose of 1.5 mg/kg, i.p. from day 1 to day 40. Treatment with doxycycline (50 and 100 mg/kg, p.o), tocopherol (5 mg and 10 mg/kg, p.o) alone, doxycycline (50 mg/kg, p.o) in combination with tocopherol (10 mg/kg, p.o), and ropinirole (0.5 mg/kg, i.p.) was given for 40 days 1 h prior to administration of rotenone. All behavioral parameters were analyzed on weekly basis. On day 41, animals were sacrificed and the striatum region was isolated for neurotransmitters estimation (dopamine, serotonin, norepinephrine, GABA and glutamate), biochemical analysis (GSH, nitrite, LPO, mitochondrial complexes I and IV), inflammatory markers estimation (IL-6, IL-1β and TNF-α) and activity of MAO-A, MAO-B. Doxycycline and tocopherol in combination significantly attenuated behavioral, neurotransmitters and biochemical alterations induced by rotenone in experimental rats as compared to alone treatment with DOX and TOCO. Similarly, DOX and TOCO combination significantly reduced the level of inflammatory markers, prevented the biochemical changes, decreased MAO-A and MAO-B and improved complex-I, complex-IV, cAMP levels significantly. The current study revealed that a combination of doxycycline with tocopherol contributed to the prevention of PD like symptoms in rats by antioxidant, anti-inflammatory, MAO inhibitory and neuromodulatory mechanisms. [ABSTRACT FROM AUTHOR]

A substantial challenge in human brain aging is to find a suitable model to mimic neuronal aging in vitro as accurately as possible. Using directly converted neurons (iNs) from human fibroblasts is considered a promising tool in human aging since it retains the aging-associated mitochondrial donor signature. Still, using iNs from aged donors can pose certain restrictions due to their lower reprogramming and conversion efficacy than those from younger individuals. To overcome these limitations, our study aimed to establish an in vitro neuronal aging model mirroring features of in vivo aging by acute exposure on young iNs to either human stress hormone cortisol or the mitochondrial stressor rotenone, considering stress as a trigger of in vivo aging. The impact of rotenone was evident in mitochondrial bioenergetic properties by showing aging-associated deficits in mitochondrial respiration, cellular ATP, and MMP and a rise in glycolysis, mitochondrial superoxide, and mitochondrial ROS; meanwhile, cortisol only partially induced an aging-associated mitochondrial dysfunction. To replicate the in vivo aging-associated mitochondrial dysfunctions, using rotenone, a mitochondrial complex I inhibitor, proved to be superior to the cortisol model. This work is the first to use stress on young iNs to recreate aging-related mitochondrial impairments. [ABSTRACT FROM AUTHOR]

Background: Spermidine is a natural biologically active substance that has widespread influences on the body. Objective: This study aims to enhance our understanding of the potential effect of spermidine on long non‐coding RNA MALAT1 and explore the underlying mechanism in the rotenone‐induced rat model of Parkinson's disease. Methods: Rats were sacrificed after locomotor behavioral testing. Striatal tissues were used to assess the expression of MALAT1, oxidative stress markers, and autophagy markers. Results: Our study found that treatment with spermidine for 2 weeks during the induction of the model significantly improved behavioral assessment, dopamine levels, and attenuated the histopathological changes that occurred in PD in comparison to the non‐treated group. Conclusion: Our preliminary study supports the protective effect of spermidine on the activation of autophagy and its antioxidant properties. Part of the antioxidant activity is due to the inhibition of MALAT1. However, MALAT1 does not correlate with the spermidine‐induced autophagy pathway. [ABSTRACT FROM AUTHOR]

Inward rectifying potassium channels sensitive to ATP levels (KATP) have been the subject of investigation for several decades. Modulators of KATP channels are well-established treatments for metabolic as well as cardiovascular diseases. Experimental studies have also shown the potential of KATP modulation in neurodegenerative disorders. However, to date, data regarding the effects of KATP antagonists/agonists in experiments related to neurodegeneration remain inconsistent. The main source of confusion in evaluating available data seems to be the choice of experimental models. The present study aims to provide a comprehensive understanding of the effects of both opening and blocking KATP channels in two forms of SH-SY5Y cells. Our results offer valuable insights into the significance of metabolic differences between differentiated and non-differentiated SH-SY5Y cells, particularly in the context of glibenclamide and diazoxide effects under normal conditions and during the initiation of pathological events simulating Parkinson's disease in vitro. We emphasize the analysis of mitochondrial functions and changes in mitochondrial network morphology. The heightened protein expression of KATP channels identified in non-differentiated SH-SY5Y cells seems to be a platform for a more significant impact of KATP modulators in this cell type. The efficiency of rotenone treatment in inducing morphological changes in the mitochondrial network depends on the differentiation status of SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Skin aging is associated with the increased production of mitochondrial reactive oxygen species (mtROS) due to mitochondrial dysfunction, and various phytonutrients and estrogens have been shown to improve skin health. Thus, the aim of the current study was to examine damage to dermal fibroblasts by chemically induced mitochondrial dysfunction and to study the mechanism of the protective effects of carotenoids, polyphenols, and estradiol. Rotenone, a Complex I inhibitor, caused mitochondrial dysfunction in human dermal fibroblasts, substantially reducing respiration and ATP levels, followed by increased mitochondrial and cytosolic ROS, which resulted in apoptotic cell death, an increased number of senescent cells, increased matrix metalloproteinase-1 (MMP1) secretion, and decreased collagen secretion. Pre-treatment with carotenoid-rich tomato extracts, rosemary extract, and estradiol reversed these effects. These protective effects can be partially explained by a cooperative activation of antioxidant response element (ARE/Nrf2) transcriptional activity by the protective compounds and rotenone, which led to the upregulation of antioxidant proteins such as NQO1. To determine if ARE/Nrf2 activity is crucial for cell protection, we inhibited it using the Nrf2 inhibitors ML385 and ochratoxin A. This inhibition markedly reduced the protective effects of the test compounds by diminishing their effect to reduce cytosolic ROS. Our study results indicate that phytonutrients and estradiol protect skin cells from damage caused by mtROS, and thus may delay skin cell senescence and improve skin health. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) is possibly caused by genetic factors, environmental factors, and gut microbiota dysbiosis. This study aims to explore whether the microbiota contributes to the behavior abnormalities of PD. Methods: We transplanted gut microbiota from patients with PD or healthy controls (HC) into microbiota-free honeybees. We also established two more groups, namely the rotenone (ROT) group, in which PD-like symptoms of honeybees were induced by rotenone, and the conventional (CV) group, in which honeybees were colonized with conventional gut microbiota. The climbing assay was performed to assess the motor capabilities of honeybees. Histopathological examination was conducted to evaluate the integrity of gut mucosa. Tyrosine hydroxylase (TH) gene expression levels and dopamine (DA) concentrations in the brain were also examined. Additionally, metagenomics and full-length 16S rRNA analyses were performed to identify alterations in gut microbiota profiles, both in PD patients and honeybees. Results: Honeybees in the PD and ROT groups exhibited slower climbing speeds, downregulated TH gene expression, and impaired gut barriers. Both the HC and PD groups of honeybees successfully harbored a portion of gut microbiota from corresponding human donors, and differences in microbial composition were identified. Morganella morganii and Erysipelatoclostridium ramosum exhibited significantly increased relative abundance in the HC group, while Dorea longicatena, Collinsella aerofaciens, Lactococcus garvieae, Holdemanella biformis, Gemmiger formicilis, and Blautia obeum showed significantly increased relative abundance in the PD group. Functional predictions of microbial communities in the PD group indicated an increased synthesis of hydrogen sulfide and methane. Conclusion: A novel PD model was induced in honeybees with rotenone and gut microbiota from PD patients. This study linked PD-related behaviors to altered gut microbiota, highlighting a potential gut microbiota-brain axis involvement in PD pathogenesis. We identify previously unrecognized associations of Dorea longicatena, Collinsella aerofaciens, Lactococcus garvieae, Holdemanella biformis, Gemmiger formicilis, and Blautia obeum with PD. Additionally, pathways related to hydrogen sulfide and methane synthesis have been previously suggested as potential contributors to the development of PD, and our research further supports this hypothesis. [ABSTRACT FROM AUTHOR]

As an important pest on winter wheat, Rhopalosiphum padi (L.) causes damage to the wheat yield by sucking plant nutrients, transmitting plant viruses and producing mildew. R. padi has been reported to develop resistance to pyrethroids and neonicotinoids. To explore potential alternative approaches for R. padi control, the activity of 10 botanical insecticides was evaluated. Results suggested that the toxicity of rotenone and pyrethrins to R. padi were the highest and near to the commonly used chemical insecticides. When exposed to the low-lethal concentrations (LC10, LC30) of rotenone or pyrethrins for 24 h, the lifespan and fecundity of adults in F0 generation decreased significantly compared to control. The negative effect could also be observed in the F1 generation, including the decreased average offspring, longevity of adult, and prolonged nymph period. The population parameters in F1 generation of R. padi were also inhibited by exposing to the low-lethal concentrations of rotenone or pyrethrins, including the decreased net reproductive rate, intrinsic rate of natural increase, finite rate of population increase, and gross reproduction rate. Co-toxocity factor results showed that mixtures of rotenone and thiamethoxam, pyrethrins and thiamethoxam showed synergistic effect. Our work suggested that rotenone and pyrethrins showed negative effect on the population growth under low-lethal concentrations. They are suitable for R. padi control as foliar spraying without causing population resurgence. [ABSTRACT FROM AUTHOR]

In oxidative phosphorylation, respiratory complex I serves as an entry point in the electron transport chain for electrons generated in catabolic processes in the form of NADH. An ancestral version of the complex, lacking the NADH-oxidising module, is encoded in a significant number of bacterial genomes. Amongst them is Desulfitobacterium hafniense, a strict anaerobe capable of conserving energy via organohalide respiration. This study investigates the role of the complex I-like enzyme in D. hafniense energy metabolism using rotenone as a specific complex I inhibitor under different growth conditions. The investigation revealed that the complex I-like enzyme was essential for growth with lactate and pyruvate but not in conditions involving H2 as an electron donor. In addition, a previously published proteomic dataset of strain DCB-2 was analysed to reveal the predominance of the complex under different growth conditions and to identify potential redox partners. This approach revealed seven candidates with expression patterns similar to Nuo homologues, suggesting the use of diverse electron sources. Based on these results, we propose a model where the complex I-like enzyme serves as an electron entry point into the respiratory chain for substrates delivering electrons within the cytoplasm, such as lactate or pyruvate, with ferredoxins shuttling electrons to the complex. [ABSTRACT FROM AUTHOR]

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is critically involved in the degeneration of dopamine (DA) neurons in the substantia nigra, a common pathological feature of Parkinson's disease (PD). Previous studies have demonstrated that the NAD+-dependent acetylase Sirtuin 3 (SIRT3) participates in maintaining mitochondrial function and is downregulated in aging-related neurodegenerative disorders. The exact mechanism of action of SIRT3 on mitochondrial bioenergetics in PD pathogenesis, however, has not been fully described. In this study, we investigated the regulatory role of SIRT3-mediated deacetylation of mitochondrial complex II (succinate dehydrogenase) subunit A (SDHA) and its effect on neuronal cell survival in rotenone (ROT)-induced rat and differentiated MN9D cell models. The results revealed that SIRT3 activity was suppressed in both in vivo and in vitro PD models. Accompanying this downregulation of SIRT3 was the hyperacetylation of SDHA, impaired activity of mitochondrial complex II, and decreased ATP production. It was found that the inhibition of SIRT3 activity was attributed to a reduction in the NAD+/NADH ratio caused by ROT-induced inhibition of mitochondrial complex I. Activation of SIRT3 by icariin and honokiol inhibited SDHA hyperacetylation and increased complex II activity, leading to increased ATP production and protection against ROT-induced neuronal damage. Furthermore, overexpression of SDHA also exerted potent protective benefits in cells treated with ROT. In addition, treatment of MN9D cells with the NAD+ precursor nicotinamide mononucleotide increased SIRT3 activity and complex II activity and promoted the survival of cells exposed to ROT. These findings unravel a regulatory SIRT3-SDHA axis, which may be closely related to PD pathology. Bioenergetic rescue through SIRT3 activation-dependent improvement of mitochondrial complex II activity may provide an effective strategy for protection from neurodegeneration. [ABSTRACT FROM AUTHOR]

Bursaphelenchus xylophilus is a pathogenic nematode responsible for pine wilt disease, which can cause the demise of pine trees and discoloration of trunks. As rotenone is an important botanical pesticide, its impact on B. xylophilus was investigated through RNA-seq to understand the response mechanism of nematode. The bioassay results yielded the 12-h LC30 (1.35 mg L−1) and LC50 (2.60 mg L−1) values for rotenone. Differential gene expression analysis identified 172 and 614 differentially expressed genes (DEGs) in B. xylophilus exposed to two different concentrations of rotenone (1.35 and 2.60 mg L−1). To validate these findings, the expression patterns of 10 DEGs were confirmed through RT-qPCR. Additionally, all DEGs were categorized into eight gene expression profiles using STEM. Notably, the gene ontology (GO) processes of ''single-organism process,'' ''metabolic process,'' and ''catalytic activity'' were prominently enriched in rotenone-treated samples, suggesting a role for metabolic and catalytic pathways in the nematode's response to rotenone stress. KEGG pathways related to ''carbon metabolism,'' ''drug metabolism-cytochrome P450,'' and ''metabolism of xenobiotics by cytochrome P450'' were similarly enriched, indicating potential mechanisms for detoxification resistance and oxidative stress resistance. The analysis pointed to the pivotal roles of detoxification- and oxidoreduction-related genes, as well as signal transduction-related genes, in enabling B. xylophilus to adapt to rotenone exposure. These insights could markedly enhance our understanding of nematode resistance mechanisms and potentially inform the development of more effective rotenone-based strategies for controlling B. xylophilus.

Rotenone (ROT), a widely used natural pesticide, has an uncertain effect on reproductive toxicity. In this study, we used 20 mice distributed randomly into four groups, with each group receiving ROT doses of 0, 2, 4, and 8 mg/kg/day for 28 days. The results demonstrated that ROT induced significant testicular damage, including impaired spermatogenesis, inhibition of testosterone synthesis, and apoptosis of Leydig cells. Additionally, ROT disrupted the normal ultrastructure of the endoplasmic reticulum (ER) in testicular tissue, leading to ER stress in Leydig cells. To further explore whether ROT-induced apoptosis in Leydig cells is related to ER stress, the mouse Leydig cell line (TM3 cells) was treated with ROT at 0, 250, 500, and 1000 nM. ROT inhibited TM3 cell viability, induced cytotoxicity, and reduced testosterone content in the culture supernatants. Furthermore, ROT treatment triggered apoptosis in TM3 cells by activating ER stress and the PERK-eIF2α-CHOP signalling pathway. Pre-treatment of TM3 cells exposed to ROT with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated these effects, decreasing apoptosis and preserving testosterone levels. Further intervention with the PERK inhibitor GSK2606414 reduced ROT-induced apoptosis and testosterone reduction by inhibiting PERK activity. In summary, ROT-induced male reproductive toxicity is specifically driven by apoptosis, with the PERK-eIF2α-CHOP signalling pathway activated by ER stress playing a crucial role in the apoptosis of Leydig cells triggered by ROT.

Objective To investigate the mechanism and protective effect of Humanin (HN) on rotenone (Rot)-induced toxic damage for dopamine neurons. Methods The Rot-poisened PC12 cell model was constructed, and the control group, the Rot poisening group, the HN pretreated Rot poisening group, and the HN treatment group were set up. ELISA was used to detect the content of HN inside and outside of Rot-infected cells, CCK-8 assay was used to detect cell viability, and ATP detection kit was used to detect the intracellular ATP content. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the level of reactive oxygen species (ROS) in cells. Western blotting was performed to detect the expression level of mitochondrial autophagy regulatory proteins Pink1, Parkin, p62, LC3, mitochondrial biogenesis regulatory protein PGC1α, division/fusion regulatory proteins OPA1, MFN2, DRP1, p-DRP1 and antioxidant stress regulatory proteins Keap1 and Nrf2. HBAD-mcherry-EGFP-LC3 adenovirus transfected cells was used to observed the number of autophagosomes and autophagolysosomes. Results The results showed that the intracellular concentration of HN in PC12 in the Rot poisening group was significantly higher than that in the control group (P < 0.05);Compared with the control group, the Rot poisening group had significantly decreased activity of PC12 cells, decreased ATP content and increased production of ROS. After the poisen of Rot in PC12 cells, the expression of Pink1 and p-Parkin, the ratio of LC3Ⅱ/LC3Ⅰ and the expression of p-DRP1 in mitochondrial fusion protein was increased, while the expression of p62, the expression of mitochondrial biogenesis protein PGC1α, mitochondrial fusion proteins MFN2 and OPA1, and antioxidant stress proteins Keap1 and Nrf2 were decreased (all P < 0.05). The number of autophagosomes and autophagolysosomes in PC12 cells in the Rot poisening group was higher than that in the control group (P < 0.05), and HN pretreatment (20 μmol/L) could significantly improve the changes mentioned above caused by Rot poisening (P < 0.05). Conclusion HN ameliorates Rot-induced toxic damage for dopamine neurons by inhibiting mitophagy and mitochondrial division and promoting mitochondrial biogenesis and fusion, and anti-oxidative stress.

One prominent aspect of Parkinson's disease (PD) is the presence of elevated levels of free radicals, including reactive oxygen species (ROS). Syagrus coronata (S. coronata), a palm tree, exhibits antioxidant activity attributed to its phytochemical composition, containing fatty acids, polyphenols, and flavonoids. The aim of this investigation was to examine the potential neuroprotective effects of S. coronata fixed oil against rotenone-induced toxicity using Drosophila melanogaster. Young Drosophila specimens (3–4 d old) were exposed to a diet supplemented with rotenone (50 µM) for 7 d with and without the inclusion of S. coronata fixed oil (0.2 mg/g diet). Data demonstrated that rotenone exposure resulted in significant locomotor impairment and increased mortality rates in flies. Further, rotenone administration reduced total thiol levels but elevated lipid peroxidation, iron (Fe) levels, and nitric oxide (NO) levels while decreasing the reduced capacity of mitochondria. Concomitant administration of S. coronata exhibited a protective effect against rotenone, as evidenced by a return to control levels of Fe, NO, and total thiols, lowered lipid peroxidation levels, reversed locomotor impairment, and enhanced % cell viability. Molecular docking of the oil lipidic components with antioxidant enzymes showed strong binding affinity to superoxide dismutase (SOD) and glutathione peroxidase (GPX1) enzymes. Overall, treatment with S. coronata fixed oil was found to prevent rotenone-induced movement disorders and oxidative stress in Drosophila melanogaster. [ABSTRACT FROM AUTHOR]

Rotenone (RTN) induces neurotoxicity and motor dysfunction in rats, mirroring the pathophysiological traits of Parkinson's disease (PD), including striatal oxidative stress, mitochondrial dysfunction, and changes in neural structure. This makes RTN a valuable model for PD research. Berberine (BBR), an isoquinoline alkaloid recognized for its antioxidative, anti-inflammatory, and neuroprotective properties, was evaluated for its ability to counteract RTN-induced impairments. Rats received subcutaneous RTN at 0.5 mg/kg for 21 days, resulting in weight loss and significant motor deficits assessed through open-field, bar catalepsy, beam-crossing, rotarod, and grip strength tests. BBR, administered orally at 30 or 100 mg/kg doses, one hour prior to RTN exposure for the same duration, effectively mitigated many of the RTN-induced motor impairments. Furthermore, BBR treatment reduced RTN-induced nitric oxide (NO) and lipid peroxidation (LPO) levels, bolstered antioxidative capacity, enhanced mitochondrial enzyme activities (e.g., succinate dehydrogenase (SDH), ATPase, and the electron transport chain (ETC)), and diminished striatal neuroinflammation and apoptosis markers. Notably, the co-administration of trigonelline (TGN), an inhibitor of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, significantly attenuated BBR's protective effects, indicating that BBR's neuroprotective actions are mediated via the Nrf2 pathway. These results underscore BBR's potential in ameliorating motor impairments akin to PD, suggesting its promise in potentially delaying or managing PD symptoms. Further research is warranted to translate these preclinical findings into clinical settings, enhancing our comprehension of BBR's therapeutic prospects in PD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is an extrapyramidal movement disorder associated with a hypokinetic condition generated by impairment in dopaminergic neuronal viability in the nigrostriatal region of the brain. Current medications can only provide symptomatic management; to date, no permanent cure is available. To compensate for this lacuna, researchers are gaining interest in antigen‐based therapy, and Bacille‐Calmette‐Guerin (BCG) is one of the vaccines with a high safety margin that acts by stimulating immunoreactive T‐cells in the CNS and reducing expression of pro‐inflammatory cytokines including interleukin (IL)‐1β and tumor necrotic factor (TNF‐α) to produce neuroprotection. A previous study reported that BCG exerts a neuroprotective effect against several neurodegenerative disorders, such as Alzheimer's disease. Objective: The objective of this study is to explore the neuroprotective effect of the BCG vaccine against the rotenone model of PD. Methods: Rotenone (1.5 mg/kg, s.c) for 28 days, and BCG vaccine (2 × 107 cfu, i.p) single dose was injected to rats, and behavioral assessments were performed on the 21st and 28th day. On the 29th day, rats were sacrificed, and brains were isolated for biochemical and neurochemical estimation. Results: BCG vaccine significantly restored rotenone‐induced motor deficits (open field test, narrow beam walk, and rotarod), biochemical levels (GSH, SOD, catalase, MDA, and nitrite), neurotransmitters (dopamine, 5‐hydroxy tryptamine, norepinephrine, 3,4‐dihydroxyphenylacetic acid, hemovanillic acid, and 5‐hydroxy indoleacetic acid), and levels of inflammatory cytokines (IL‐1β and TNF‐α) in the striatum. It also prevents histopathological changes by reducing eosinophilic lesions in the striatum. Conclusion: From the results, we conclude that BCG vaccine showed neuroprotection through antioxidant and anti‐inflammatory effect. Thus, in the future, it can be used as a neuroprotective agent for other neurological disorders, including PD. [ABSTRACT FROM AUTHOR]

Parkinson’s disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson’s disease (PD) and Alzheimer’s disease (AD). Although it is assumed that alpha-synuclein (α -Syn), amyloid beta (A β ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10 μ M) for 24 h. ROT provokes loss of Δ Ψ m , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of α -synuclein (α -Syn, Ser129), induces accumulation of intracellular A β (iA β ), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- α (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p- α -Syn, iA β , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a leading neurodegenerative disorder affecting 1–3 percent of the elderly population. Oxidative stress is the primary factor for the neurodegeneration of Substantia Nigra (SN). The current study aims to assess the seed extracts of Moringa oleifera (MO) on rotenone-mediated motor function impairments in a PD mouse model. For this purpose, two different seed extracts of MO were prepared, including aqueous MO (AqMO) and ethanolic MO (EthMO). Male Swiss albino mice were grouped into five groups. Mice received 2.5 mg/kg rotenone for 21 consecutive days, and control mice received the vehicle. Extract-treated mice received 200 mg/kg AqMO and EthMO separately, orally and daily for 28 days. Sinemet-treated mice received 20 mg/kg, oral dose, as a positive group. The motor function performance was evaluated using standard neurobehavioral tests. The antioxidant potentials of MO seed extracts were estimated by lipid peroxidation (LPO), reduced glutathione (GSH), glutathione-s-transferase (GST) and catalase (CAT) activities in mice brain homogenates. The PD mice brain SN sections were investigated for neurodegeneration. MO seed extract-treated mice showed a significant reduction in motor dysfunction compared to rotenone-treated mice as assessed through the open field, beam walk, pole climb-down, tail suspension, stride length and stepping tests. Increased antioxidant capacities of the PD mice brains of MO extract-administered groups were observed compared to the control. A histological study showed reduced signs of neurodegeneration, vacuolation around multipolar cells and cytoplasmic shrinkage in MO extract-treated mice SN brain sections. Collectively, MO seed extracts protected the animals from locomotor deficits induced by rotenone, possibly through antioxidant means, and seem to have potential applications in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a predominant neuromotor disorder characterized by the selective death of dopaminergic neurons in the midbrain. The majority of PD cases are sporadic or idiopathic, with environmental toxins and pollutants potentially contributing to its development or exacerbation. However, clinical PD patients are often associated with a reduced stroke frequency, where circulating blood platelets are indispensable. Although platelet structural impairment is evident in PD, the platelet functional alterations and their underlying molecular mechanisms are still obscure. Therefore, we investigated rotenone (ROT), an environmental neurotoxin that selectively destroys dopaminergic neurons mimicking PD, on human blood platelets to explore its impact on platelet functions, thus replicating PD conditions in vitro. Our study deciphered that ROT decreased thrombin‐induced platelet functions, including adhesion, activation, secretion, and aggregation in human blood platelets. As ROT is primarily responsible for generating intracellular reactive oxygen species (ROS), and ROS is a key player regulating the platelet functional parameters, we went on to check the effect of ROT on platelet ROS production. In our investigation, it became evident that ROT treatment resulted in the stimulation of ROS production in human blood platelets. Additionally, we discovered that ROT induced ROS production by augmenting Ca2+ mobilization from inositol 1,4,5‐trisphosphate receptor. Apart from this, the treatment of ROT triggers protein kinase C associated NADPH oxidase‐mediated ROS production in platelets. In summary, this research, for the first time, highlights ROT‐induced abnormal platelet functions and may provide a mechanistic insight into the altered platelet activities observed in PD patients. [ABSTRACT FROM AUTHOR]

Parkinson's disease is the most common neurodegenerative movement disorder, the pathogenesis of which is partly related with oxidant status and inflammatory responses. The administration of citral with antioxidant and anti-inflammatory properties may alleviate the negative effects of Parkinson. The present study aimed to assess the effects of citral nanoliposome on Parkinson's treatment in a rat model. In this study, citral nanoliposome was successfully produced through employing a facile method. Additionally, 40 Wistar rats were divided into four groups (n = 10), one of which was considered as Sham and received no treatment. However, the other groups were administrated with rotenone, and/or treated with 5 and 10 mg/kg of citral for 21 days. Behavioral responses were evaluated based on the forced swimming test and hippocampal-dependent memory deficit. The rates were examined for tissue lipid peroxide (LPO), as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in brain. Further, they were investigated in terms of expression of brain-derived neurotrophic factor (BDNF), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB). The results suggested more immobility, higher LPO level, and a rise in the expression of TNF-α, IL-6, and NF-κB (P = 0.001) following rotenone administration. Furthermore, this treatment decreased climbing, retention latency, SOD and GPx activities, and BDNF expression (P = 0.001). The use of citral, especially in higher dose, reversed all the adverse effects of rotenone on behavioral responses, antioxidant status, BDNF, and inflammatory genes. Parkinson represents a closed relationship with movement deficiency, increased inflammation, and reduced oxidant status. Citral administration can be considered as a therapeutic option following future studies. [ABSTRACT FROM AUTHOR]

Beaulieu J, Yates MC, Astorg L, Trépanier-Leroux D, Jeon H, Rudko SP, Humphries S, Fraser DJ, Cristescu ME, Derry AM. 2024. Environmental DNA for assessing impact and recovery of aquatic communities in an invaded mountain lake. Lake Reserv Manage. 40:111–131. The eradication of invasive species and associated side effects that influence the reestablishment of biological communities is a major challenge for conservation management of invaded ecosystems. We present a before-and-after-disturbance whole lake manipulation study from a high-elevation mountain lake in which we applied a 2-pronged approach to environmental DNA (eDNA) for assessing (1) impact and recovery of aquatic communities to the chemical eradication of invasive brook trout (Salvelinus fontinalis) and (2) the success of chemical eradication of the invasive fish. Using 18S and cytochrome oxidase I (COI) eDNA metabarcoding, we contribute to a paucity of literature that has comprehensively addressed nontarget effects of rotenone for invasive fish eradication on aquatic communities. We found that key trophic groups (phytoplankton, fungi, zooplankton, and macroinvertebrates) changed in community composition in response to rotenone applications. Fungi and macroinvertebrates, but not zooplankton and phytoplankton, reverted back toward pre-rotenone communities over the time scale of 2 yr. However, COI failed to detect several key species for food web reestablishment that were detected using physical specimen collection, likely due to low primer efficiency. We also found that quantitative polymerase chain reaction (qPCR), using species-specific primers, was effective for detecting brook trout presence/absence, although strong eDNA signals likely produced from carcasses in the ecosystem limited the utility of eDNA immediately following rotenone treatment. We provide specific recommendations for lake managers for the future application of eDNA approaches to monitor invasive fish eradication efforts and nontarget community effects for lake ecosystem restoration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]