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Microbiome Nov 2021Parkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently,...
Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis.
BACKGROUND
Parkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis.
RESULTS
We demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon.
CONCLUSIONS
Our current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis. Video abstract.
Topics: Animals; Brain-Gut Axis; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Parkinson Disease; Rotenone; Signal Transduction; Toll-Like Receptor 4
PubMed: 34784980
DOI: 10.1186/s40168-021-01107-9 -
Nature Genetics Mar 2021Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing...
Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype-Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.
Topics: Cell Differentiation; Dopaminergic Neurons; Genetic Predisposition to Disease; Humans; Induced Pluripotent Stem Cells; Neurogenesis; Oxidative Stress; Quantitative Trait Loci; Receptor, Fibroblast Growth Factor, Type 1; Rotenone; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 33664506
DOI: 10.1038/s41588-021-00801-6 -
BMC Complementary Medicine and Therapies Jan 2020Danshensu is an active constituent in the extracts of Danshen which is a traditional Chinese medical herb. Rotenone inhibits complex I of the mitochondrial electron...
BACKGROUND
Danshensu is an active constituent in the extracts of Danshen which is a traditional Chinese medical herb. Rotenone inhibits complex I of the mitochondrial electron transport chain in dopaminergic neurons leading to glutathione (GSH) level reduction and oxidative stress. The aim of this study is to investigate neuroprotective effects of Danshensu on rotenone-induced Parkinson's disease (PD) in vitro and in vivo.
METHODS
In vitro, SH-SY5Y human neuroblastoma cell line was pretreated with Danshensu and challenged with rotenone. Then the reactive oxygen species (ROS) production was assayed. In vivo, male C57BL/6 mice were intragastrically administered with Danshensu (15, 30, or 60 mg/kg), followed by oral administration with rotenone at a dose of 30 mg/kg. Pole and rotarod tests were carried out at 28 d to observe the effects of Danshensu on PD.
RESULTS
Danshensu repressed ROS generation and therefore attenuated the rotenone-induced injury in SH-SY5Y cells. Danshensu improved motor dysfunction induced by rotenone, accompanied with reducing MDA content and increasing GSH level in striatum. Danshensu increased the number of TH positive neurons, the expression of TH and the dopamine contents. The expressions of p-PI3K, p-AKT, Nrf2, hemeoxygenase (HO-1), glutathione cysteine ligase regulatory subunit (GCLC), glutathione cysteine ligase modulatory subunit (GCLM) were significantly increased and the expression of Keap1 was decreased in Danshensu groups.
CONCLUSIONS
The neuroprotective effects of Danshensu on rotenone-induced PD are attributed to the anti-oxidative properties by activating PI3K/AKT/Nrf2 pathway and increasing Nrf2-induced expression of HO-1, GCLC, and GCLM, at least in part.
Topics: Animals; Blotting, Western; Cell Line, Tumor; Disease Models, Animal; Flow Cytometry; Humans; Lactates; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Rotarod Performance Test; Rotenone
PubMed: 32020857
DOI: 10.1186/s12906-019-2738-7 -
Neurobiology of Disease Feb 2020Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal... (Review)
Review
Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal milieu, due to intestinal hyper-permeability and/or microbial dysbiosis, initiates or exacerbates PD pathogenesis. One factor that can cause intestinal hyper-permeability and dysbiosis is chronic stress which has been shown to accelerate neuronal degeneration and motor deficits in Parkinsonism rodent models. We hypothesized that stress-induced intestinal barrier dysfunction and microbial dysbiosis lead to a pro-inflammatory milieu that exacerbates the PD phenotype in the low-dose oral rotenone PD mice model. To test this hypothesis, mice received unpredictable restraint stress (RS) for 12 weeks, and during the last six weeks mice also received a daily administration of low-dose rotenone (10 mg/kg/day) orally. The initial six weeks of RS caused significantly higher urinary cortisol, intestinal hyperpermeability, and decreased abundance of putative "anti-inflammatory" bacteria (Lactobacillus) compared to non-stressed mice. Rotenone alone (i.e., without RS) disrupted the colonic expression of the tight junction protein ZO-1, increased oxidative stress (N-tyrosine), increased myenteric plexus enteric glial cell GFAP expression and increased α-synuclein (α-syn) protein levels in the colon compared to controls. Restraint stress exacerbated these rotenone-induced changes. Specifically, RS potentiated rotenone-induced effects in the colon including: 1) intestinal hyper-permeability, 2) disruption of tight junction proteins (ZO-1, Occludin, Claudin1), 3) oxidative stress (N-tyrosine), 4) inflammation in glial cells (GFAP + enteric glia cells), 5) α-syn, 6) increased relative abundance of fecal Akkermansia (mucin-degrading Gram-negative bacteria), and 7) endotoxemia. In addition, RS promoted a number of rotenone-induced effects in the brain including: 1) reduced number of resting microglia and a higher number of dystrophic/phagocytic microglia as well as (FJ-C+) dying cells in the substantia nigra (SN), 2) increased lipopolysaccharide (LPS) reactivity in the SN, and 3) reduced dopamine (DA) and DA metabolites (DOPAC, HVA) in the striatum compared to control mice. Our findings support a model in which chronic stress-induced, gut-derived, pro-inflammatory milieu exacerbates the PD phenotype via a dysfunctional microbiota-gut-brain axis.
Topics: Animals; Brain; Disease Models, Animal; Gastrointestinal Diseases; Gastrointestinal Microbiome; Humans; Parkinson Disease; Rotenone
PubMed: 30579705
DOI: 10.1016/j.nbd.2018.12.012 -
Frontiers in Immunology 2022Mitochondria are central players in host immunometabolism as they function not only as metabolic hubs but also as signaling platforms regulating innate immunity....
Mitochondria are central players in host immunometabolism as they function not only as metabolic hubs but also as signaling platforms regulating innate immunity. Environmental exposures to mitochondrial toxicants occur widely and are increasingly frequent. Exposures to these mitotoxicants may pose a serious threat to organismal health and the onset of diseases by disrupting immunometabolic pathways. In this study, we investigated whether the Complex I inhibitor rotenone could alter immunometabolism and disease susceptibility. embryos were exposed to rotenone (0.5 µM) or DMSO (0.125%) until they reached the L4 larval stage. Inhibition of mitochondrial respiration by rotenone and disruption of mitochondrial metabolism were evidenced by rotenone-induced detrimental effects on mitochondrial efficiency and nematode growth and development. Next, through transcriptomic analysis, we investigated if this specific but mild mitochondrial stress that we detected would lead to the modulation of immunometabolic pathways. We found 179 differentially expressed genes (DEG), which were mostly involved in detoxification, energy metabolism, and pathogen defense. Interestingly, among the down-regulated DEG, most of the known genes were involved in immune defense, and most of these were identified as commonly upregulated during infection. Furthermore, rotenone increased susceptibility to the pathogen (PA14). However, it increased resistance to (SL1344). To shed light on potential mechanisms related to these divergent effects on pathogen resistance, we assessed the activation of the mitochondrial unfolded protein response (UPR), a well-known immunometabolic pathway in which links mitochondria and immunity and provides resistance to pathogen infection. The UPR pathway was activated in rotenone-treated nematodes further exposed for 24 h to the pathogenic bacteria and or the common bacterial food source (OP50). However, alone suppressed UPR activation and rotenone treatment rescued its activation only to the level of DMSO-exposed nematodes fed with . Module-weighted annotation bioinformatics analysis was also consistent with UPR activation in rotenone-exposed nematodes consistent with the UPR being involved in the increased resistance to . Together, our results demonstrate that the mitotoxicant rotenone can disrupt immunometabolism in ways likely protective against some pathogen species but sensitizing against others.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dimethyl Sulfoxide; Escherichia coli; Pseudomonas aeruginosa; Rotenone
PubMed: 35273616
DOI: 10.3389/fimmu.2022.840272 -
PloS One 2022Rotenone is a commonly used insecticidal chemical in agriculture and it is an inhibitor of mitochondrial complex Ⅰ. Previous studies have found that rotenone induces...
Rotenone is a commonly used insecticidal chemical in agriculture and it is an inhibitor of mitochondrial complex Ⅰ. Previous studies have found that rotenone induces the production of reactive oxygen species (ROS) by inhibiting electron transport in the mitochondria of somatic and germ cells. However, there is little precise information on the effects of rotenone exposure in porcine oocytes during in vitro maturation, and the mechanisms underlying these effects have not been determined. The Cumulus-oocyte complexes were supplemented with different concentrations of rotenone to elucidate the effects of rotenone exposure on the meiotic maturation of porcine oocytes during in vitro maturation for about 48 hours. First, we found that the maturation rate and expansion of cumulus cells were significantly reduced in the 3 and 5 μM rotenone-treated groups. Subsequently, the concentration of rotenone was determined to be 3 μM. Also, immunofluorescence, western blotting, and image quantification analyses were performed to test the rotenone exposure on the meiotic maturation, total and mitochondrial ROS, mitochondrial function and biogenesis, mitophagy and apoptosis in porcine oocytes. Further experiments showed that rotenone treatment induced mitochondrial dysfunction and failure of mitochondrial biogenesis by repressing the level of SIRT1 during in vitro maturation of porcine oocytes. In addition, rotenone treatment reduced the ratio of active mitochondria to total mitochondria, increased ROS production, and decreased ATP production. The levels of LC3 and active-caspase 3 were significantly increased by rotenone treatment, indicating that mitochondrial dysfunction induced by rotenone increased mitophagy but eventually led to apoptosis. Collectively, these results suggest that rotenone interferes with porcine oocyte maturation by inhibiting mitochondrial function.
Topics: Swine; Animals; Female; Rotenone; Reactive Oxygen Species; Oocytes; Cumulus Cells; Mitochondria
PubMed: 36441709
DOI: 10.1371/journal.pone.0277477 -
Microbiology Spectrum Aug 2023Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were...
Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity against two orthopoxviruses. Despite the eradication of smallpox, some orthopoxviruses remain important human pathogens, as exemplified by the recent 2022 monkeypox virus (MPXV) outbreak. Although smallpox vaccines are effective against MPXV, access to those vaccines is limited. In addition, current antiviral treatment against MPXV infections is limited to the use of the FDA-approved drugs tecovirimat and brincidofovir. Thus, there is an urgent need to identify novel antivirals for the treatment of MPXV infection and other potentially zoonotic orthopoxvirus infections. Here, we show that 13 compounds, derived from two different libraries, previously found to inhibit several RNA viruses, also inhibit VACV. Notably, 11 compounds also displayed inhibitory activity against MPXV.
Topics: Humans; Mpox (monkeypox); Mycophenolic Acid; Smallpox; Antimycin A; Monensin; Rotenone; Valinomycin; Monkeypox virus; Antiviral Agents
PubMed: 37278625
DOI: 10.1128/spectrum.04745-22 -
Folia Neuropathologica 2019Rotenone ([2R-(2α,6aα,12aα)]-1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-[1]benzopyran[3,4-b]furo [2,3-h][1]benzopyran-6(6aH)-one) is a naturally... (Review)
Review
Rotenone ([2R-(2α,6aα,12aα)]-1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-[1]benzopyran[3,4-b]furo [2,3-h][1]benzopyran-6(6aH)-one) is a naturally occurring compound derived from the roots and stems of Derris, Tephrosia, Lonchocarpus and Mundulea plant species. Since its discovery at the end of the 19th century, rotenone has been widely used as a pesticide for controlling insects, ticks and lice, and as a piscicide for management of nuisance fish in lakes and reservoirs. In 2000, Betarbet et al. reproduced most of the behavioural, biochemical and pathological features of Parkinson's disease (PD) in rotenone-treated rats. Since that time, rotenone has received much attention as it would be one of the environmental neurotoxins implicated in etiopathogenesis of PD. Moreover, it represents a common experimental model to investigate the underlying mechanisms leading to PD and evaluate the new potential therapies for the disease. In the current general review, we aimed to address recent advances in the hazards of the environmental applications of rotenone and discuss the updates on the rotenone model of PD and whether it is implicated in the etiopathogenesis of the disease.
Topics: Animals; Cell Death; Disease Models, Animal; Humans; Inflammation; Parkinson Disease; Reactive Oxygen Species; Rotenone
PubMed: 32337944
DOI: 10.5114/fn.2019.89857 -
Journal of Molecular Neuroscience : MN Nov 2022Rotenone is a commercial pesticide commonly used to model Parkinson's disease (PD) due to its ability to induce dopaminergic degeneration. Studies have confirmed that...
Rotenone is a commercial pesticide commonly used to model Parkinson's disease (PD) due to its ability to induce dopaminergic degeneration. Studies have confirmed that rotenone causes microglial activation, which seems to contribute to the toxic effects seen in rodent models. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related neuropeptides that have robust neuroprotective and anti-inflammatory properties. However, their ability to regulate microglial activity in response to rotenone is not fully understood. Using rotenone as an inflammatory stimulus, we tested whether PACAP or VIP could mitigate microglial activation in BV2 microglial cells. Rotenone dose-dependently reduced cell viability and the percentage of apoptotic cells. It also increased the release of nitric oxide (NO) in culture media and the expression of microglial activation markers and pro-inflammatory markers, including CD11b, MMP-9 and IL-6, and heightened the endogenous levels of PACAP and its preferring receptor PAC1. Co-treatment with PACAP or VIP prevented rotenone-induced increase of NO, CD11b, MMP-9 and IL-6. These results indicate that both PACAP and VIP are able to prevent the pro-inflammatory effects of rotenone in BV2 cells, supporting the idea that these molecules can have therapeutic value in slowing down PD progression.
Topics: Vasoactive Intestinal Peptide; Pituitary Adenylate Cyclase-Activating Polypeptide; Microglia; Rotenone; Matrix Metalloproteinase 9; Interleukin-6
PubMed: 35199308
DOI: 10.1007/s12031-022-01968-1 -
Biochemical Society Transactions Feb 2023The prevalence of neurological diseases is currently growing due to the combination of several factor, including poor lifestyle and environmental imbalance which enhance... (Review)
Review
The prevalence of neurological diseases is currently growing due to the combination of several factor, including poor lifestyle and environmental imbalance which enhance the contribution of genetic factors. Parkinson's disease (PD), a chronic and progressive neurological condition, is one of the most prevalent neurodegenerative human diseases. Development of models may help to understand its pathophysiology. This review focuses on studies using invertebrate models to investigate certain chemicals that generate parkinsonian-like symptoms models. Additionally, we report some preliminary results of our own research on a crustacean (the crab Ucides cordatus) and a solitary ascidian (Styela plicata), used after induction of parkinsonism with 6-hydroxydopamine and the pesticide rotenone, respectively. We also discuss the advantages, limits, and drawbacks of using invertebrate models to study PD. We suggest prospects and directions for future investigations of PD, based on invertebrate models.
Topics: Humans; Animals; Parkinsonian Disorders; Parkinson Disease; Rotenone; Invertebrates; Disease Models, Animal
PubMed: 36645005
DOI: 10.1042/BST20221172