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Vitamin C treatment affected the food intake ability of larvae in a dosage-dependent manner. (a) The levels of food intake were impacted by vitamin C treatment. There were changes in food intake ability when control and dUCH knockdown larvae were treated with different concentrations of vitamin C (one-way ANOVA with Tukey’s test, ∗p<0.05, ∗∗p<0.01, and ∗∗∗∗p<0.0001, population size N=10 and biological replication n=7, error bars represent the standard deviation of data). (b) The relative levels of vitamin C intake. The differences in relative levels of vitamin C intake were statistically significant (one-way ANOVA with Tukey’s test, ∗∗∗∗p<0.0001, population size N=10 and biological replication n=7, error bars represent the standard deviation of data). (c) The effects of vitamin C treatment on larval weight. The body weights of control and dUCH knockdown larvae were not reduced by vitamin C treatment (one-way ANOVA with Dunnett's test, ∗∗p<0.01 and ∗∗∗∗p<0.0001, population size N=8 and biological replication n=5, error bars represent the standard deviation of data). (d) The effects of vitamin C treatment on larval size. The body size of dUCH knockdown larvae were not reduced by vitamin C treatment (one-way ANOVA with Dunnett's test, ∗p<0.05, n=15, error bars represent the standard deviation of data). TH-Control (+; +; TH-GAL4/+) and TH-dUCH KD (+; +; TH-GAL4/UAS-dUCH.IR).
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Parkinson’s disease (PD) is a common neurodegenerative disorder and characterized by progressive locomotive defects and loss of dopaminergic neurons (DA neuron). Currently, there is no potent therapy to cure PD, and the medications merely support to control the symptoms. It is difficult to develop an effective treatment, since the PD onset mechanis...
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Citations
... However, it is di cult to draw conclusions from this result as the sample size of the ascorbate GWAS was small, and larger GWAS for ascorbate is needed to better clarify its association with PD. Earlier research has shown that vitamin C de ciencies are common in PD patients [44] and that vitamin C supplementation can reduce oxidative damage in animal models [45,46] . Thus, their results differed from our MR study where genetically elevated ascorbate should decrease the risk of PD while vitamin C does not. ...
Background
The prevalence of neurodegenerative disorders (NDDs) is increasing, and there is no cure for any of these diseases. Antioxidants have been associated with several diseases in observational studies. However, the relationship between antioxidants and neurodegenerative diseases remains unclear. The purpose of this study is to use publicly available genome-wide association studies (GWAS) summary statistics to examine the causal relationship between diet-derived antioxidants and the risk of NDDs.
Methods
Single-nucleotide polymorphisms associated with diet-derived antioxidants (vitamin A, vitamin B6, vitamin C, vitamin E, carotene, β-carotene, lycopene, zinc, and selenium) and their metabolites (α-tocopherol, γ-tocopherol, ascorbate, and retinol) were employed as instrumental variables. The NDDs we studied included Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), which were obtained from GWASs conducted in the European population. Two-sample Mendelian randomization (MR) was performed together with a series of sensitivity analyses. The main statistical analyses were conducted using package “TwoSampleMR (V.0.5.6)” in R (V.4.2.0)
Results
Genetically predicted α-tocopherol led to a lower risk of ALS (OR 0.45; 95% CI, 0.31, 0.66; p = 3.97E-05) based on the random-effect IVW method, and no evidence of heterogeneity and horizontal pleiotropy was found. In addition, we found a potential protective effect of vitamin E and ascorbate on PD, carotene on ALS, and retinol on FTD. However, no circulating antioxidants studied affect the risk for AD.
Conclusion
This study indicated that some diet-derived antioxidants or their metabolites showed evidence of causality in NDDs and provided promising targets for therapeutics.
... Parkinson's disease (PD) is a progressive neurological disorder characterized by αsynucleinopathy in the form of Lewy bodies (LB) and selective loss of dopaminergic neurons (DA-ergic) in the brain [1]. Globally, more than 1% of the population above 60 is affected by this disease [2]. PD patients exhibit some motor (bradykinesia, rigidity, resting tremor, postural instability) and some non-motor (dementia, sensory abnormalities, sleep disorders, and autonomic dysfunction) symptoms. ...
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease. Pathophysiologically, it is characterized by intracytoplasmic aggregates of α-synuclein protein in the Lewy body and loss of dopaminergic neurons from substantia nigra pars compacta and striatum regions of the brain. Although the exact mechanism of neurodegeneration is not fully elucidated, it has been reported that environmental toxins such as MPTP, rotenone, paraquat, and MPP+ induce oxidative stress, which is one of the causative factors for it. To date, there is no complete cure. However, the indispensable role of oxidative stress in mediating PD indicates that antioxidant therapy could be a possible therapeutic strategy against the disease. The deficiency of vitamins has been extensively co-related to PD. Dietary supplementation of vitamins with antioxidant, anti-inflammatory, anti-apoptotic, and free radical scavenging properties could be the potential neuroprotective therapeutic strategy. This review summarizes the studies that evaluated the role of vitamins (A, B, C, D, E, and K) in PD. It will guide future studies in understanding the potential therapeutic role of vitamins in disease pathophysiology and may provide a framework for designing treatment strategies against the disease.
... It is a water-soluble antioxidant that can shield the body's water-soluble components by scavenging aqueous free radicals and reactive oxygen species (ROS) (Choi et al., 2004;Kocot et al., 2017). Vitamin C is an essential biomolecule for various neurological functions such as neuronal differentiation, maturation, survival, and the synthesis and transmission of neurotransmitters (Man Anh et al., 2019). Furthermore, its protective role has been studied in several neurodegenerative disorders, such as AD and PD (Hamid et al., 2022;Kocot et al., 2017). ...
... As a consequence, the interest in antioxidant molecules for therapeutic applications has been increasing. For example, Man Anh et al. (2019) studied the neuroprotective effect of vitamin C in a Drosophila model with PDlike phenotype and demonstrated its potential to reduce PD symptoms. However, they observed that its administration in high doses, as well as long-term use, lead to significant side-effects. ...
... On the other hand, Ma and collaborators (2018) verified that pretreatment with proanthocyanidis, a class of natural flavonoids, reduced the rotenone-induced oxidation in human neuroblastoma cells SH-SY5Y. In addition, they also observed that flavonoids were able to considerably block rotenone-induced apoptosis through Caspase-9 and Caspase-3 activity inhibition, as well as the inhibition of the mitogen-activated protein kinases, p38, JNK and ERK (Man Anh et al. 2019). ...
Oxidative stress is strongly involved in the pathogenesis of neurodegenerative diseases, like Parkinson´s disease (PD). Particularly, an excess of reactive oxygen species (ROS) released by the cells promotes an oxidative stress condition, which is a main cause of tissue injury leading to nervous system dysfunction. In this work, the antioxidant, neuroprotective and anti-inflammatory activities of different fractions from the brown seaweed Bifurcaria bifurcata are presented and related with their chemical profile. The antioxidant capacity was evaluated by the Folin-Ciocalteu method, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Neuroprotective capacity was evaluated to prevent neurological cell death mediated by the neurotoxin 6-hydroxydopamine (6-OHDA) on SH-SY5Y cells, and their anti-inflammatory effects on RAW 264.7 macrophages. The ethyl acetate fractions (100 µg mL−1) exhibited significant antioxidant and neuroprotective activities in the in vitro models assayed. Furthermore, two of the most polar fractions obtained with methanol and water also evidenced a significant neuroprotective potential. Bifurcaria bifurcata fractions treatment decreased ROS production, mitochondrial dysfunction, and Caspase-3 activity. Regarding the anti-inflammatory potential, five fractions (100 µg mL−1) inhibited nitric oxide (NO) production and reduced the interleukin – 6 (IL-6) and tumor necrosis factor (TNF-α) levels. Mannitol, identified as the major component of the most bioactive fraction, protected SH-SY5Y cells against the 6-OHDA neurotoxicity mediating ROS generation mitigation, mitochondrial dysfunction, and DNA damage, together with the Caspase-3 activity inhibition. Results suggest that B. bifurcata is a relevant source of neuroprotective agents, with particular interest for preventive therapeutics.
... Another investigation studied the neuroprotective effect of vitamin C in chronic restraint stress-induced rats, which improved synaptic activities and cognitive function. Moreover, findings from experiments performed on a Drosophila model with PD-like phenotypes, have shown that the administration of vitamin C at high doses leads to significant side effects; in addition, long-term treatment could prevent the degeneration of dopaminergic neurons [51]. ascorbate-conjugated nanocarriers were developed by Salmaso et al. [52] to selectively target the ascorbate transporter (SVCT2) expressed in the epithelial cells of the choroid plexus. ...
Neurodegenerative disorders (NDs) affect a great number of people worldwide and also have a significant socio-economic impact on the aging population. In this context, nanomedicine applied to neurological disorders provides several biotechnological strategies and nanoformulations that improve life expectancy and the quality of life of patients affected by brain disorders. However, available treatments are limited by the presence of the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (B–CSFB). In this regard, nanotechnological approaches could overcome these obstacles by updating various aspects (e.g., enhanced drug-delivery efficiency and bioavailability, BBB permeation and targeting the brain parenchyma, minimizing side effects). The aim of this review is to carefully explore the key elements of different neurological disorders and summarize the available nanomaterials applied for neurodegeneration therapy looking at several types of nanocarriers. Moreover, nutraceutical-loaded nanoparticles (NPs) and synthesized NPs using green approaches are also discussed underling the need to adopt eco-friendly procedures with a low environmental impact. The proven antioxidant properties related to several natural products provide an interesting starting point for developing efficient and green nanotools useful for neuroprotectio
... Cell and animal studies of vitamin C support the therapeutic potential of this antioxidant in the treatment of PD. In a model of dUCH using Drosophila, where a homolog of the PD-related gene UCH-L1 was a knockdown, treatment with low dose ascorbate reduced dopaminergic neuron loss and motor dysfunction, although side effects on physiology occurred with high doses and long-term treatment [94]. Ascorbate also reduces ROS and inducible nitric oxide synthase (iNOS) in MPP + treated astrocytes as well as upregulates endogenous antioxidants through a mechanism of NFκB activation in both astrocytes and MPTP treated mice [95]. ...
Parkinson's disease (PD) is a progressive neurodegenerative disorder that arises due to a complex and variable interplay between elements including age, genetic, and environmental risk factors that manifest as the loss of dopaminergic neurons. Contemporary treatments for PD do not prevent or reverse the extent of neurodegeneration that is characteristic of this disorder and accordingly, there is a strong need to develop new approaches which address the underlying disease process and provide benefit to patients with this debilitating disorder. Mitochondrial dysfunction, oxidative damage, and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons seen in PD. However, results of studies aiming to inhibit these pathways have shown variable success, and outcomes from large-scale clinical trials are not available or report varying success for the interventions studied. Overall, the available data suggest that further development and testing of novel therapies are required to identify new potential therapies for combating PD. Herein, this review reports on the most recent development of antioxidant and anti-inflammatory approaches that have shown positive benefit in cell and animal models of disease with a focus on supplementation with natural product therapies and selected synthetic drugs.
... Even controversy exists about the protective role of vitamin C in PD since one epidemiological study highlighted a decreased risk of PD in individuals consuming diets rich in vitamin C, whereas other studies showed no effects or even an increased risk of PD with consumption of vitamin C (Etminan et al. 2005;Weber and Ernst 2006;Seidl and Potashkin 2011). Controversial outcomes in different preclinical models and clinical trials in the form of oral dosage, dietary supplementation and combinational administration with other antioxidants have raised serious doubt about the efficacy of vitamin C in treating Parkinsonism (Pardo et al. 1993;Nagayama et al. 2004;Bagga et al. 2008;Hughes et al. 2016;Man Anh et al. 2019). ...
As conventional therapeutics can only treat the symptoms of Parkinson's disease (PD), major focus of research in recent times is to slow down or prevent the progression of neuronal degeneration in PD. Non-targeted antioxidants have been an integral part of the conventional therapeutics regimen; however, their importance have lessened over time because of their controversial outcomes in clinical PD trials. Inability to permeate and localize within the mitochondria remains the main drawback on the part of non-targeted antioxidants inspite of possessing free radical scavenging properties. In contrast, mitochondrial-targeted antioxidants (MTAs), a special class of compounds have emerged having high advantages over non-targeted antioxidants by virtue of efficient pharmacokinetics and better absorption rate with capability to localize many fold inside the mitochondrial matrix. Preclinical experimentations indicate that MTAs have the potential to act as better alternatives compared to conventional non-targeted antioxidants in treating PD; however, sufficient clinical trials have not been conducted to investigate the efficacies of MTAs in treating PD. Controversial clinical outcomes on the part of non-targeted antioxidants and lack of clinical trials involving MTAs have made it difficult to go ahead with a direct comparison and in turn have slowed down the progress of development of safer and better alternate strategies in treating PD. This review provides an insight on the roles MTAs and non-targeted antioxidants have played in the treatment of PD till date in preclinical and clinical settings and discusses about the limitations of mitochondria-targeted and non-targeted antioxidants that can be resolved for developing effective strategies in treating Parkinsonism.
... This model could display pathophysiological features and mimic PD symptoms including mobility defects such as difficulty in walking, slow movement, tremor, and progressive DA neuron degeneration [12,17]. Furthermore, knockdown of dUCH resulted in increased levels of ROS leading to oxidative stress and antioxidant agents consisting of vitamin C, curcumin, and Portulaca oleracea extract were demonstrated to improve the PD-like phenotypes in this fly model [18][19][20]. Therefore, this model might be useful for screening agents with therapeutic effects on Parkinson's disease. ...
... In this study, the effect of PLE on larval motility by crawling assay and adult flies by climbing assay was investigated. As a previous report [18], in this study, the dUCHknockdown larvae exhibited not only abnormal behaviors but also decreased crawling speeds, and vitamin C at 0.5 mM could improve the motility of dUCH-knockdown larvae. Mobility of knockdown larvae (TH > dUCH-IR) increased after being treated with PLE at all treated concentrations. ...
Parkinson’s disease (PD) is characterized by progressive locomotive defects and loss of dopaminergic neurons. Polyscias fruticosa leaves are used by Vietnamese as herbal medicines to support the treatment of some diseases related to neurodegeneration such as Parkinson’s and Alzheimer’s diseases. However, recent scientific data have not provided sufficient evidence for the use of P. fruticosa leaves to treat PD or decelerate PD progression. In the present study, the capacity of P. fruticosa leaf extract for PD treatment on the dietary supplementation was investigated using dUCH-knockdown Drosophila model. The results indicated that P. fruticosa leaf extract decelerated dopaminergic neuron degeneration induced by dUCH knockdown in not only the larval stage but also the adult stage, which might result in the amelioration in locomotor ability of dUCH-knockdown larvae and flies. Furthermore, antioxidant activities and some key phytochemicals such as saponins, polyphenols, and flavonoids that might contribute to the effects of the P. fruticosa leaf extract were identified.
... On the other hand, our previous results with the Drosophila model carrying a specific knockdown of dUCH (a homolog of the human UCHL-1) in dopaminergic neurons suggested an interference pathway by oxidative stress (41). The knockdown flies expressed Parkinson's disease phenotypes that were recovered by antioxidant treatment with vitamin C or curcumin (24,27). ...
Aim:
Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) plays an important role in the ubiquitin-proteasome system and is distributed mostly in the brain. Previous studies have shown that mutated forms or reduction of UCH-L1 are related to neurodegenerative disorders, but the mechanisms of pathogenesis are still not well understood. To study its roles in motor neuronal health, we utilized the Drosophila model in which dUCH, a homolog of human UCH-L1, was specifically knocked down in motor neurons.
Results:
The reduction of dUCH in motor neurons induced excessive reactive oxygen species production and multiple aging signals, including locomotive defects, muscle degeneration, enhanced apoptosis, and shortened longevity. Additionally, there is a decrease in the density of the synaptic active zone and glutamate receptor area at the neuromuscular junction. Interestingly, all these defects were rescued by vitamin C treatment, suggesting a close association with oxidative stress. Strikingly, knockdown dUCH at motor neurons exhibited aberrant morphology and function of mitochondria, such as mtDNA depletion, an increase in mitochondrial size, and overexpression of antioxidant enzymes.
Innovation:
This research indicates a new, possible pathogenesis of dUCH deficiency in the ventral nerve cord and peripheral nervous systems, which starts with abnormal mitochondria, leading to oxidative stress and premature aging. There is also direct evidence that aging not only takes place in knockdown tissues but also leads to aging of other tissues.
Conclusion:
Taken together, using Drosophila model, our findings strongly emphasize how the UCH-L1 shortage affects motor neurons and further demonstrate the crucial roles of UCH-L1 in neuronal health.
... Among them, the dUCH-knocked down Drosophila melanogaster model has an advantage with high number of individuals in the population and can mimic the main PD phenotypes, including the defect in locomotor abilities and the progressive of DA neuron [8]. Besides that, antioxidant compounds such as vitamin C, curcumin, and vegetal such as Portulaca oleracea, Crocus sativus, and Ginkgo biloba also have been reported to mitigate the PD-like phenotypes in fly models [9] [10] [11]. ...
... Previous reports demonstrated that antioxidant compounds could ameliorate PD-like symptoms in dUCH-knockdown fly model [9] [10]. We thereby examined the antioxidant capacity of rumdul fruit water extract (RFWE) by DPPH radical scavenging activity assay in which vitamin C (vitC) was used as the standard compound. ...
... The results showed that the IC 50 value of RFWE was 85:62 ± 1:05 μg/mL (Figure 1(b)), equivalent to an antioxidant capacity of 14:49 ± 1:08 μM vitamin C (Figure 1(a)). Based on the equivalent antioxidant index of RFWE and vitamin C (presented in Table S1) and a previous report on the effect of vitC treatment [9], we decided to use RFWE at concentrations of 3, 6, 12, and 18 mg/mL for further experiments on dUCH-knockdown fly model. ...
Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by progressive deterioration of motor function and loss of dopaminergic neurons in the substantia nigra. Although PD is more common in people over 60 years old, people with young-onset PD tend to increase recently. Up to now, there is no cure for PD; therapies mainly focus on reducing symptoms and improving patient quality of life. Thus, the requirement of exploring new medications is needed. There is a strong relationship between oxidative stress and PD. Therefore, antioxidant compounds have been considered as a novel therapy for PD. In this study, we indicated a new potential candidate for PD treatment, rumdul fruit (Sphaerocoryne affinis—a member of the Annonaceae family), due to evaluating its activities on the fly model of Parkinson. Our experimental results showed that rumdul fruit water extract (RFWE) has a strong antioxidant capacity with IC50 value in DPPH assay which was 85.62±1.05 μg/mL. The use of RFWE at concentrations of 3, 6, and 12 mg/mL could strongly ameliorate the locomotor disabilities and dopaminergic neuron degeneration. Although the RFWE at high concentrations like 12 mg/mL and 18 mg/mL could induce some side effects on fly development and viability, our data strongly demonstrated that RFWE effectively rescued PD phenotypes on the fly model. Although component in the plant extract, as well as the molecular mechanism helping to recover the phenotype, has not been elucidated yet, the research contributed strong scientific evidence for further research on applying rumdul as a novel natural source for PD treatment.
