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Suppression of NO and PGE 2 production by BEOV in Aβ-stimulating BV2 microglia. (A) BV2 cells were cultured with different concentrations of BEOV (1, 2, 5, 10, 20, 50, 75, 100, 200, 400 μM) for 24 h. Cell viability was detected using the CCK-8. *: BEOV group vs untreated group. n = 6 wells per group, * P < 0.05, ** P < 0.01, and *** P < 0.001, respectively. (B) The level of NO in culture medium was measured with the Griess reagent. (C) The level of PGE 2 in culture medium was measured with an ELISA kit. #: Aβ group vs untreated group; *: Aβ group vs Aβ + BEOV group. n = 6 wells per group, ### P < 0.001, * P < 0.05, ** P < 0.01, and *** P < 0.001, respectively.
Source publication
Neuroinflammation plays a pivotal role in the pathophysiology of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease (AD). During brain neuroinflammation, activated microglial cells resulting from amyloid-beta (Aβ) overload trigger toxic proinflammatory responses. Bis(ethylmaltolato)oxidovanadium (IV), an important vanad...
Contexts in source publication
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... test whether BEOV exert cytotoxicity on BV2 microglia, the CCK-8 assay was used in this study. The results showed no obvious cytotoxicity of BEOV on BV2 microglia within 24 h treatment, until the concentration of BEOV reached 75 μM (Fig. 1A). Therefore, nontoxic concentrations (5, 10, 20 μM) of BEOV were used in subsequent experiments for the treatment of BV2 cells. In the neuroimmune system, NO and PGE 2 are two major mediators released by hyperactivated microglia. 41 Aβ-activated BV2 microglia overproduce both NO and PGE 2 and this is regarded as a general ...
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... BV2 microglia and APPswe/PS1E9 transgenic mice comparing with untreated BV2 microglia and WT mice, respectively. Treatment with different doses of BEOV, particularly the high doses of BEOV (20 μM for BV2 cells and 1.0 mM for AD mice, respectively), significantly inhibited the reduction of PPARγ expression in both Aβ-stimulated BV2 microglia (136.2, 100, 128.5, 130.6, and 149.6%; for the cell of BV2, Aβ-stimulated BV2, Aβ-stimulated BV2 treated with 5, 10, and 20 μM BEOV, respectively) and hippocampus of APPswe/PS1E9 transgenic mice (146.0, 100, 151.1, and 166.5%; for the mice of WT, AD, AD treated with 0.2 and 1.0 mmol/l BEOV, respectively). Immunofluorescence staining was also performed ...
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... elucidate the underlying mechanism of BEOV in attenuated Aβ-induced neuroinflammation, the levels of IκB-α and p65 phosphorylation were measured after adding GW9662 to the culture of BV2 cells. Western blot analysis showed that inhibition of PPARγ by GW9662 markedly restored the levels of p-IκB-α and p-NF-κB that were reduced by BEOV treatment (Fig. 10A and B). Meanwhile, the results of immunofluorescence staining also showed that inhibition of PPARγ by GW9662 rehabilitated the NF-κB/p65 nuclear translocation that was inhibited by BEOV treatment (Fig. 10C and D). Taken together, all these results demonstrated that BEOV treatment relieved Aβ-stimulated neuroinflammation by inactivating the ...
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... analysis showed that inhibition of PPARγ by GW9662 markedly restored the levels of p-IκB-α and p-NF-κB that were reduced by BEOV treatment (Fig. 10A and B). Meanwhile, the results of immunofluorescence staining also showed that inhibition of PPARγ by GW9662 rehabilitated the NF-κB/p65 nuclear translocation that was inhibited by BEOV treatment (Fig. 10C and D). Taken together, all these results demonstrated that BEOV treatment relieved Aβ-stimulated neuroinflammation by inactivating the NF-κB pathway via a PPARγ -dependent ...
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... Quantification results were normalized to the levels of GAPDH. (E) The levels of TNF-α, IL-6, and IL-1β in the culture medium were detected by ELISA kit. n = 6 wells per group, #: Aβ group vs untreated group or Aβ + BEOV group; *: Aβ + BEOV + GW9662 group vs Aβ + BEOV group. ## P < 0.01, ### P < 0.001, * P < 0.05, and ** P < 0.01, respectively. Fig. 10 BEOV-induced inactivation of NF-κB signaling was eliminated by PPARγ inhibitor GW9662. (A, B) Aβ-stimulating BV2 microglia were co-treated with BEOV (20 μM) and GW9662 (20 μM) for 24 h. The protein expression levels of p-IκB-α, IκB-α, p-p65, and p65 were detected by western blot analysis. Quantification results were normalized to the ...
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... confirmed that microglial activation and proinflammatory mediator overproduction are important pathophysiologic phenomena involved in AD formation and progression. BEOV could attenuate neuroinflammation generated in Aβ-stimulated BV2 microglia and APPswe/PS1E9 transgenic mouse brain through PPARγ -mediated inhibition of NF-κB signaling pathway (Fig. 11). Our findings provide for the first time an important insight into the potentiality for BEOV to alleviate AD pathology via targeting neuroinflammation. Moreover, it shows a promising future for other vanadium compounds to play a role in anti-neuroinflammation and AD ...
Citations
... Consistent with our results, the previous study also found activation of PPARγ could repress the expression of inflammatory factors by negatively interfering with the NF-κB pathway. 39 This suggested PA might inhibit the inflammation through the PPARγ/NF-κB pathway in treating AD. 51 We also explored the downstream effect of activation of the PPARγ/NF-κB pathway after PA treatment. The results showed the PA treatment decreased apoptosis in conditioned medium-cultured N2a cells. ...
Aims
We aimed to explore the role and molecular mechanism of polygalacic acid (PA) extracted from traditional Chinese medicine Polygala tenuifolia in the treatment of Alzheimer's disease (AD).
Methods
The network pharmacology analysis was used to predict the potential targets and pathways of PA. Molecular docking was applied to analyze the combination between PA and core targets. Aβ42 oligomer‐induced AD mice model and microglia were used to detect the effect of PA on the release of pro‐inflammatory mediators and its further mechanism. In addition, a co‐culture system of microglia and neuronal cells was constructed to assess the effect of PA on activating microglia‐mediated neuronal apoptosis.
Results
We predict that PA might regulate inflammation by targeting PPARγ‐mediated pathways by using network pharmacology. In vivo study, PA could attenuate cognitive deficits and inhibit the expression levels of inflammation‐related factors. In vitro study, PA can also decrease the production of activated microglia‐mediated inflammatory cytokines and reduce the apoptosis of N2a neuronal cells. PPARγ inhibitor GW9662 inversed the neuroprotective effect of PA. Both in vivo and in vitro studies showed PA might attenuate the inflammation through the PPARγ/NF‐κB pathway.
Conclusions
PA is expected to provide a valuable candidate for new drug development for AD in the future.
... Nevertheless, the role of PPARγ in CPSP, and especially thalamic pain, is still unclear. Nuclear factor kappa B (NF-κB) is a key signaling pathway for regulating inflammation, and its expression can be hindered by PPARγ [15]. Szanto and colleagues reported that activation of the STAT6 pathway upregulates PPARγ to exert anti-inflammatory effects [16]. ...
... Pioglitazone (20 mg/kg dissolved in 5% DMSO + 40% PEG300 + 5% Tween20 + 45% ddH2O), a selective agonist of PPARγ [15], was administered through a 30-min intraperitoneal injection once per day for 5 consecutive days prior to microinjection of saline or Coll IV. Behavioral tests were conducted on days 1, 3, and 5 after microinjection. ...
Background:Thalamic pain frequently occurs after stroke and is a challenging clinical issue. However, the mechanisms underlying thalamic pain remain unclear. Neuroinflammation is a key determining factor in the occurrence and maintenance of hemorrhage-induced thalamic pain. Pioglitazone is an agonist of peroxisome proliferator-activated receptor gamma (PPARγ) and shows anti-inflammatory effects in multiple diseases. The present work focused on exploring whether PPARγ is related to hemorrhage-induced thalamic pain.
Methods:Immunostaining was conducted to analyze the cellular localization of PPARγ and co-localization was evaluated with NeuN, ionized calcium-binding adapter molecular 1 (IBA1), and glia fibrillary acidic protein (GFAP). Western blot analyses were used to evaluate MyD88, pNF-κB/NF-κB, pSTAT6/STAT6, IL-1β, TNF-α, iNOS, Arg-1, IL-4, IL-6, and IL-10 expression. Behavioral tests in mice were conducted to evaluate continuous pain hypersensitivity.
Results:We found that pioglitazone appeared to mitigate the contralateral hemorrhage-induced thalamic pain while inhibiting inflammatory responses. Additionally, Pioglitazone induced phosphorylation of STAT6 and suppressed the phosphorylation NF-κB in our model of thalamic pain. These effects could be partially reversed with the PPARγ antagonist GW9662.
Conclusion:The PPARγ agonist pioglitazone can mitigate mechanical allodynia by suppressing the NF-κB inflammasome while activating the STAT6 signal pathway, which are well-known to be associated with inflammation.
... Furthermore, the neuroprotective ability of VAC could be correlated with the activation of PPARγ and AMPK signaling [114]. Another vanadium compound, BEOV, significantly reduced the phosphorylation of tau and inhibited Aβ-induced inflammation by inhibiting the NF-κB signal both in vitro and in vivo [115]. BEOV also blocked the neurotoxicity induced by endoplasmic reticulum (ER) stress by inhibiting Bip and p-eIF2α [116] and ameliorated spatial learning and memory in AD mouse models [117]. ...
Vanadium is a well-known essential trace element, which usually exists in oxidation states in the form of a vanadate cation intracellularly. The pharmacological study of vanadium began with the discovery of its unexpected inhibitory effect on ATPase. Thereafter, its protective effects on β cells and its ability in glucose metabolism regulation were observed from the vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s disease (AD) is the most common dementia disease in elderly people. However, there are still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which is characterized by senile plaques composed of the amyloid-beta (Aβ) protein in the parenchyma of the brain and the neurofibrillary tangles (NFTs), which are derived from the hyperphosphorylated tau protein in the neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the impaired insulin signaling in the brain. In this review, we summarize the advances in applicating the vanadium compound to AD treatment in experimental research and point out the limitations of the current study using vanadium compounds in AD treatment. We hope this will help future studies in this field.
... As a result, the glucose transporter 4 (GLUT4) in cytosol were translocated onto the plasma membrane to enhance the glucose uptake [87]. In-sulin triggered translocation of GLUT4 is very critical in the process of hippocampal dependent memory consolidation [88]. Of note, the insulin signaling pathway was reg-ulated by negative feedback. ...
Vanadium is a well-known essential trace element, which usually exists in oxidation states in form of vanadate cation intracellularly. The pharmacological study of vanadium begins at the discovery of its unexpected inhibitory effect on ATPase. Thereafter, the protective effects on cells and the abilities in glucose metabolism regulation were observed from vanadium compound, leading to the application of vanadium compounds in clinical trials for curing diabetes. Alzheimer’s dis-ease (AD) is the most common dementia disease in elderly people. However, there is still no efficient agents for treating AD safely to date. This is mainly because of the complexity of the pathology, which are characterized by the senile plaques composed by amyloid-beta (Aβ) protein in the parenchyma of brain and the neurofibrillary tangles (NFTs) derived from hyperphosphorylated tau protein in neurocyte, along with mitochondrial damage, and eventually the central nervous system (CNS) atrophy. AD was also illustrated as type-3 diabetes, because of the observations of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), as well as the im-paired insulin signaling in brain. In this review, we summarized the advance of applicating vanadium compound on AD treatment in experimental research and pointed out the limitation of the current study on using vanadium compounds in AD treatment. We hope it will help the future study in this field.
... BEOV also attenuated neuroinflammatory processes, and it was shown to inhibit proinflammatory NFκ-B signalling, to inhibit microglial and astrocytic activation and to reduce the cerebral levels of proinflammatory cytokines and inducible nitric oxide synthase (iNOS). The anti-inflammatory effects of BEOV were thought to occur via activating PPARγ, where it increased levels, resulting in the repression of NFκ-B signalling [225]. ...
Alzheimer’s disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.
... In particular, Bis(ethylmaltolato) oxidovanadium (IV) (BEOV), which has been reported to have hypoglycemic properties, was given to APPSwe/PS1dE9 mice (Table 1). He and colleagues reported that a treatment with BEOV for 3 months significantly decreased Aβ levels PPARγ and IDE activation, as well as by inhibition of BACE1 activity in 6-month-old APPSwe/PS1dE9 [149][150][151]. BEOV also decreased the expression of PTP1B, which induced the activation of the insulin pathway IRS-1/PI3K/Akt, hence inhibiting GSK3β and leading to a reduction in tau hyperphosphorylation [149][150][151]. ...
... He and colleagues reported that a treatment with BEOV for 3 months significantly decreased Aβ levels PPARγ and IDE activation, as well as by inhibition of BACE1 activity in 6-month-old APPSwe/PS1dE9 [149][150][151]. BEOV also decreased the expression of PTP1B, which induced the activation of the insulin pathway IRS-1/PI3K/Akt, hence inhibiting GSK3β and leading to a reduction in tau hyperphosphorylation [149][150][151]. In addition, authors reported that BEOV was involved in the modulation of the autophagic process that increased the clearance of Aβ aggregates [149]. ...
Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.
... When neuroinflammation occurs, microglia are activated as immune cells of the nervous system. Activation of microglial cells leads to amyloid overload, which further amplifies the pro-inflammatory response [81]. ...
Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide. The accumulation of amyloid-β (Aβ) protein and plaque formation in the brain are two major causes of AD. Interestingly, growing evidence demonstrates that the gut flora can alleviate AD by affecting amyloid production and metabolism. However, the underlying mechanism remains largely unknown. This review will discuss the possible association between the gut flora and Aβ in an attempt to provide novel therapeutic directions for AD treatment based on the regulatory effect of Aβ on the gut flora.
... In addition, we examined the therapeutic effects of vanadium compound Bis(2-ethyl-3-hydroxy-4-pyronato) oxovanadium (IV) (BEOV), which was originally synthesized as a substitution of vanadate for curing diabetes mellitus (DM) in AD models. We found that BEOV significantly reduced the levels of Aβ and tau phosphorylation, and inhibited the inflammation induced by Aβ [13], blocked the endoplasmic reticulum (ER) stress induced neurotoxicity [14], and ameliorated the spatial learning and memory in AD mouse models [15]. Moreover, we found that the biological activity of BEOV is dependent on proliferator-activated receptor gamma (PPARγ), which is similar with the activity of bis (5-hydroxy-4-oxo-4H-pyran-2hydroxy-benzoatato) oxovanadium (IV) (BSOV) [16]. ...
... The activation of nuclear factor-kB (NF-kB) was suppressed by BEOV via proliferator-activated receptor gamma (PPARg). This was demonstrated by GW9662, a PPARg inhibitor, which eliminated the above effects of BEOV in vitro [13]. These effects of BEOV are similar with insulin in regulating insulin receptor substrates (IRS), which subsequently activate AKT. ...
... The evidences of the therapeutic effects of BEOV on different AD mice models is summarized in Table 1. [13,15], increased the expression of PPARg SY5Y cell line with Swedish mutation of APP Increased Ab burden VAC elevated the levels of PPARg, AMPKa and GSK-3b [12] Tg(APPswe, PSEN1dE9) Ab senile plaques, spatial learning impaired begin on 12 months of age. ...
Alzheimer’s disease (AD) is an intractable neurodegenerative disease that leads to dementia, primarily in elderly people. The neurotoxicity of amyloid-beta (Aβ) and tau protein has been demonstrated over the last two decades. In line with these findings, several etiological hypotheses of AD have been proposed, including the amyloid cascade hypothesis, the oxidative stress hypothesis, the inflammatory hypothesis, the cholinergic hypothesis, et al. In the meantime, great efforts had been made in developing effective drugs for AD. However, the clinical efficacy of the drugs that were approved by the US Food and Drug Association (FDA) to date were determined only mild/moderate. We recently adopted a vanadium compound bis(ethylmaltolato)-oxidovanadium (IV) (BEOV), which was originally used for curing diabetes mellitus (DM), to treat AD in a mouse model. It was shown that BEOV effectively reduced the Aβ level, ameliorated the inflammation in brains of the AD mice, and improved the spatial learning and memory activities of the AD mice. These finding encouraged us to further examine the mechanisms underlying the therapeutic effects of BEOV in AD. In this review, we summarized the achievement of vanadium compounds in medical studies and investigated the prospect of BEOV in AD and DM treatment.
Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no “curative” drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα, CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ, CSF1R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD.
Neurodegenerative disorders are chronic brain diseases that affect humans worldwide. Although many different factors are thought to be involved in the pathogenesis of these disorders, alterations in several key elements such as the ubiquitin–proteasome system (UPS), the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the endocannabinoid system (ECS or endocannabinoidome) have been implicated in their etiology. Impairment of these elements has been linked to the origin and progression of neurodegenerative disorders, while their potentiation is thought to promote neuronal survival and overall neuroprotection, as proved with several experimental models. These key neuroprotective pathways can interact and indirectly activate each other. In this review, we summarize the neuroprotective potential of the UPS, ECS, and Nrf2 signaling, both separately and combined, pinpointing their role as a potential therapeutic approach against several hallmarks of neurodegeneration.
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