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  1. Article: Investigations into the Role of Metabolism in the Inflammatory Response of BV2 Microglial Cells.

    Maher, Pamela

    Antioxidants (Basel, Switzerland)

    2021  Volume 10, Issue 1

    Abstract: Although the hallmarks of Alzheimer's disease (AD) are amyloid beta plaques and neurofibrillary tangles, there is growing evidence that neuroinflammation, mitochondrial dysfunction and oxidative stress play important roles in disease development and ... ...

    Abstract Although the hallmarks of Alzheimer's disease (AD) are amyloid beta plaques and neurofibrillary tangles, there is growing evidence that neuroinflammation, mitochondrial dysfunction and oxidative stress play important roles in disease development and progression. A major risk factor for the development of AD is diabetes, which is also characterized by oxidative stress and mitochondrial dysfunction along with chronic, low-grade inflammation. Increasing evidence indicates that in immune cells, the induction of a pro-inflammatory phenotype is associated with a shift from oxidative phosphorylation (OXPHOS) to glycolysis. However, whether hyperglycemia also contributes to this shift is not clear. Several different approaches including culturing BV2 microglial cells in different carbon sources, using enzyme inhibitors and knocking down key pathway elements were used in conjunction with bacterial lipopolysaccharide (LPS) activation to address this question. The results indicate that while high glucose favors NO production, pro-inflammatory cytokine production is highest in the presence of carbon sources that drive OXPHOS. In addition, among the carbon sources that drive OXPHOS, glutamine is a very potent inducer of IL6 production. This effect is dampened in the presence of glucose. Together, these results may provide new prospects for the therapeutic manipulation of neuroinflammation in the context of diabetes and AD.
    Language English
    Publishing date 2021-01-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox10010109
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Preventing and Treating Neurological Disorders with the Flavonol Fisetin.

    Maher, Pamela

    Brain plasticity (Amsterdam, Netherlands)

    2021  Volume 6, Issue 2, Page(s) 155–166

    Abstract: Neurological disorders, including neurodegenerative diseases, have a significant negative impact on both patients and society at large. Since the prevalence of most of these disorders increases with age, the consequences for our aging population are only ...

    Abstract Neurological disorders, including neurodegenerative diseases, have a significant negative impact on both patients and society at large. Since the prevalence of most of these disorders increases with age, the consequences for our aging population are only going to grow. It is now acknowledged that neurological disorders are multi-factorial involving disruptions in multiple cellular systems. While each disorder has specific initiating mechanisms and pathologies, certain common pathways appear to be involved in most, if not all, neurological disorders. Thus, it is becoming increasingly important to identify compounds that can modulate the multiple pathways that contribute to disease development or progression. One of these compounds is the flavonol fisetin. Fisetin has now been shown in preclinical models to be effective at preventing the development and/or progression of multiple neurological disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke (both ischemic and hemorrhagic) and traumatic brain injury as well as to reduce age-associated changes in the brain. These beneficial effects stem from its actions on multiple pathways associated with the different neurological disorders. These actions include its well characterized anti-inflammatory and anti-oxidant effects as well as more recently described effects on the regulated cell death oxytosis/ferroptosis pathway, the gut microbiome and its senolytic activity. Therefore, the growing body of pre-clinical data, along with fisetin's ability to modulate a large number of pathways associated with brain dysfunction, strongly suggest that it would be worthwhile to pursue its therapeutic effects in humans.
    Language English
    Publishing date 2021-02-09
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 2827963-3
    ISSN 2213-6312 ; 2213-6312
    ISSN (online) 2213-6312
    ISSN 2213-6312
    DOI 10.3233/BPL-200104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper.

    Maher, Pamela

    Antioxidants (Basel, Switzerland)

    2020  Volume 9, Issue 11

    Abstract: Alterations occur in the homeostasis of the transition metals iron ( ... ...

    Abstract Alterations occur in the homeostasis of the transition metals iron (Fe
    Language English
    Publishing date 2020-11-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox9111113
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases.

    Maher, Pamela

    International journal of molecular sciences

    2019  Volume 20, Issue 12

    Abstract: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no ... ...

    Abstract Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.
    MeSH term(s) Alzheimer Disease/drug therapy ; Amyotrophic Lateral Sclerosis/drug therapy ; Animals ; Apoptosis ; Brain/drug effects ; Brain/metabolism ; Brain/physiopathology ; Flavonoids/pharmacology ; Flavonoids/therapeutic use ; Humans ; Huntington Disease/drug therapy ; Inflammation ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/physiopathology ; Oxidative Stress ; Parkinson Disease/drug therapy
    Chemical Substances Flavonoids
    Language English
    Publishing date 2019-06-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms20123056
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Investigations into the Role of Metabolism in the Inflammatory Response of BV2 Microglial Cells

    Maher, Pamela

    Antioxidants. 2021 Jan. 14, v. 10, no. 1

    2021  

    Abstract: Although the hallmarks of Alzheimer’s disease (AD) are amyloid beta plaques and neurofibrillary tangles, there is growing evidence that neuroinflammation, mitochondrial dysfunction and oxidative stress play important roles in disease development and ... ...

    Abstract Although the hallmarks of Alzheimer’s disease (AD) are amyloid beta plaques and neurofibrillary tangles, there is growing evidence that neuroinflammation, mitochondrial dysfunction and oxidative stress play important roles in disease development and progression. A major risk factor for the development of AD is diabetes, which is also characterized by oxidative stress and mitochondrial dysfunction along with chronic, low-grade inflammation. Increasing evidence indicates that in immune cells, the induction of a pro-inflammatory phenotype is associated with a shift from oxidative phosphorylation (OXPHOS) to glycolysis. However, whether hyperglycemia also contributes to this shift is not clear. Several different approaches including culturing BV2 microglial cells in different carbon sources, using enzyme inhibitors and knocking down key pathway elements were used in conjunction with bacterial lipopolysaccharide (LPS) activation to address this question. The results indicate that while high glucose favors NO production, pro-inflammatory cytokine production is highest in the presence of carbon sources that drive OXPHOS. In addition, among the carbon sources that drive OXPHOS, glutamine is a very potent inducer of IL6 production. This effect is dampened in the presence of glucose. Together, these results may provide new prospects for the therapeutic manipulation of neuroinflammation in the context of diabetes and AD.
    Keywords Alzheimer disease ; amyloid ; antioxidants ; carbon ; cells ; diabetes ; enzyme inhibitors ; glucose ; glutamine ; glycolysis ; hyperglycemia ; inflammation ; interleukin-6 ; lipopolysaccharides ; mitochondria ; neuroglia ; oxidative phosphorylation ; oxidative stress ; phenotype ; risk factors ; therapeutics
    Language English
    Dates of publication 2021-0114
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    Note NAL-light
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox10010109
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Using Plants as a Source of Potential Therapeutics for the Treatment of Alzheimer's Disease.

    Maher, Pamela A

    The Yale journal of biology and medicine

    2020  Volume 93, Issue 2, Page(s) 365–373

    Abstract: Alzheimer's disease (AD) is the most common form of dementia with the numbers expected to increase dramatically as our society ages. There are no treatments to cure, prevent, or slow down the progression of the disease. Age is the single greatest risk ... ...

    Abstract Alzheimer's disease (AD) is the most common form of dementia with the numbers expected to increase dramatically as our society ages. There are no treatments to cure, prevent, or slow down the progression of the disease. Age is the single greatest risk factor for AD. However, to date, AD drug discovery efforts have generally not taken this fact into consideration. Multiple changes associated with brain aging, including neuroinflammation and oxidative stress, are important contributors to disease development and progression. Thus, due to the multifactorial nature of AD, the one target strategy to fight the disease needs to be replaced by a more general approach using pleiotropic compounds to deal with the complexity of the disease. In this perspectives piece, our alternative approach to AD drug development based on the biology of aging is described. Starting with plants or plant-derived natural products, we have used a battery of cell-based screening assays that reflect multiple, age-associated toxicity pathways to identify compounds that can target the aspects of aging that contribute to AD pathology. We have found that this combination of assays provides a replicable, cost- and time-effective screening approach that has to date yielded one compound in clinical trials for AD (NCT03838185) and several others that show significant promise.
    MeSH term(s) Aging/drug effects ; Aging/physiology ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/prevention & control ; Antioxidants/pharmacology ; Curcumin/pharmacology ; Eriodictyon ; Ethnopharmacology ; Flavonols/pharmacology ; Humans ; Indole Alkaloids/pharmacology ; Neuroprotective Agents/pharmacology ; Plant Preparations/pharmacology
    Chemical Substances Antioxidants ; Flavonols ; Indole Alkaloids ; Neuroprotective Agents ; Plant Preparations ; voacangalactone ; Curcumin (IT942ZTH98) ; fisetin (OO2ABO9578)
    Language English
    Publishing date 2020-06-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 200515-3
    ISSN 1551-4056 ; 0044-0086
    ISSN (online) 1551-4056
    ISSN 0044-0086
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin.

    Liang, Zhibin / Maher, Pamela

    Antioxidants (Basel, Switzerland)

    2022  Volume 11, Issue 11

    Abstract: Alzheimer's disease (AD) is the most frequent age-associated disease with no treatments that can prevent, delay, slow, or stop its progression. Thus, new approaches to drug development are needed. One promising approach is the use of phenotypic screening ...

    Abstract Alzheimer's disease (AD) is the most frequent age-associated disease with no treatments that can prevent, delay, slow, or stop its progression. Thus, new approaches to drug development are needed. One promising approach is the use of phenotypic screening assays that can identify compounds that have therapeutic efficacy in target pathways relevant to aging and cognition, as well as AD pathology. Using this approach, we identified the flavanone sterubin, from Yerba santa (
    Language English
    Publishing date 2022-11-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox11112197
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases

    Pamela Maher

    International Journal of Molecular Sciences, Vol 20, Iss 12, p

    2019  Volume 3056

    Abstract: Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no ... ...

    Abstract Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.
    Keywords oxidative stress ; cognitive dysfunction ; inflammation ; cell death ; synapse loss ; protein aggregation ; neurodegenerative disease ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: The Role of AMP-activated Protein Kinase in Oxytosis/Ferroptosis: Protector or Potentiator?

    Currais, Antonio / Kepchia, Devin / Liang, Zhibin / Maher, Pamela

    Antioxidants & redox signaling

    2022  

    Abstract: Significance: ...

    Abstract Significance:
    Language English
    Publishing date 2022-04-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1483836-9
    ISSN 1557-7716 ; 1523-0864
    ISSN (online) 1557-7716
    ISSN 1523-0864
    DOI 10.1089/ars.2022.0013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Corrigendum to 'Defining a pharmacological inhibitor fingerprint for oxytosis/ferroptosis' [Free Radic. Biol. Med. 171 (2021) 219-231].

    Soriano-Castell, David / Currais, Antonio / Maher, Pamela

    Free radical biology & medicine

    2022  Volume 184, Page(s) 15

    Language English
    Publishing date 2022-04-01
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 807032-5
    ISSN 1873-4596 ; 0891-5849
    ISSN (online) 1873-4596
    ISSN 0891-5849
    DOI 10.1016/j.freeradbiomed.2022.03.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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