Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The pathophysiological mechanism of Alzheimer's disease involves Aβ-amyloid peptide, Tau protein, oxidative stress, and an exacerbated neuro-inflammatory response.

“The pathophysiological mechanism involves the presence of Aβ-amyloid peptide, Tau protein, oxidative stress, and an exacerbated neuro-inflammatory response.”

May combine two claims.

Alzheimer's disease is characterized by accumulation of beta-amyloid protein fragments in plaques outside brain neurons and twisted strands of tau protein in tangles inside neurons.

“AD is characterized by the accumulation of the protein fragment beta-amyloid in plaques outside the brain neurons and twisted strands of the protein tau in the form of tangles inside neurons.”

• cites [1] (Alzheimers Dement., 2020). No authors listed. 2020 Alzheimer’s disease facts and figures, Alzheimers Dement., Online ahead of print.Not checked yet

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• cites [2] Amor, 2014, Inflammation in neurodegenerative diseases—An update, Immunology sourceNot checked yet

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Currently available anti-Alzheimer's disease therapies provide modest but meaningful benefits by mitigating symptoms, reducing clinical progression, and delaying disability.

“They provide modest but meaningful benefits since they help in mitigating symptoms, reducing clinical progression, and delaying disability [5].”

• cites [5] Jeremic, 2021, Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: A systematic review, Ageing Res. Rev. sourceNot checked yet

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Increase in life expectancy is one factor that has led to an increase in the number of Alzheimer's disease cases worldwide.

“The increase in life expectancy is one of the factors that has led to an increase in the number of AD cases worldwide [3,4].”

• cites [3] Kumar, 2020, Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases, Front. Physiol.Not checked yet

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• cites [4] Siokas, V., Aloizou, A.M., Tsouris, Z., Liampas, I., Liakos, P., Calina, D., Docea, A.O., Tsatsakis, A., Bogdanos, D.P., and Hadjigeorgiou, G.M. (2021). ADORA2A rs5760423 and CYP1A2 rs762551 Polymorphisms as Risk Factors for Parkinson’s Disease. J. Clin. Med., 10. sourceNot checked yet

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The cholinergic hypothesis argues that the reduction of learning and mnemonic processes at the base of Alzheimer's disease is due to low levels of acetylcholine in neurons.

“The cholinergic hypothesis argues that the reduction of learning and mnemonic processes at the base of the disease are due to low levels of ACh in neurons”

• cites [15] Ladner, 1998, Pharmacological drug treatment of Alzheimer disease: The cholinergic hypothesis revisited, J. Neuropathol. Exp. Neurol. sourceNot checked yet

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In the non-amyloidogenic pathway, γ-secretase cleaves APP in the Aβ peptide region, preventing senile plaque formation and exerting a neuroprotective action.

“γ-Secretase cleaves APP in the region of the Aβ peptide, thus preventing the formation of senile plaque and thus exerting a neuroprotective action.”

• cites [18] Cheignon, 2018, Oxidative stress and the amyloid beta peptide in Alzheimer’s disease, Redox Biol. sourceNot checked yet

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Both acetylcholinesterase and butyrylcholinesterase are useful therapeutic targets for the treatment of Alzheimer's disease.

“Consequently, both enzymes are useful therapeutic targets for the treatment of AD [16].”

• cites [16] Lane, 2006, Targeting acetylcholinesterase and butyrylcholinesterase in dementia, Int. J. Neuropsychopharmacol. sourceNot checked yet

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In healthy neuronal cells, tau protein assembles and stabilizes microtubules and determines their binding with other cytoskeleton components.

“in healthy neuronal cells, following consecutive and reversible enzymatic processes of phosphorylation and dephosphorylation, it has the task of assembling and stabilizing microtubules and determining their binding with other components of the cytoskeleton [19,20].”

• cites [19] Maccioni, 2001, The molecular bases of Alzheimer’s disease and other neurodegenerative disorders, Arch. Med. Res. sourceNot checked yet

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• cites [20] Solhuber, 2014, Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer’s Disease, Curr. Neuropharmacol. sourceNot checked yet

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Microglia can bind Aβ plaques via Toll-like receptors or receptors for advanced glycation end products, promoting microglia activation and greater secretion of pro-inflammatory cytokines, chemokines, and reactive oxygen species.

“microglia can bind Aβ plaques via Toll-like receptors (TLRs) or receptors for advanced glycation end products (RAGE), both expressed on the cell surface. This process promotes microglia activation, which in turn causes a greater secretion of pro-inflammatory cytokines, chemokines, and ROS, as well.”

• cites [22] Glass, 2010, Mechanisms underlying inflammation in neurodegeneration, Cell sourceNot checked yet

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Hyperactivation of inflammatory processes and immune response has an ambiguous cause/effect role, and its alteration could constitute a self-defence mechanism useful in slowing Alzheimer's disease pathology.

“Therefore, the hyperactivation of both inflammatory processes and immune response has an ambiguous cause/effect role and its alteration could constitute a self-defence mechanism useful in slowing the pathology.”

May combine two claims.

Activated microglia initially exert a phagocytic response towards plaques mediated by release of insulin-degrading enzyme, and then a neuroprotective action.

“The presence of activated microglia would seem at first to exert a phagocytic response towards the plaques, mediated by the release of the insulin-degrading enzyme (IDE), and then a neuroprotective action [23].”

• cites [23] 2006, Inflammation in Alzheimer disease: Driving force, bystander or beneficial response?, Nat. Med.Not checked yet

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Factors released after microglia activation contribute to stimulation of astrocytes, whose activation amplifies pro-inflammatory signals.

“These factors contribute to the stimulation of astrocytes, whose activation amplifies the pro-inflammatory signals [22].”

• cites [22] Glass, 2010, Mechanisms underlying inflammation in neurodegeneration, Cell sourceNot checked yet

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In the amyloidogenic pathway, sAPPβ is released and mainly converted into the neurotoxic Aβ1-40/42 peptide, the main constituent of Aβ agglomerates.

“sAPPβ is released and mainly converted into the neurotoxic Aβ1-40/42 peptide, the main constituent of the Aβ agglomerates [18].”

• cites [18] Cheignon, 2018, Oxidative stress and the amyloid beta peptide in Alzheimer’s disease, Redox Biol. sourceNot checked yet

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Approved drugs for Alzheimer's disease except memantine have acetylcholinesterase inhibitor activity, increasing acetylcholine and favoring modulation of the synaptic process.

“The approved drugs, except memantine, have acetylcholinesterase inhibitors (AChEI), so they increase the presence of acetylcholine (ACh) that favors the modulation of the synaptic process.”

• cites [1] (Alzheimers Dement., 2020). No authors listed. 2020 Alzheimer’s disease facts and figures, Alzheimers Dement., Online ahead of print.Not checked yet

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• cites [6] Epperly, 2017, Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms, Am. Fam. PhysicianNot checked yet

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Oxidative stress is also deeply involved in the rise and progression of Aβ plaques, neurofibrillary tangles, dysregulated metallostasis, and abnormal neuroinflammation, creating a self-feeding vicious cycle.

“but OS is also deeply involved in the rise and progression of these mechanisms, thus creating a self-feeding vicious cycle.”

• cites [26] Nesi, 2017, Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer’s Disease, Curr. Top. Med. Chem.Not checked yet

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Either as cause or consequence, oxidative stress could be defined as a fil rouge connecting all the Alzheimer's disease hallmarks described.

“Either cause or consequence, OS could be defined as a fil rouge connecting all the AD hallmarks already described [26].”

• cites [26] Nesi, 2017, Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer’s Disease, Curr. Top. Med. Chem.Not checked yet

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Neurofibrillary tangles contain aggregates of tau protein in a hyperphosphorylated state.

“NTFs contain, as their first component, aggregates of the protein tau (τ) in a hyperphosphorylated state.”

• cites [19] Maccioni, 2001, The molecular bases of Alzheimer’s disease and other neurodegenerative disorders, Arch. Med. Res. sourceNot checked yet

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• cites [20] Solhuber, 2014, Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer’s Disease, Curr. Neuropharmacol. sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Natural compounds are attractive complementary and alternative options for the management of neurodegenerative diseases.

“natural compounds emerge as attractive complementary and alternative options for the management of neurodegenerative diseases [7].”

• cites [7] Quispe, 2022, Ethnobotany, Phytochemistry, Biological Activities, and Health-Promoting Effects of the Genus Bulbophyllum, Evid. -Based Complementary Altern. Med.Not checked yet

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According to the World Health Organization, approximately 80% of the world's population depends on phytochemicals or products of medicinal plants.

“According to the World Health Organization, approximately 80% of the world’s population depends on phytochemicals or products of medicinal plants [11].”

• cites [11] Welcome, 2020, Blood brain barrier inflammation and potential therapeutic role of phytochemicals, PharmaNutrition sourceNot checked yet

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Cholinergic dysfunction was the first hypothesis postulated and is considered one of the most relevant causes of Alzheimer's disease.

“Cholinergic dysfunction was the first hypothesis postulated and is considered one of the most relevant causes of AD.”

• cites [17] Zagórska, A., and Jaromin, A. (2020). Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy. Molecules, 25. sourceNot checked yet

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Insoluble tau aggregates envelop the nucleus of the neuronal cell, causing neuronal death and ultimately cognitive dementia.

“These insoluble aggregates envelop the nucleus of the neuronal cell, causing neuronal death and, ultimately, cognitive dementia [18].”

• cites [18] Cheignon, 2018, Oxidative stress and the amyloid beta peptide in Alzheimer’s disease, Redox Biol. sourceNot checked yet

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Mild cognitive impairment could be considered a prodromal phase, representing a transitional condition between healthy aging and very mild Alzheimer's disease.

“MCI could be considered a prodromal phase, representing a transitional condition between healthy aging and very mild AD [28].”

• cites [28] Grundman, 2004, Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials, Arch. Neurol. sourceNot checked yet

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In the brains of Alzheimer's disease patients, very high levels of copper, zinc, and iron ions have been observed, giving rise to the metal ion hypothesis.

“In the brains of AD patients, a very high level of these ions was instead observed, thus giving rise to the “metal ion hypothesis”.”

• cites [24] Bacci, A., Runfola, M., Sestito, S., and Rapposelli, S. (2021). Beyond Antioxidant Effects: Nature-Based Templates Unveil New Strategies for Neurodegenerative Diseases. Antioxidants, 10. sourceNot checked yet

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Microglia and astrocytes release pro-inflammatory mediators such as cytokines, chemokines, reactive oxygen species, and complement proteins, promoting a neuroprotective function through cytotoxic and phagocytic activity.

“Both systems release pro-inflammatory mediators, such as cytokines, chemokines, reactive oxygen species (ROS), and complement proteins, thus promoting a neuroprotective function thanks to cytotoxic and phagocytic activity.”

• cites [21] Tuppo, 2005, The role of inflammation in Alzheimer’s disease, Int. J. Biochem. Cell Biol. sourceNot checked yet

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In pathological conditions, a protracted inflammatory condition leads to disproportionate release of pro-inflammatory factors and increased oxidative stress, reversing neuroprotection into neurotoxicity.

“In pathological conditions, the protracted inflammatory condition led to a disproportionate release of pro-inflammatory factors and to an increase of OS, which reverses the neuroprotection into neurotoxicity.”

• cites [23] 2006, Inflammation in Alzheimer disease: Driving force, bystander or beneficial response?, Nat. Med.Not checked yet

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Reduced acetylcholine is associated with insufficient synthetic action of choline O-acetyltransferase and high catalytic action of acetylcholinesterase, leading to loss of cholinergic transmission at the pre-synaptic level.

“reduced ACh, is associated with an insufficient synthetic action of choline O-acetyltransferase (ChAt) and a high catalytic action of acetylcholinesterase (AChE), finally, lead to the loss of cholinergic transmission at the pre-synaptic level [15].”

• cites [15] Ladner, 1998, Pharmacological drug treatment of Alzheimer disease: The cholinergic hypothesis revisited, J. Neuropathol. Exp. Neurol. sourceNot checked yet

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Memantine is an antagonist of the NMDA receptor subtype of glutamate receptor and reduces the excitotoxic effects of glutamate release.

“Memantine is an antagonist of the NMDA receptor subtype of glutamate receptor and reduces the excitotoxic effects of glutamate release [1,6].”

• cites [1] (Alzheimers Dement., 2020). No authors listed. 2020 Alzheimer’s disease facts and figures, Alzheimers Dement., Online ahead of print.Not checked yet

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• cites [6] Epperly, 2017, Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms, Am. Fam. PhysicianNot checked yet

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Amyloid plaques are extracellular deposits of amyloid beta protein generated from sequential proteolytic cleavage of amyloid precursor protein.

“Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein, which is generated from sequential proteolytic cleavage of its precursor called APP (amyloid precursor protein).”

• cites [18] Cheignon, 2018, Oxidative stress and the amyloid beta peptide in Alzheimer’s disease, Redox Biol. sourceNot checked yet

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In pathological conditions, excessive hyperphosphorylation of tau by specific kinases and phosphatases seems to lead to conformational changes that prevent microtubule stabilization and lead to formation of neurofibrillary tangles.

“the excessive hyperphosphorylation by specific kinases and phosphatases seems to lead to conformational changes of the protein itself, which not only prevents the stabilization of microtubules but also leads to the formation of NFTs.”

• cites [18] Cheignon, 2018, Oxidative stress and the amyloid beta peptide in Alzheimer’s disease, Redox Biol. sourceNot checked yet

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The most common aspects of Alzheimer's disease involve accumulation of beta-amyloid plaques, tau proteins, and neuroinflammation; these are the main targets for candidate anti-Alzheimer vaccines.

“The most common aspects of AD involve the accumulation of beta-amyloid plaques, tau proteins, and neuroinflammation; these are the main targets for candidate anti-Alzheimer vaccines [48,49,50].”

• cites [48] Cacabelos, 2020, How plausible is an Alzheimer’s disease vaccine?, Expert Opin. Drug Discov. sourceNot checked yet

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• cites [49] Rafii, 2022, Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial, JAMA Neurol. sourceNot checked yet

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• cites [50] Lacosta, 2018, Safety, tolerability and immunogenicity of an active anti-Aβ(40) vaccine (ABvac40) in patients with Alzheimer’s disease: A randomised, double-blind, placebo-controlled, phase I trial, Alzheimers Res. sourceNot checked yet

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Behavioural and psychological symptoms of dementia are highly prevalent in all types of dementia and may occur in mild cognitive impairment and all stages of Alzheimer's disease patients.

“BPSD are highly prevalent in all types of dementia and may occur in MCI and all stages of AD patients”

• cites [29] Nussbaum, 2017, Modern treatment approaches in psychoses. pharmacogenetic, neuroimagistic and clinical implications, FarmaciaNot checked yet

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Non-pharmacological treatments are frequently chosen as a first-line option to mitigate Alzheimer's disease symptoms and represent the most valid alternative and/or complement to pharmacological treatment.

“The non-pharmacological treatments (NPT) are frequently chosen as a first-line option to mitigate AD symptoms and represent the most valid alternative and/or complement to pharmacological treatment [3,31].”

• cites [3] Kumar, 2020, Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases, Front. Physiol.Not checked yet

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• cites [31] Calina, D., Buga, A.M., Mitroi, M., Buha, A., Caruntu, C., Scheau, C., Bouyahya, A., El Omari, N., El Menyiy, N., and Docea, A.O. (2020). The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation-Evidence from In Vivo Studies. J. Clin. Med., 9. sourceNot checked yet

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All three acetylcholinesterase inhibitor drugs delay neurodegeneration and stabilise cognition when used in patients with mild to severe Alzheimer's disease symptoms, as shown in clinical trials.

“All three drugs delay neurodegeneration and stabilise cognition when used in patients with mild to severe AD symptoms, as shown in clinical trials.”

• cites [33] Atri, 2019, Current and Future Treatments in Alzheimer’s Disease, Semin. Neurol. sourceNot checked yet

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• cites [35] Adejare, A. (2017). Current Medications for the Treatment of Alzheimer’s Disease. Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders, Academic Press. sourceNot checked yet

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• cites [36] Tricco, 2018, Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer’s Disease: Systematic Review and Network Metaanalysis, J. Am. Geriatr. Soc. sourceNot checked yet

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Behavioural and psychological symptoms of dementia are associated with more rapid decline, worse quality of life, higher distress, earlier institutionalization, and greater health care employment and costs.

“BPSD is associated with more rapid decline, worse quality of life, higher distress, earlier institutionalization, and greater health care employment and costs”

• cites [30] Zucchella, 2018, The Multidisciplinary Approach to Alzheimer’s Disease and Dementia. A Narrative Review of Non-Pharmacological Treatment, Front. Neurol. sourceNot checked yet

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Aducanumab therapy appears to be able to slow the course of Alzheimer's disease in its early stages.

“Aducanumab therapy appears to be able to slow the course of the disease in its early stages.”

• cites [32] Howard, 2020, Questions EMERGE as Biogen claims aducanumab turnaround, Nat. Rev. Neurol. sourceNot checked yet

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Evidence on nutraceuticals allows projecting a scenario where Alzheimer's disease could have possible preventive treatments and/or a slowing palliative effect in patients who already suffer from it.

“such evidence allows us to project a scenario where AD could have possible preventive treatments and/or have a slowing palliative effect in patients who already suffer from it [73,74,75].”

• cites [73] Chen, X., Drew, J., Berney, W., and Lei, W. (2021). Neuroprotective Natural Products for Alzheimer’s Disease. Cells, 10. sourceNot checked yet

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• cites [74] Venkatesan, 2015, Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: A comprehensive review, Biomed. Res. Int. sourceNot checked yet

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• cites [75] Tsoukalas, 2021, Reversal of brain aging by targeting telomerase: A nutraceutical approach, Int. J. Mol. Med. sourceNot checked yet

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• AssumptionRests on an assumption: The effects of phytochemicals observed in preclinical cell-line and animal models of Alzheimer's disease are predictive of effects in human Alzheimer's disease patients.

May combine two claims.

Alzheimer's disease and other neurodegenerative diseases are based on a few etiological events intertwined with each other; therefore, a more holistic approach could contribute to development of more resolutive therapies.

“these kinds of pathologies are based on a few etiological events intertwined with each other; therefore, a more holistic approach could contribute to the development of more resolutive therapies.”

• cites [57] Albertini, 2021, From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology, Med. Res. Rev. sourceNot checked yet

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One of the most followed multi-target ligand design strategies consists in combining different pharmacophores provided by specific biological activities, linked together by suitable linkers or directly fused/merged, into a single molecule.

“One of the most followed MTDL design strategies consists in combining different pharmacophores provided by specific biological activities, linked together by suitable linkers or directly fused/merged, into a single molecule.”

• cites [57] Albertini, 2021, From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology, Med. Res. Rev. sourceNot checked yet

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Non-pharmacological treatments improve patients' quality of life, reduce caregiver stress, and ameliorate the environment.

“NPTs improve patients’ Quality of Life (QoL), reduce the stress of caregivers, and ameliorate the environment”

• cites [30] Zucchella, 2018, The Multidisciplinary Approach to Alzheimer’s Disease and Dementia. A Narrative Review of Non-Pharmacological Treatment, Front. Neurol. sourceNot checked yet

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In complementary therapies with acetylcholinesterase inhibitors, memantine's beneficial effects are observed, producing a decline in Alzheimer's disease; however, this condition is visible within a maximum period of 3 years, after which Alzheimer's disease continues to progress.

“In complementary therapies with AChEI, its beneficial effects are observed, producing a decline in AD; however, it has been reported that this condition is visible within a maximum period of 3 years, after which AD continues to progress [37].”

• cites [37] Korabecny, 2018, Newly Developed Drugs for Alzheimer’s Disease in Relation to Energy Metabolism, Cholinergic and Monoaminergic Neurotransmission, Neuroscience sourceNot checked yet

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Market-tested drugs have already passed clinical trials and have proven their safety and efficacy for their primary application, allowing drastic reduction of time for new market approval.

“market-tested drugs have already passed clinical trials and have proven their safety and efficacy for their primary application, allowing for drastically reducing the time for new market approval [40].”

• cites [40] Mallikarjun, 2016, Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks, EBioMedicine sourceNot checked yet

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Various investigations have shown that nutraceuticals are capable of fulfilling neuroprotective functions on molecular mechanisms that trigger Alzheimer's disease, acting as antioxidants or anti-neuroinflammatory drugs, affecting aggregation of β amyloid peptides, hyperphosphorylation of Tau protein, and decrease of acetylcholine in cholinergic neurons.

“Various investigations have shown that nutraceuticals are capable of fulfilling neuroprotective functions on molecular mechanisms that trigger AD, acting as antioxidants or anti-neuroinflammatory drugs, taking effect on the aggregation of β amyloid peptides, the hyperphosphorylation of the Tau protein and the decrease of the neurotransmitter ACh in cholinergic neurons [70,71,72]”

• cites [70] Almanza, 2019, Endoplasmic reticulum stress signalling-from basic mechanisms to clinical applications, FEBS J. sourceNot checked yet

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• cites [71] 2020, Natural antioxidants’ effects on endoplasmic reticulum stress-related diseases, Food Chem. Toxicol. sourceNot checked yet

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• cites [72] Kim, 2015, The Role of Oxidative Stress in Neurodegenerative Diseases, Exp. Neurobiol. sourceNot checked yet

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Although aducanumab has been approved by the FDA, its clinical effectiveness is still controversial.

“Although this drug has been approved by the FDA, its clinical effectiveness is still controversial [32].”

• cites [32] Howard, 2020, Questions EMERGE as Biogen claims aducanumab turnaround, Nat. Rev. Neurol. sourceNot checked yet

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Drug repurposing offers advantages such as reaching wider markets and greater numbers of patients and bypassing much of the exploratory work needed to identify new molecules, new mechanisms of action, formulation, manufacturing procedures, and pharmacokinetics.

“Drug repurposing offers different advantages such as reaching wider markets and greater numbers of patients and bypassing much of the exploratory work needed to identify new molecules, new mechanisms of action, formulation, manufacturing procedures and pharmacokinetics.”

• cites [40] Mallikarjun, 2016, Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks, EBioMedicine sourceNot checked yet

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Therapies with phytopharmaceuticals with known neuroprotective effects could generate neuroenhancers that may greatly improve cognitive capacity in patients with Alzheimer's disease, reducing the main disadvantages of conventional pharmacology.

“Therapies with phytopharmaceuticals with known neuroprotective effects could generate neuroenhancers that may greatly improve cognitive capacity in patients with AD, reducing the main disadvantages of conventional pharmacology [31].”

• cites [31] Calina, D., Buga, A.M., Mitroi, M., Buha, A., Caruntu, C., Scheau, C., Bouyahya, A., El Omari, N., El Menyiy, N., and Docea, A.O. (2020). The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation-Evidence from In Vivo Studies. J. Clin. Med., 9. sourceNot checked yet

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• AssumptionRests on an assumption: The effects of phytochemicals observed in preclinical cell-line and animal models of Alzheimer's disease are predictive of effects in human Alzheimer's disease patients.

May combine two claims.

Memantine monotherapy has shown beneficial effects in the short and long term in patients with moderate to severe Alzheimer's disease, improving quality of life, cognition, and behavioral and psychological symptoms.

“Monotherapy has shown beneficial effects in the short and long term in patients with moderate to severe AD, improving their quality of life, cognition, and behavioral and psychological symptoms of neurodegenerative diseases [33,34]”

• cites [33] Atri, 2019, Current and Future Treatments in Alzheimer’s Disease, Semin. Neurol. sourceNot checked yet

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• cites [34] Yiannopoulou, 2020, Current and Future Treatments in Alzheimer Disease: An Update, J. Cent. Nerv. Syst. Dis. sourceNot checked yet

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A recent study assessing repurposed Alzheimer's disease therapies represented in Phase I, II, and III since February 2020 identified 53 clinical trials investigating 58 total repurposed drugs with various initial clinical applications.

“A recent study assessing the repurposed AD therapies represented in Phase I, II, and III since February 2020 identified 53 clinical trials investigating 58 total repurposed drugs with the various initial clinical application (20% hematologic-oncologic, 18% cardiovascular, 14% psychiatric, 12% diabetes, 10% are neurologic, 26% other conditions) [41].”

• cites [41] Bauzon, 2020, Repurposed agents in the Alzheimer’s disease drug development pipeline, Alzheimers Res. sourceNot checked yet

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Memantine is normally well-tolerated without the gastrointestinal adverse effects presented by acetylcholinesterase inhibitors, but some patients manifest dizziness, constipation, headache, cough, and drowsiness.

“It is normally well-tolerated without the adverse effects presented by the AChEI at the gastrointestinal level, which are the most severe; however, some patients have manifested negative effects such as dizziness, constipation, headache, cough, and drowsiness [33,35,36].”

• cites [33] Atri, 2019, Current and Future Treatments in Alzheimer’s Disease, Semin. Neurol. sourceNot checked yet

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• cites [35] Adejare, A. (2017). Current Medications for the Treatment of Alzheimer’s Disease. Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders, Academic Press. sourceNot checked yet

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• cites [36] Tricco, 2018, Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer’s Disease: Systematic Review and Network Metaanalysis, J. Am. Geriatr. Soc. sourceNot checked yet

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It has been proposed that most bioactive molecules act as direct antioxidants and do not depend on endogenous intracellular enzymes to exert their primary action by directly reacting with free radicals.

“It has been proposed that most bioactive molecules act as direct antioxidants and they do not have a dependence on endogenous intracellular enzymes to exert their primary action by directly reacting with free radicals [69,121].”

• cites [69] Kitic, D., Miladinovic, B., Randjelovic, M., Szopa, A., Sharifi-Rad, J., Calina, D., and Seidel, V. (2022). Anticancer Potential and Other Pharmacological Properties of Prunus armeniaca L.: An Updated Overview. Plants, 11. sourceNot checked yet

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• cites [121] Dhyani, 2022, Anticancer potential of alkaloids: A key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine, Cancer Cell Int. sourceNot checked yet

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Aβ peptides have a high affinity for Cu ions, producing a 1:1 complex, which favors aggregation and formation of amyloid plaques.

“Peptides (Aβ) have a high affinity for Cu ions, producing a 1:1 complex, which favors the aggregation and formation of amyloid plaques.”

• cites [125] Prosdocimi, 2016, On the generation of OH(.) radical species from H2O2 by Cu(I) amyloid beta peptide model complexes: A DFT investigation, J. Biol. Inorg. Chem. sourceNot checked yet

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May combine two claims.

Although Alzheimer's disease has complex multifactorial effects, oxidative stress is key to the initiation of the pathophysiological process in cholinergic neurons.

“Although AD has complex multifactorial, effects OS is key to the initiation of the pathophysiological process in cholinergic neurons [107,108,109].”

• cites [107] Butterfield, 2019, Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease, Nat. Rev. Neurosci. sourceNot checked yet

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• cites [108] Berger, 2016, Peroxisomes in brain development and function, Biochim. Biophys. Acta sourceNot checked yet

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• cites [109] Cheng, 2018, The Association of Tau With Mitochondrial Dysfunction in Alzheimer’s Disease, Front. Neurosci. sourceNot checked yet

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May combine two claims.

In the reaction between Aβ and Cu, H2O2 and ROS increase, evidencing a key role of H2O2 in the development of Alzheimer's disease pathology.

“In this reaction, H2O2 and the increase in ROS are linked, thus evidencing the key role of the H2O2 molecule in the development of AD pathology [125].”

• cites [125] Prosdocimi, 2016, On the generation of OH(.) radical species from H2O2 by Cu(I) amyloid beta peptide model complexes: A DFT investigation, J. Biol. Inorg. Chem. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The human neuroblastoma SH-SY5Y is among the most used cell lines, a subclone of the parental neuronal line SK-N-SH, which originated in 1970 from a biopsy metastatic tumor.

“The human neuroblastoma SH-SY5Y is among the most used cell lines [131,136,137,138,139,140,141,142], a subclone of a parental neuronal line SK-N-SH, which originated in 1970 from a biopsy metastatic tumor.”

• cites [131] Huang, 2020, alpha-Cyperone Attenuates H2O2-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2, Front. Pharm. sourceNot checked yet

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• cites [136] Izuta, 2008, Protective effects of Chinese propolis and its component, chrysin, against neuronal cell death via inhibition of mitochondrial apoptosis pathway in SH-SY5Y cells, J. Agric. Food Chem. sourceNot checked yet

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• cites [137] Juan-García, A., Caprioli, G., Sagratini, G., Mañes, J., and Juan, C. (2021). Coffee Silverskin and Spent Coffee Suitable as Neuroprotectors against Cell Death by Beauvericin and α-Zearalenol: Evaluating Strategies of Treatment. Toxins, 13. sourceNot checked yet

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• cites [138] Espin, 2017, Neuroprotective Effects of Bioavailable Polyphenol-Derived Metabolites against Oxidative Stress-Induced Cytotoxicity in Human Neuroblastoma SH-SY5Y Cells, J. Agric. Food Chem. sourceNot checked yet

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• cites [139] Han, 2010, Neuroprotective effect of 3,5-di-O-caffeoylquinic acid on SH-SY5Y cells and senescence-accelerated-prone mice 8 through the up-regulation of phosphoglycerate kinase-1, Neuroscience sourceNot checked yet

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• cites [140] Miyamae, 2011, 3,4,5-tri-O-caffeoylquinic acid inhibits amyloid beta-mediated cellular toxicity on SH-SY5Y cells through the upregulation of PGAM1 and G3PDH, Cytotechnology sourceNot checked yet

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• cites [141] Uberti, 2002, Pergolide protects SH-SY5Y cells against neurodegeneration induced by H(2)O(2), Eur. J. Pharm. sourceNot checked yet

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• cites [142] Shipley, 2016, Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line, J. Vis. Exp.Not checked yet

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May combine two claims.

Tau does not allow the correct transit of peroxisomes, and abnormally phosphorylated cytoskeleton protein is a possible cause of the increased oxidizing environment.

“implying that Tau does not allow the correct transit of these organelles, being an abnormally phosphorylated cytoskeleton protein, the possible cause of the increase in the oxidizing environment.”

• cites [127] Kou, 2011, Peroxisomal alterations in Alzheimer’s disease, Acta Neuropathol. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Oxidation processes can affect DNA, causing nucleotide dimerization and errors in replication processes.

“Oxidation processes can affect DNA, causing nucleotide dimerization and causing errors in replication processes.”

• cites [115] Quispe, 2022, Resveratrol’ biotechnological applications: Enlightening its antimicrobial and antioxidant properties, J. Herb. Med. sourceNot checked yet

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May combine two claims.

When hyperphosphorylated Tau protein is overexpressed, peroxisome depletion occurs, suggesting that this depletion causes H2O2 and ROS increase.

“However, when the hyperphosphorylated Tau protein is overexpressed (which is a pathophysiological indicator of AD) a depletion of these organelles has been evidenced, suggesting it is the cause of H2O2 and ROS increase [72,108,126].”

• cites [72] Kim, 2015, The Role of Oxidative Stress in Neurodegenerative Diseases, Exp. Neurobiol. sourceNot checked yet

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• cites [108] Berger, 2016, Peroxisomes in brain development and function, Biochim. Biophys. Acta sourceNot checked yet

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• cites [126] Zhao, 2013, Oxidative stress and the pathogenesis of Alzheimer’s disease, Oxid. Med. Cell. Longev. sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SH-SY5Y cells can have a mixed culture and differentiate into specialized neurons through markers, allowing adrenergic, cholinergic, and dopaminergic models, and are a basic model for neurodegenerative pathologies such as Alzheimer's disease.

“Their most important characteristics are their ability to have a mixed culture (adherent and in suspension) and to differentiate into specialized neurons through markers, allowing adrenergic, cholinergic, and dopaminergic models [142,143], to be a basic model for the study of neurodegenerative pathologies, such as AD.”

• cites [142] Shipley, 2016, Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line, J. Vis. Exp.Not checked yet

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• cites [143] Kovalevich, 2013, Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology, Methods Mol. Biol. sourceNot checked yet

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May combine two claims.

Chlorogenic acids treatment significantly inhibited autophagy caused by Aβ25-35 by modulating lysosomal function in SH-SY5Y cells, thereby attenuating loss of CA1 neurons and cognitive defects in APP/PS1 mice.

“Gao et al. [152] demonstrated that chlorogenic acids treatment significantly inhibited autophagy caused by Aβ25-35 by modulating lysosomal function in SH-SY5Y cells, thereby attenuating the loss of CA1 neurons and cognitive defects in APP/PS1 mice”

• cites [152] Gao, 2020, Chlorogenic Acid Alleviates Abeta25-35-Induced Autophagy and Cognitive Impairment via the mTOR/TFEB Signaling Pathway, Drug Desigh Dev. sourceNot checked yet

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May combine two claims.

One of the main pathological characteristics of Alzheimer's disease is formation of amyloid plaques in the extracellular matrix of the cerebral cortex, caused by overproduction of the Aβ peptide mediated by cholinergic cells.

“One of the main pathological characteristics of AD is the formation of amyloid plaques in the extracellular matrix of the cerebral cortex, caused by the overproduction of the Aβ peptide mediated by cholinergic cells.”

• cites [161] Cheng, 2018, XBP1 and PERK Have Distinct Roles in Abeta-Induced Pathology, Mol. Neurobiol. sourceNot checked yet

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May combine two claims.

Quinic acid and chlorogenic acid extracted from plant matrices can inhibit the catalytic activities of AChE and BuChE, avoiding the cholinergic deficits that occur in Alzheimer's disease and trigger memory loss.

“Studies have revealed that QA and chlorogenic acid extracted from plant matrices can inhibit the catalytic activities of these enzymes, avoiding the cholinergic deficits that occur in AD which trigger memory loss.”

May combine two claims.

Lipidiol and amberboin sesquiterpenes inhibit cholinesterases with an IC50 < 9 M and are potential candidates for learning and memory improvement in patients with Alzheimer's disease and possible preventive treatment for this neurodegenerative pathology.

“Arya et al. [168] carried out an analysis of lipidiol and amberboin sesquiterpenes belonging to an important category of terpenoids found mainly in herbaceous plants and capable of causing inhibition in cholinesterases with an IC50 < 9 M, being potential candidates for learning and memory improvement in patients with AD, and possible preventive treatment for this neurodegenerative pathology.”

• cites [168] Arya, A., Chahal, R., Rao, R., Rahman, M.H., Kaushik, D., Akhtar, M.F., Saleem, A., Khalifa, S.M.A., El-Seedi, H.R., and Kamel, M. (2021). Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy. Biomolecules, 11. sourceNot checked yet

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May combine two claims.

BACE performs proteolysis by generating soluble APPβ and CTFβ; CTFβ undergoes γ-secretase proteolysis to generate toxic Aβ neuropeptides with 40-43 amino acids, finally causing the amyloid plaques characteristic of Alzheimer's disease.

“This protein known as the BACE performs proteolysis by generating a soluble fragment in the extracellular space known as “soluble APPβ” and an additional fragment bound to the plasma membrane, CTFβ peptide that undergoes proteolysis yet again by γ-secretase to generate toxic neuropeptides Aβ with 40–43 amino acids, finally causing the amyloid plaques characteristic of AD [165,166,167].”

• cites [165] Wang, 2020, Current understanding of metal ions in the pathogenesis of Alzheimer’s disease, Transl. Neurodegener. sourceNot checked yet

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• cites [166] Arendash, 2008, Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice, Brain Res. sourceNot checked yet

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• cites [167] Williams, 2012, Flavonoids, cognition, and dementia: Actions, mechanisms, and potential therapeutic utility for Alzheimer disease, Free Radic. Biol. Med. sourceNot checked yet

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May combine two claims.

Quinic acid and caffeoylquinic acid can exert neuroprotective properties through inhibition of AChE and BuChE, suggesting a possible mechanism that slows acetylcholine and butyrylcholine hydrolysis in the brain.

“Results showed that QA had greater inhibition potential than CQA, concluding that these bioactive molecules can exert neuroprotective properties through the inhibition of AchE and BuChe, suggesting a possible mechanism that slows the ACh and butyrylcholine hydrolysis in the brain [150].”

• cites [150] Oboh, 2013, Comparative study on the inhibitory effect of caffeic and chlorogenic acids on key enzymes linked to Alzheimer’s disease and some pro-oxidant induced oxidative stress in rats’ brain-in vitro, Neurochem. Res. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Chinese propolis components inhibited tunicamycin-induced neuronal death in SH-SY5Y cells and decreased induced caspase 3 activation and mitochondrial membrane potential disruption.

“The authors reported the inhibition of neuronal death, and that propolis decreased the induced activation of caspase 3 and the effects on mitochondrial membrane potential disruption [136].”

• cites [136] Izuta, 2008, Protective effects of Chinese propolis and its component, chrysin, against neuronal cell death via inhibition of mitochondrial apoptosis pathway in SH-SY5Y cells, J. Agric. Food Chem. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The worldwide increasing tendency toward using phytochemicals may be due to low toxicity and synergistic effects.

“The worldwide increasing tendency toward using phytochemicals may be due to low toxicity, and synergistic effects [199,200,201].”

• cites [199] Anekonda, 2005, Can herbs provide a new generation of drugs for treating Alzheimer’s disease?, Brain Res. Brain Res. Rev. sourceNot checked yet

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• cites [200] Semwal, 2022, Diosgenin: An Updated Pharmacological Review and Therapeutic Perspectives, Oxidative Med. Cell. Longev. sourceNot checked yet

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• cites [201] Sharifi-Rad, J., Quispe, C., Turgumbayeva, A., Mertdinç, Z., Tütüncü, S., Aydar, E.F., Özçelik, B., Anna, S.-W., Mariola, S., and Koziróg, A. (Z. Für Nat. C, 2022). Santalum Genus: Phytochemical constituents, biological activities and health promoting-effects, Z. Für Nat. C, Online ahead of print. sourceNot checked yet

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May combine two claims.

The neuroinflammatory immune response causes invasion of the glia by circulating immune cells and production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, nitric oxide, prostaglandin E2, chemokines, and ROS.

“This immune response causes both an invasion of the glia by circulating immune cells and the production of pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL) IL-1β and IL-6-, nitric oxide (NO), prostaglandin E2 (PGE2), chemokines, and ROS.”

• cites [117] Agostinho, 2010, Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease, Curr. Pharm. Des. sourceNot checked yet

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• cites [154] Ceulemans, 2010, The dual role of the neuroinflammatory response after ischemic stroke: Modulatory effects of hypothermia, J. Neuroinflammation sourceNot checked yet

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May combine two claims.

Amyloid plaque formation is caused by proteolytic cleavage of APP and intracellular NFT.

“This phenomenon is caused by proteolytic cleavage of the APP and intracellular NFT [161].”

• cites [161] Cheng, 2018, XBP1 and PERK Have Distinct Roles in Abeta-Induced Pathology, Mol. Neurobiol. sourceNot checked yet

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The quote only partly states this claim.

The caffeoylquinic acid derivatives restored glutathione concentration after H2O2-induced intracellular depletion.

“In addition, the restoration of glutathione concentration suffered an intracellular depletion induced by H2O2.”

• cites [153] Kim, 2005, Neuroprotective effects of 3,5-dicaffeoylquinic acid on hydrogen peroxide-induced cell death in SH-SY5Y cells, Phytother. Res. sourceNot checked yet

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May combine two claims.

Phytochemicals' activity against Alzheimer's disease occurs through anti-amyloid, anticholinesterase, anti-inflammatory, and antioxidant mechanisms.

“Phytochemicals’ activity against AD occurred through different mechanisms such as their anti-amyloid, anticholinesterase, anti-inflammatory, and antioxidant properties [198].”

• cites [198] Walker, 2007, Anti-inflammatory and immune therapy for Alzheimer’s disease: Current status and future directions, Curr. Neuropharmacol. sourceNot checked yet

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May combine two claims.

Phytochemicals rarely fit the ideal drug-like profile due to their scarce bioavailability; therefore, their manipulation also aims to ameliorate their pharmacokinetics.

“However, phytochemicals rarely fit in the ideal drug-like profile due to their scarce bioavailability; therefore, their manipulation also aims to ameliorate their pharmacokinetics [210,211].”

• cites [210] Dey, 2021, Cinnamomum Species: Bridging Phytochemistry Knowledge, Pharmacological Properties and Toxicological Safety for Health Benefits, Front. Pharmacol. sourceNot checked yet

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• cites [211] Docea, A.O., Calina, D., Buga, A.M., Zlatian, O., Paoliello, M.M.B., Mogosanu, G.D., Streba, C.T., Popescu, E.L., Stoica, A.E., and Birca, A.C. (2020). The Effect of Silver Nanoparticles on Antioxidant/Pro-Oxidant Balance in a Murine Model. Int. J. Mol. Sci., 21. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Phytol has low absorption and poor solubility leading to reduced bioavailability that hinders the clinical use of this compound.

“Phytol is found in nature and exerts a wide range of biological effects, but low absorption and poor solubility lead to reduced bioavailability which hinders the clinical use of this compound [221].”

• cites [221] Islam, 2018, Phytol: A review of biomedical activities, Food Chem Toxicol sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

A limitation in the use of phytopharmaceuticals corresponds to their bioavailability, a crucial aspect in pharmacokinetics, but it can be overcome through administration methods such as cyclodextrins, implants, nanoparticles, niosomes or liposomes.

“However, there is a limitation in the use of phytopharmaceuticals and this corresponds to their bioavailability, a crucial aspect in terms of pharmacokinetics, but which can be overcome through the use of administration methods such as cyclodextrins, implants, nanoparticles, niosomes or liposomes.”

May combine two claims.

Nanoparticles allow adequate targeted transport of phytochemicals to the central nervous system with controlled release time.

“After several decades of research in nanotechnology to transport drugs to the CNS, it is possible to have nanoparticles that allow an adequate transport of phytochemicals in a targeted way and with a control in the release time [213,214].”

• cites [213] Quispe, 2021, Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment, Cancer Cell Int. sourceNot checked yet

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• cites [214] Islam, 2021, Neuropharmacological Effects of Quercetin: A Literature-Based Review, Front. Pharmacol. sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Phytochemicals have antioxidant, anti-inflammatory, anti-amyloid, and anticholinesterase properties, which are the four fundamental pillars identified in the pathophysiological process of Alzheimer's disease.

“Phytochemicals have antioxidant, anti-inflammatory, anti-amyloid, and anticholinesterase properties, which are the four fundamental pillars identified in the pathophysiological process of Alzheimer’s.”

• AssumptionRests on an assumption: Oxidative stress, neuroinflammation, protein aggregation, and cholinergic deficit are the four fundamental pillars of the pathophysiological process of Alzheimer’s disease.

May combine two claims.

A high percentage of phytochemicals with high molecular weight and high lipophilicity will not be able to cross into the brain compartment, combined with chemical instability in the bloodstream.

“A high percentage of phytochemicals with high molecular weight and a high degree of lipophilicity will not be able to cross into the brain compartment, combined with chemical instability in the bloodstream [208].”

• cites [208] Cortes, 2015, Nanoparticle technology for treatment of Parkinson’s disease: The role of surface phenomena in reaching the brain, Drug Discov. Today sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

According to previous studies, the four FDA-approved Alzheimer's drugs maintain maximum effectiveness three years after administration, causing advancement of the pathology after this time.

“However, according to previous studies, these drugs maintain maximum effectiveness three years after administration, causing advancement of the pathology after this time.”

Probably not a substantial claim: may not pass S4 (based).

Currently, the approach to therapy against Alzheimer's disease is based on inhibiting one pathophysiological mechanism at a time, a role played by the four FDA-approved drugs, including AChEIs and NMDA receptor agonists.

“Currently, the approach to therapy against AD is based on inhibiting one pathophysiological mechanism at the same time, a role played by the four FDA-approved drugs, including AChEIs and NMDA receptor agonists.”

May combine two claims.

Micro and nanospheres, polymeric micelles, nanocapsules and nanoparticulate systems improve specific targeting of bioactive compounds, decrease systemic toxicity, improve therapeutic efficiency, and protect active substances against biochemical degradation.

“In the last decade, micro and nanospheres, polymeric micelles, nanocapsules and, in general, nanoparticulate systems have been shown to have an effect in improving the specific targeting of bioactive compounds, decreasing their systemic toxicity, improving the therapeutic efficiency rate and protecting active substances against biochemical degradation [217,218].”

• cites [217] Quispe, 2022, Therapeutic Applications of Curcumin in Diabetes: A Review and Perspective, Biomed. Res. Int. sourceNot checked yet

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• cites [218] Naqvi, 2020, Nanotechnology: A Promising Approach for Delivery of Neuroprotective Drugs, Front. Neurosci. sourceNot checked yet

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May combine two claims.

Various components of plants, such as phenolic compounds, flavonoids and non-flavonoids and/or carotenoids, have neuroprotective effects, acting at the level of blocking progression of Alzheimer's disease and having beneficial properties on Alzheimer's disease prevention.

“It has been shown that various components of plants, such as phenolic compounds, flavonoids and non-flavonoids and/or carotenoids, have neuroprotective effects, which not only act at the level of blocking the progression of AD but also have beneficial properties on AD prevention.”