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Oxidative Stress and Inflammation - Pathogenesis in Degeneration of the Retina

Neurodegenerative diseases of the retina are mostly attributable to oxidative stress and inflammation.(1)  Diseases of the retina target the retinal epithelial cells, and photoreceptors. Photoreceptors are the processing centers in the retina, and are the primary area of vision. The retina has the highest metabolic rate of any tissue in the body. Furthermore, the retina must endure oxidative stress from chronic exposure to light, which will damage the retina. In addition, retina degeneration is associated with inflammation. The result is that with age, the retina becomes damaged, and blindness is the end effect in older people.

 

AGE RELATED MACULAR DEGENERATION. Degeneration of retinal cells (photoreceptor and retinal pigment epitheilium (RPE) cells) by oxidative stress and inflammation is responsible for age-related macular degeneration (AMD).

  • PHOTORECEPTORS - Are comprised of rods and cones.  Are under constant threat of oxidative threats, including excessive stress from light, high oxygen requirements, All of which make photo receptors susceptible to degradation and death of the photo receptors.

(1) Oxidative Stress - NrFT2. Cellular Transcription Factor for Endogenous Antioxidant Protective Factors

  • CARNOSIC ACID

Carnosic Acid is an electrophilic antioxidant which crosses the blood brain barrier. Carnoisc acid is a potent activator of Nrf2, a transcription factor that causes the increased production of endogenous antioxidants. Additionally, carnoisc acid is unqiue in that it does not deplete endogenous levels of glutathionine, the key cellular antioxidant, unlike other antioxidants.(2) In a study of high intensity lighting on photooxidative damage of the retina, adding carnoisc acid to AREDS ingredients greatly increased protection of retina vs AREDS alone.(3)

  • LYCIUM BARBARIM (WOLFBERRY)

    Protects the eye and retina in multiple ways. First, lycium bararum protects the photreceptor cells from light-induced retina damage by activating Nrf2.(4)

    2) Inflammation - NLRP3 inflammasome activation is involed in the pathogenesis of AMD.

    • BLACK CURRANT / BILBERRY EXTRACT (C3G)

    C3G is considered the most important anthocyanin in maintaining health of the retina. Recently, research indicates that cyanidin-3-glucoside (C3G) has potent anti-inflammation properties and may inhibit  inflammasome damage to retinal epithelium cells.(5) C3G further reduces oxidative stress of the retina, and light induced retinal degeneration,  by activating Nrf2 endogenous levels.(6)

     

    VISION VITALITY (Carnosic Acid | Lycium Barbarum | C3G)

     

    REFERENCES:
    (1) Rohowetz RJ, et al, Reactive Oxygen Species-Mediated Damage of Retinal Neurons: Drug Development Targets for Therapies of Chronic Neurodegeneration of the Retina. Int J Mol Sci. 2018 Oct

    (2) Rezaie T, et al. Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2012 Nov

    (3) Wong P, et al, Enhancing the efficacy of AREDS antioxidants in light-induced retinal degeneration.  Mol Vis. 2017 Oct

    (4)  Tang L, et al. Antioxidant effects of Lycium barbarum polysaccharides on photoreceptor degeneration in the light-exposed mouse retina. Biomed Pharmacother. 2018 Jul

    (5) Jin X, et al. Cyanidin-3-glucoside Alleviates 4-Hydroxyhexenal-Induced NLRP3 Inflammasome Activation via JNK-c-Jun/AP-1 Pathway in Human Retinal Pigment Epithelial Cells.  J Immunol Res. 2018

    (6) Wang Y, et al. Cyanidin-3-glucoside and its phenolic acid metabolites attenuate visible light-induced retinal degeneration in vivo via activation of Nrf2/HO-1 pathway and NF-κB suppression.  Mol Nutr Food Res. 2016 Jul

    Carnosic Acid - Protects Retina and Supports Healthy Cartilage

    Carnosic acid, an extract from the herb Rosemary, is a powerful activator of cellular endogenous antioxidants, through involvement in increasing Nrf2 transcription.  Since carnosic acid crosses the blood-brain barrier, there is significant provisioning of protection of the brain and neural tissue.(1) In addition, the retina is primarily neural tissue, which benefits greatly from carnosic acid.

              RETINA - MITIGATING AGING EYE DETERIORATION

    • Reduces Light Induced Damage - Continued light exposure created free  radicals in the retina, which are destructive to the photoreceptors. (1,2)
    • Age-Related Macular degeneration (AMD) - Photoreceptors are also loss in AMD. Studies involving lab animals suggest that the addition of carnosic acid (rosemary extract) to other vision supplements, i.e. AREDS, may maximize effectiveness in reducing retinal damage. (3)
    • Slows Photoreceptor Degeneration. In mouse models of retinitis pigmentosa, carnosic acid has been shown to slow the loss of photoreceptors.(4)
    • Reduces Acyrlamide Toxicity - A toxic compound resulting from the heating of carbohydrates, and occurs in many everyday foods, including potato chips, and other heated foods.Acrylamide crosses the blood-brain barrier and is destructive to the  retina. (5,6)

               CARTILAGE - BENEFICIAL EFFECTS FOR OSTEOARTHRITIS

    • Activates Heme-Oxygenase-1  (HO--1). HO-1 promotes reduction of inflammation in the cartilage, which is characteristic of cartilage degeneration.  As such, carnosic acid promotes preservation of cartilage and inhibition of the degenerative process. Researchers concluded that carnosic acid both prevents cartilage degeneration and the severity of osteoarthritis, as evidenced by animal models.(7)
    • Chondrocytes, the cartilage producing cells, are negatively impacted by inflammation, and carnosic acid, improves the function and longevity of the chondrocytes. (8)
    • Improves  Chondrocyte Gene Expression. Helps maintain the ability of the chondrocyte to produce cartilage.(8). 

     

     VISION VITALITY    (with CARNOSIC ACID)

     

     

     

    REFERENCES:

    (1) Rezaie T, et al. Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced retinal degeneration. Invest, Ophthalmol Vis Sci, 2012 Nov

    (2) Contin MA, et al. Light pollution: the possible consequences of excessive illumination on retina. Eye (Lond). 2016 Feb

    (3) Wong P, et al, Enhancing the efficacy of AREDS antioxidants in light-induced retinal degeneration. Mol Vis. 2017 Oct

    (4) Kang K, et al. Carnosic acid slows photoreceptor degeneration in the Pde6b(rd10) mouse model of retinitis pigmentosa. Sci Rep. 2016 Mar

    (5) Albalawi A, et al. Protective effect of carnosic acid against acrylamide-induced toxicity in RPE cells. Food Chem Toxicol. 2017 Oct

    (6) Albalawi A, et al. Carnosic acid attenuates acrylamide-induced retinal toxicity in zebrafish embryos. Exp Eye Res. 2018 Oct;

     (6) Ishitobi H, et al. Carnosic acid attenuates cartilage degeneration through induction of heme oxygenase-1 in human articular chondrocytes.

    (7) Ravaili S, et al. Recently highlighted nutraceuticals for preventive management of osteoarthritis. World J Orthop. 2018 Nov

    (8) Schwager J, et al.  Carnosol and Related Substances Modulate Chemokine and Cytokine Production in Macrophages and Chondrocytes. Molecules. 2016 Apr

     

    Herbal Extracts - Neurogenesis & Recovery of Cognition Impairments

    Aging of the brain involves the loss of neurons (hippocapmus shrinkage), loss of synapse integrity between neurons, build-up of toxic amyloid proteins, neuron tangles, defects in blood flow  and chronic inflammation. Under normal age progression, these events do not happen over night and may take years before impairments in cognition become noticed.

    Ultimate anti-aging strategies for the brain and memory should target the progressive decline of the brain and promote reversal and recovery of some cognition impairments.

    Emerging research in the study of herbal ingredients show their tremendous potential use in mitigating the decline in brain function with age.

    • NEUROGENESIS - is the formation of new neurons, specifically in the hippocampus area in the brain.The hippocampus is essential in providing the capacity for memory and learning. Dementia and Alzheimer's disease are associated with brain shrinkage which is correlated to the loss of neurons in the hippocampus. The formation of new neurons may reverse brain shrinkage.

                        Herbs and Extracts

      •  Andrographolide - As an extract from Andrographis Paniculata. Lab research has shown stimulation of neurogenesis in the hippocampus by andorgrapholide. Specifically " increased cell proliferation and the density of immature neurons in the dentate gyrus." (1) The dentate gyrus is an area of the hippocampus involved in memory formation.
      • Centella asiatica - Acts as a potent memory enhancer, via  increasing hippocampus neurogenesis and support for brain tissue regeneration. (2)
      • Baicalin (3)
      • Panax Ginseng (4)
      • Curcumin (5)
      • Epimedium (Icariin)  (6)
      • Apigenin (7)
      • BRAIN TISSUE REGENERATION. While in the same theme as neurogenesis, brain tissue regeneration refers to the enhancement and regeneration of critical neuron structures - axons and dendrites. Dendrites transmit signals from the synapse to the body of the neuron. Axons transmit signals away from the body of the neuron and are covered with a myelin sheath which increase speed of the impulse providing rapid impulse transmission. Aging degenerates the structural integrity of dendrites and axon/myelin complex.

                           Herbs and Extracts

      •  Centella asiatica - Improves structural integrity of axons / myelination and proliferation of dendritic branching and length. Such improvements have been shown to enhance learning and improve memory. (8) Centella asiatica also has been shown to improve learning and memory in normal lab mice.
      • Luteolin - Baicalin - promote neuronal survival and neuron differentiation through the outgrowth of neurites  (axons and dendrites) from the neuron.(9.10)
      • Rosemary (Carnosic Acid) - Strongly promotes neurite outgrowth as a function of powerful Nrf2 activity. Suppressed Nrf2 activation suppresses neuron differentiation.(11)

        • RECOVERY OF COGNITIVE IMPAIRMENT - the  to reversal of certain functional impairments which may improve cognitive function. Many research animal models for cognitive impairment are characteristically similar to Alzheimer's disease (AD). Impairment usually involves cerebral vascular disease, synaptic dysfunction. and more.
                  Herbs and Extracts
        • Andrographolide - Impairment of synaptic function between neurons plays a significant role in the loss of cognitive function. This is seen in the progression of AD. In research animals with AD-like cognitive disease, the treatment of andrographolide over a 3 month span imporved synaptic function and protected important synaptic proteins.
        • Furthermore, andrographolide has been shown to reduce inflammation in the brain and levels of pathological tau protein and beta amyloid in animal models.(12)
        • Andrographolide reduces inflammation and dysfunction of the cerebral endothelial cells, which may affect vascular flow to the brain.(13)
        • Centella asiactica - in senescence-accelerated lab mice, which had accelerated aging of the brain, administration of centella asiatica significantly improved synaptic plasticity and reduced beta amyloid build-up. Such treated mice showed significant benefits in memory and learning. (14)
        • NEUROPROTECTION - AMYLOID & NON-AMYLOID (α-synuclein) TOXICITY | CHRONIC INFLAMMATION - The aging brain is under continual assault and must be protected to prevent cognitive decline and loss of neurons. Key areas of protection include the build-up of amyoid plaques which are toxic to neurons and synapses. Moreover, chronic inflammation in the brain accelerates destruction of the brain and is believed to be the facilitator of degenerative brain diseases.
          • Centella asiatica (15)
          • Epimedium (Icariin)(16,17)
          • Apigenin and luteolin (18,19)
          • Baicalin (20)
          • Schisandra (21)
          • Rosemary (Carnosic Acid)(22)
        • REVERSES INSULIN RESISTANCE IN BRAIN NEURONS - Aging brains become increasingly incapable of using glucose as an energy source. Without this energy neurons age faster and die. Reversing the insulin resistance maintains healthy neurons. Brain insulin resistance is associated with Alzheimer's Disease.
        • Further reduction in glucose availability is caused by methylglyoxal - a powerful intermediate in the formation of Advanced Glycation End Products (AGEs).
        • Curcumin - Improves insulin sensitivity in neurons. (23)
        • Sulforaphane - Reverses reduction of glucose uptake by neurons caused by methylglyoxal (a precusor of advanced glycation end products). Sulforaphane also normalizes brain-derived neurotrophic factor (BDNF) signaling, which is critical for maintaining brain function. BDNF pathways are disrupted in Alzheimer's Disease. (24)

         

        YELLOW LONGEVITY

        YELLOW NATURALLY

        MEMORY ACTION

        XGEVITY

        LONGEVITY NATURALLY

         

        REFERENCES:

        NEUROGENESIS

        (1)   Varela-Nallar L, et al. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus. Neural Plast, 2015.

        (2)  Sirichoat A, et al. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus. Nutrients. 2015 Oct 5

        (3) Zhang K, et al. Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression. Sci Rep. 2016 Aug 9

        (4) Jiang B, et al.  Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol. 2012 Jul;

         (5) Pluta R, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin? Folia Neuropathol. 2015

        (6) Li F, et al. Icariin decreases both APP and Aβ levels and increases neurogenesis in the brain of Tg2576 mice. Neuroscience. 2015 Sep 24

        (7) Taupin P. Apigenin and related compounds stimulate adult neurogenesis. Mars, Inc., the Salk Institute for Biological Studies: WO2008147483. Expert Opin Ther Pat. 2009 Apr

        BRAIN TISSUE REGENERATION

        (8) Yogeswarin L, et al. Recent Updates in Neuroprotective and Neuroregenerative Potential of Centella asiatica. Malays J Med Sci 2016 Jan.

        (9) Chen PY, et al. Up-Regulation of miR-34a Expression in Response to the Luteolin-Induced Neurite Outgrowth of PC12 Cells. J Agric Food Chem. 2015 Apr

        (10) Li M, et al. Neuronal differentiation of C17.2 neural stem cells induced by a natural flavonoid, baicalin. Chembiochem. 2011 Feb 11;

        (11) Kosaka K, et al. Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells. J Biochem. 2010 Jan;

         

        RECOVERING COGNITIVE DYSFUNCTION

        (12) Rivera DS, et al. Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodon degus). Neurobiol Aging. 2016 Jul 5

        (13) Chang CC, et al. Andrographolide, a Novel NF-κB Inhibitor, Inhibits Vascular Smooth Muscle Cell Proliferation and Cerebral Endothelial Cell Inflammation. Acta Cardiol Sin. 2014 Jul;

        (14) Xing L, et al. Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice. Fitoterapia. 2013 Jun.

        NEUROPROTECTION - AMYLOID TOXICITY AND INFLAMMATION

        (15) Gray NE, et al. Centella asiatica Attenuates Amyloid-β-Induced Oxidative Stress and Mitochondrial Dysfunction. J Alzheimers Dis. 2015

        (16) Zhang L, et al. Icariin reduces α-synuclein over-expression by promoting α-synuclein degradation. Age (Dondr.) 2015 Aug

        (17) Chen YJ, et al. Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer's Disease Mice. CNS Neurosci Ther, 2016 Jan

        (18) Dirscherl K, et al. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 2010 Jan

        (19) Rezai-Zedeh K, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflammation. 2008 Sep

        (20) Chen C, et al. Baicalin attenuates alzheimer-like pathological changes and memory deficits induced by amyloid β1-42 protein.  Metab Brain Dis. 2015 Apr

        (21) Song F, et al. Schizandrin A Inhibits Microglia-Mediated Neuroninflammation through Inhibiting TRAF6-NF-κB and Jak2-Stat3 Signaling Pathways. PLoS One. 2016 Feb 26;

        (22) Habtemariam S. The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer's Disease. Evid Based Complement Alternat Med, 2016

        REVERSES BRAIN INSULIN RESISTANCE IN BRAIN NEURONS

        (23) Feng HL, et al. Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice. Int J Immunopathol. 2016 Jul 27

        (24) Angeloni C, et al. Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity. Chem Res Toxicol, 2015 Jun 15

        Brain & Neurodegenerative Diseases - The Central Role of Mitochondria

        All aging starts at the cellular level including degeneration of the brain. Science has now identified dysfunction of the neuron mitochondria as the early central initiator in brain degeneration. When the neuronal mitochondria become dysfunctional, there is an inadequate supply of energy to the neuron, and subsequently the neuron dies. Early stages of neurodegenerative diseases have mitochondrial dysfunction common in their pathogenesis including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and amyotrophic lateral sclerosis (ALS). Indeed, the failure of cellular bioenergetics has been linked to neuron death and dementia.(1,2)


        Research suggests that modulation and inhibition of mitochondrial dysfunction may increase neuron survival and provide a basis for extended brain longevity. As a cytoprotective agent, activation of transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) protects the functioning of the mitochondria and is viewed as a target for possible prevention and treatment of neurodegenerative diseases associated with aging. Sulforaphane (and precursor Glucoraphanin) is one of the most powerful natural nrf2 activators, and may play a role in the intervention of age-related brain degeneration. (2) In addition, the natural extract andrographolide, carnosic acid and carnosol have been identified as a very strong nrf2 activators. (3, 4)

        XGEVITY

        AIR VITALITY

        Both Contain the following nrf2 activators:

        • Glucoraphanin / sulforaphane – from broccoli
        • Andrographolide – from andrographis paniculata
        • Carnosol & Carnosic Acid – from rosemary extract

         

        REFERENCES:


        (1) Grimm A, et al. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease. Biogerontology. 2015 Oct 14.
        (2) Denzer I, et al. Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds.
        Pharmacol Res. 2015 Nov 25.
        (3) Wu KC, et al. Screening of natural compounds as activators of the keap1-nrf2 pathway.
        Planta Med. 2014
        (4) de Oliveira MR. The Dietary Components Carnosic Acid and Carnosol as Neuroprotective Agents: a Mechanistic View. Mol Neurobiol. 2015 Nov 9