#Fisetin and apoptosis

[in-sightjournal]

Ask A Genius 1305: Experimental Cancer Treatment for His Dog: A DIY Approach

Rick Rosner: All right, so maybe we should do Rotten Tomatoes here, and I’ll tell you a crazy fucking thing I’m doing. All right, so you’ve met the brown dog, our white dog, and Frida and our brown dog, Rosie. We inherited Rosie from Carol’s mom. Rosie is 14 and a half. She has a tumour growing on the back of her right rear leg—about two inches. We didn’t discover it right away because these…

[monsterkong]

How Fisetin and Mushrooms Can Supercharge Your Longevity 🍄🍓

What if living longer didn’t just mean adding years to your life but adding life to your years? In this episode of Vibe Science, Ryan Alford and Chris Hansen explore how cutting-edge supplements like fisetin and ergothioneine are changing the wellness game. Let’s break it down! 🌿💪

The Power of Fisetin: Nature’s Longevity Secret 🌱

Fisetin, a natural compound found in strawberries, is making waves for its ability to target zombie cells—aging cells that disrupt our organs. Here’s why it’s a game-changer:

Promotes Healthy Aging: By triggering apoptosis (natural cell death), fisetin clears out these pesky zombie cells.

Reduces Inflammation: It calms cytokines that cause chronic inflammation.

While eating strawberries is great, you’d need thousands to get the benefits of fisetin supplements. 🍓💊

Ergothioneine: The Antioxidant You Didn’t Know You Needed 🍄✨

Found in mushrooms, ergothioneine is an antioxidant powerhouse that protects your mitochondria—the energy producers of your cells. What’s fascinating? Our bodies can’t make it, but we have specialized receptors for it, proving that nature intended us to consume it. 🌍

Protects DNA from Damage: Shields against UV rays and heavy metals.

Boosts Energy Production: Keeps mitochondria working efficiently.

Whether you’re a mushroom lover or not, ergothioneine supplements are the way to go for optimal health. 🍄🌟

Lab Testing: The Key to Personalized Wellness 🧪

Personalized health begins with understanding your body. Life Extension offers lab testing to measure biomarkers like insulin levels and liver function. This data helps tailor your supplement plan, ensuring you’re on the right track. 📊🩺

Top 5 Supplements Everyone Should Take 🛍️

Dr. Pavey’s go-to list for wellness includes:

Multivitamins: Ensure foundational nutrients.

Fish Oil: Balance Omega-3s for heart and brain health.

Probiotics: Support a healthy gut.

CoQ10: Vital for mitochondrial energy.

Fisetin & Ergothioneine: Target aging and boost longevity.

Why Choose Life Extension? 🌟

From rigorous testing to cutting-edge research, Life Extension stands out in the crowded supplement market. Their commitment to quality ensures you’re getting only the best for your body. 🧬✨

Start Your Wellness Journey Today! 🌈

Empower yourself with knowledge, supplements, and personalized health plans. Visit LifeExtension.com to explore their offerings and take the first step toward a healthier, longer life. 🌟✨

For more insights, check out VibeSciencePodcast.com. Here’s to living well! 🎉

[didanawisgi]

[CAUTION: This article is unusually complex. Life can be like that.]

There is growing interest in the nucleotide NAD+ (nicotinamide adenine dinucleotide) because of recent research revealing it’s regulation of diverse pathways controlling lifespan.1 A paper by Belensky et al2 in the same issue of Cell as a commentary on it1found that a precursor of NAD+ (nicotinamide riboside) extended yeast life span via activation of pathways that respond to increased NAD+, such as those that depend upon the SIR2 gene. Moreover, the beneficial effects of caloric restriction appear to be NAD+ dependent, as well as mediated by the NAD+-dependent SIRT1/Sir2 activity.3,4

The ratio of NAD+/NADH regulate many aspects of metabolism, including DNA repair, stress resistance, and cell death.4

“Changes in NAD+ metabolism have been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disease, and normal ageing.”4 In fact, the authors of paper #4 suggest that, “NAD+ synthesis through the kynurenine pathway [de novo synthesis of NAD+ from tryptophan] and/or salvage pathway [from nicotinamide] is an attractive target for therapeutic intervention in age-associated degenerative disorders.”

NAD+ is also reported to play a critical role as part of cellular respiration during the process of oxidative phosphorylation and ATP production.4 “Therefore, ATP synthesis and redox potential is directly proportional to intracellular NAD+ concentration.”4 The NAD+/NADH ratio is a measure of the metabolic state because of its importance in regulating intracellular redox state.4

Sirtuins are deacetylases that regulate large numbers of genes by removing acetyl groups from DNA. The function of the longevity gene SIRT1 has been shown to depend on the availability of NAD+. “Not surprisingly, the life-enhancing properties of sirtuins go hand in hand with those of NAD+ metabolism, suggesting a causal relationship where SIRT1 translates alterations of NAD+ levels into transcriptional events.”4 Interestingly, the DNA repair enzyme PARP (poly(ADP-ribose) polymerase) uses large amounts of intracellular NAD+ and is thereby in competition with sirtuins for the limited supply of NAD+. Under conditions of excessive expression of PARP, cellular NAD+ can be depleted, killing the cell. “Hyperactivation of PARP1 following DNA strand breaks can rapidly consume intracellular NAD+ pools, resulting in a loss of ability to synthesize ATP, and the cessation of all energy-dependent functions and consequent cell death.”4

The authors of paper #4 note that over-activation of PARP1 has been reported in the brains of Alzheimer’s disease patients, as well as in those with diabetes, MTPT-caused Parkinson’s disease, shock, and other conditions. It has been suggested that PARPs may play a role in aging by promoting NAD+ depletion. One study5 reported that PARP-1 activity in mononuclear blood cells increases with aging in at least thirteen mammalian species. In another study,5A researchers reported that “[o]ur results suggest that oxidative stress induced NAD+ depletion could play a significant role in the aging process, by compromising energy production, DNA repair and genomic surveillance.” The latter study5A examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female Wistar rats, reporting that “[o]ur results are the first to show a significant decline in intracellular NAD+ levels and NAD/NADH ratio in all organs by middle age (i.e., 12 months) compared to young (i.e., 3 month old) rats … The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.”

The authors of one paper5B write that “… when cells are subjected to oxidative stress by exposure to H2O2 [hydrogen peroxide], PARP-1 is activated and SIRT1 activity is robustly reduced, as PARP-1 activation limits NAD+ bioavailability. Treatment with PARP inhibitors in these circumstances allows the cell to maintain NAD+ levels and SIRT1 activity. … these observations indication that PARP-1 is a gatekeeper for SIRT1 activity by limiting NAD+ availability.”

The authors of paper #4 report that “[p]revious work from our group has shown for the first time that resveratrol induces a dose-dependent increase in activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT1)” but that this is unpublished data.

Interestingly, a very recent paper found that “enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models [of breast cancer], increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model.”6

Mitochondrial Biogenesis Induced by SirT1 Depends on Availability of NAD+

A very recent paper,6A in explaining how exercise or SirT1 activates PGC-1alpha, a master regulator of mitochondrial biogenesis, points out that the activity of SirT1 relies on NAD+ as a necessary coenzyme. The paper6A goes on to describe how, in its study of exercise in mice, chronic contractile activity (exercise) has a robust effect on mitochondrial biogenesis and that resveratrol acted synergistically with exercise to increase mitochondrial content when SirT1 was activated. “[T]he maximal effect of RSV [resveratrol] requires both SirT1 and a condition of energy demand in muscle that would be high in NAD+ and AMP, cofactors which activate SirT1 and AMPK, respectively.” 6A

Precursors That Can Be Taken As Supplements to Increase NAD+

There is (so far) remarkably little information on ways to increase NAD+ with natural products that are commercially available. There are three main physiological precursors: tryptophan, niacin, and niacinamide. It is reported that, “the administration of radiolabeled nicotinamide and nicotinic acid [niacin] has clearly shown that nicotinamide is a better precursor of NAD+ and that nicotinic acid is rapidly cleared by being converted to nicotinamide and excreted as nicotinuric acid.”6B Resveratrol was reported in paper #4 (but only as unpublished data) to dose-dependently increase the activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase. In another paper,7 quercetin was reported to oxidize NADH to NAD+ in rat liver, thus increasing the availability of NAD+. However, as the researchers also explain, “direct measurements of NADH/NAD+ are very difficult to perform.”7 This was as of the paper’s publication in 2005. The researchers inferred the NADH/NAD+ ratio from the ratio of beta-hydroxybutyrate to acetoacetate. Quercetin has also been reported to be a PARP-1 inhibitor.7B Niacinamide is known to be an inhibitor of PARP, thus may prevent the decrease in NAD+ that results from PARP activity. There is a salvage pathway of specific enzymes that converts niacinamide to NAD+.

Niacinamide (NAM) As a PARP Inhibitor May Explain NAM’s Antiviral Effects

Interestingly, PARP is reported to be critical for the integration of foreign DNA, as absence of the PARP enzyme interrupts the HIV life cycle.7C An early study published in 1996 on the effects of niacin reported that a daily niacin (combining niacin and niacinamide) intake in AIDS patients that equaled only 3–4 times the U.S. recommended daily allowance (at that time) of 20 mg/day experienced slower progression and improved survival.7D That was, of course, well before the current multidrug cocktails were developed that enable HIV infected individuals to survive 20 years or more, but still demonstrates the anti-viral effects of the vitamin.

Other natural PARP inhibitors include the flavonoids fisetin and tricetin8 and flavone.9

More About PARP Inhibitors

Keep in mind that PARP is an important enzyme for DNA repair and transcription. Hence, PARP inhibition has to be limited so as to avoid excessive impairment of DNA repair. “Impaired SIRT1 activity due to PARP mediated NAD+ depletion allows increased activity of several apoptotic effectors such as p53, therefore sensitizing cells to apoptosis. Adequate NAD+ levels are therefore critical to maintaining Sirt1 activity which can delay apoptosis and provide vulnerable cells with additional time to repair even after repeated exposure to oxidative stress.”5A

PARP inhibitors are now being incorporated into therapy for diseases such as cancer and diabetes.10–12 This cripples the DNA repair ability of cancer cells, which generally have deficient DNA repair to start with, further limiting their ability to repair DNA and making the cancer cells more vulnerable to apoptosis. In diabetes, moderate PARP inhibition can help maintain cellular NAD+ availability for ATP synthesis. In fact, as mentioned above, overactivation of PARP1 has been reported in diabetes, Alzheimer’s disease, traumatic brain injury, shock, and other conditions.4 A recent paper5C reported that PARP is hyperactivated by oxidative stress induced by beta amyloid; this PARP overactivation (and depletion of NAD+) could be an important source of cell death in Alzheimer’s disease.

Another recent paper “provided quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD+ catabolism in human tissue. The resulting NAD+ depletion may play a major role in the aging process by limiting energy production, DNA repair and genomic signaling.”13 In this paper, the authors note that other investigators have linked PARP1 hyperactivity to diseases such as diabetes, MPTP-induced Parkinson’s disease and injury induced brain disorders. They further reported for the first time, in this study,13 that PARP activity increases with age in human skin, correlating with both age and NAD+ depletion (in males, but not in females). Consistent with the regulation of SIRT1 activity by NAD+ availability, they found a significant decline in SIRT1 activity with age in post-pubescent males but, again, not in females. The authors suggest that one possibility is that females have a greater capacity to recycle NAD+ from the PARP metabolite nicotinamide; however this remains to be determined.

References

1. Denu. Vitamins and aging: pathways to NAD+ synthesis. Cell. 1293):453-4 (May 4, 2007). 2. Belenky et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 129:473-84 (2007). 3. Wolf. Calorie restriction increases life span: a molecular mechanism. Nutr Rev. 64(2):89-92 (2006). 4. Massudi et al. NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns. Redox Rep. 17(1):28-47 (2012). 5. Grube and Burkle. Poly(ADP-ribose) polynerase activity in mononuclear cell lines of 13 mammalian species correlates with species specific lifespan. Proc Natl Acad Sci USA. 89:11759-63 (1992). 5A. Braidy et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in Wistar rats. PLoS One. 6(4):e19194 (Apr. 2011). 5B. Canto and Auwerx. Interference between PARPs and SIRT1: a novel approach to healthy ageing? Aging. 3(5):543-7 (2011). 5C. Abeti and Duchen. Activation of PARP by oxidative stress induced by beta amyloid: implications for Alzheimer’s disease. Neurochem Res. 37:2589-96 (2012). 6. Santidrian et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 123(3):1068-81 (2013). 6A. Menzies et al. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J Biol Chem. 288(10):6968-79 (2013). 6B. Imai. The NAD world: a new systemic regulatory network for metabolism and aging — Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochem Biophys. 53:65-74 (2009). 7. Buss et al. The action of quercetin on the mitochondrial NADH to NAD+ ratio in the isolated perfused rat liver. Planta Med. 71:1118-22 (2005). 7B. Milo et al. Inhibition of carcinogen-induced cellular transformation of human fibroblasts by drugs that interact with the poly(ADP-ribose) polymerase system. FEBS J. 179(2):332-6 (1985). 7C. Murray. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis. 36:453-60 (2003) 7D. Tang et al. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. [a study of the Multicenter AIDS Cohort Study] Am J Epidemiol.143:1244-56 (1996) 8. Weseler et al. Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive disease or type 2 diabetes. J Nutr. 139:952-7 (2009). 9. Geraets et al. Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression. Eur J Pharmacol. 573:241-8 (2007). 10. Peralta-Leal et al. PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. Free Radic Biol Med. 47:13-26 (2009). 11. Soriano et al. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res. 89:684-91 (2001). 12. Du et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 112(7):1049-57 (2003). 13. Massudi et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 7(7):e42357 (July 2012).

[longhaulerbear]

Abstract Fusobacterium nucleatum (F. nucleatum) is an early pathogenic colonizer in periodontitis, but the host response to infection with this pathogen remains unclear. In this study, we built an F. nucleatum infectious model with human periodontal ligament stem cells (PDLSCs) and showed that F. nucleatum could inhibit proliferation, and facilitate apoptosis, ferroptosis, and inflammatory cytokine production in a dose-dependent manner. The F. nucleatum adhesin FadA acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β, IL-6 and IL-8. Further study showed that FadA could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling pathways. Time-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of F. nucleatum infection. NFκB1 and NFκB2 upregulated after 3 h of F. nucleatum-infection, and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with time. Using computational drug repositioning analysis, we predicted and validated that two potential drugs (piperlongumine and fisetin) could attenuate the negative effects of F. nucleatum-infection. Collectively, this study unveils the potential pathogenic mechanisms of F. nucleatum and the host inflammatory response at the early stage of F. nucleatum infection. Fusobacterium nucleatum (F. nucleatum) is one of the most frequently detected pathogens and has attracted increasing attention in recent years as an opportunistic pathogen in many systematic diseases, such as colorectal cancer,5 cardiovascular diseases,6 Alzheimer’s disease,7 and adverse pregnancy outcomes.8 F. nucleatum is an invasive bacterium that can induce a variety of host responses.9 Clinical studies have shown that the prevalence of F. nucleatum increases with the severity and progression of periodontitis.10,11 F. nucleatum can invade various host cells, such as epithelial and endothelial cells, monocytes and fibroblasts, to initiate a cascade of inflammation and induce the secretion of the proinflammatory chemokines interleukin(IL)-6 and IL-8.12,13 Toxic proteins are an important way for bacteria to exert pathogenicity, and F. nucleatum expresses a variety of virulence factors to induce various host responses As a main cell type in the periodontal ligament, periodontal ligament stem cells (PDLSCs) play an indispensable role in maintaining periodontal homeostasis.18 According to emerging evidence, the inflammatory environment caused by periodontitis leads to dysfunction and pyroptosis in PDLSCs. Ferroptosis, which is a novel necrotic cell death pathway, is triggered by iron overload.21 Perturbations in iron homeostasis are major pathogenic strategies for bacterial infection. FadA activates NF-κB and MAPK signaling pathways by interacting with PEBP1 Fusobacterium adhesin A (FadA) has been reported to be one of the most important adhesins and virulence factors of F. nucleatum.16 Among the drugs investigated, piperlongumine and fisetin exhibited the best attenuating effects, which prompted us to further assess their effects on FadA-induced inflammation. Similarly, piperlongumine and fisetin significantly decreased the FadA-induced proinflammatory cytokine production (P < 0.001) (Fig. 9a, b). Considering the ferroptotic effects of F. nucleatum on PDLSCs, we further examined the effects of piperlongumine and fisetin on ferroptosis. As shown in Fig. 9c–f, piperlongumine and fisetin reversed this trend, reduced the level of intracellular Fe2+, and ameliorated the impairment in mitochondrial function. These findings proved that PDLSCs have immunoregulatory capacity and that F. nucleatum could aggravate periodontal inflammation by impairing the immunosuppressive function of PDLSCs.

[biomedgrid]

Biomed grid| Natural Products for the Therapy of Proteinopathies Underlying the Neurodegenerative Conditions: Protein Misfolding and Fibrillization in Alzheimer’s Disease and Parkinson’s Disease

Introduction

Significant progress has been made in our understanding of dysregulated proteostasis and protein misfolding which underlie the pathogenesis of such neurodegenerative diseases as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In the 1990s the kinetics of β-amyloid (Aβ) fibrillization was well characterized [1,2]. Epidemiology had shown that mutations in amyloid precursor protein (APP) or the beta- and gamma-secretases which elevate the level of Aβ in the brain, as well as mutations which increase the propensity for Aβ to polymerize, are strongly associated with the development of Alzheimer’s disease. Oligomers of A�� are more neurotoxic than the monomers [3-5]. These observations suggested that molecules which would interfere with polymerization and fibrillization might slow the progression of AD. During the testing of natural compounds, Thioflavin-T (Th-T) was often used to monitor the state of Aβ polymerization [6].

The tendency for many proteins and peptides to convert from their native functional state into intractable amyloid aggregates was found to underlie multiple human disorders including Alzheimer and Parkinson diseases, type II diabetes, prion disease and several systemic amyloidosis (e.g. Aβ, αs, PrP, τ, IAPP, TDP-43, p53) [7-15]. Multiple therapeutic strategies have been employed to find disease-modifying agents against amyloidosis [16]. Some natural compounds found in the diet have anti-amyloid effects and may reduce the risk for AD and T2D [17,18]. Epidemiologic studies have suggested that diets with a high intake of flavonoids and polyphenolic compounds may have protective effects against AD, T2D and dementia [19-21]. Several polyphenols have progressed to clinical trials for the treatment of AD including resveratrol, curcumin, epigallocatechin-3-gallate (EGCG) and palm fruit bioactive [19,22,23].

Abbreviations: Aβ: Beta-Amyloid; αs: Alpha-Synuclein; τ: Tau Protein; PRP: Prion Protein; IAPP: Islet Amyloid Peptide; TDP-43: TAR DNA-Binding Protein 43; P53: Tumour Suppressor P53; T2D: Type 2 Diabetes Mellitus; AD: Alzheimer’s Disease; PD: Parkinson’s Disease; ALS: Amyotrophic Lateral Sclerosis

These polyphenols, demonstrating a range of anti-inflammatory, antioxidant and metal chelating bioactivities, have served as structural backbones in the computational design of novel drugs [24,25]. A PubMed literature review of natural compounds which modulate amyloid aggregation revealed 72 compounds, of which 44 are phenolic compounds including 16 flavonoids, 4 anthraquinones, 13 alkaloids (including 3 pyridines, 3 indoles, 2 porphyrins), steroids and terpenes [26].

Epidemiologic studies of diets have shown that the regular ingestion of curcumin, myricetin, EGCG, along with green tea polyphenols is associated with healthy cognitive function [19,27,28]. Cohort studies on the moderate consumption of red wine suggest that resveratrol reduces the risk of dementia, AD or cognitive decline associated with aging [21,29] Among the 72 anti-amyloid compounds identified in the PubMed search are many phenolic compounds which are found in brain-healthy diets associated with reduced risk of aging-associated amyloid pathologies [19,30,31]. These compounds include: EGCG and myricetin found in green tea; curcumin found in turmeric; caffeic acid and rosmarinic acid found in culinary herbs; oleuropein and oleocanthal found in olive oil; resveratrol found in red wine and grapes; genistein found in legumes; and cinnamaldehyde found in cinnamon. Investigations into the mechanism of action by which these compounds inhibit amyloid aggregation show that some exert their effects through the formation of covalent bonds [32-39] and others exert their effects through non-covalent interactions [40-57].

The proteinopathies, involving protein misfolding and aggregation into toxic fibrillar deposits, are common to multiple neurodegenerative conditions including AD, PD, ALS, TDP-43, IAPP, prion diseases as well as to such systemic disorders of T2D and systemic amyloidosis [58-62]. Clinical trials aimed at reducing the level of toxic misfolded protein aggregates have not been successful over the past decade, perhaps due to a futile intervention following irreversible and irreparable cell and tissue damage. More promising is the potential for preventing the organ damage in the first place, through the regular intake of a diet rich in phenolics, which have dual activity as both amyloid aggregation inhibitors and as antioxidants.

Beta amyloid (Aβ) and tau (τ) aggregates are pathognomonic for AD [63]; alpha-synuclein (αs) deposits are seen in PD [64]; prion diseases and transmissible spongiform encephalopathies (TSE) present with misfolded prion protein (PrPSC) [65]; aggregates of superoxide dismutase 1 (SOD-1) and TAR DNA-binding protein 43 (TDP-43) characterize ALS [66-68]; and fronto-temporal dementia (FTD) also manifests aggregates of TDP-43 [69]; Huntington’s disease manifests aggregation of glutamine-rich (polyQ) Huntingtin protein (htt) [70]. The toxic protein aggregates dysregulate the cellular metabolism and activate a complex cascade of events which may lead to acute inflammation or apoptosis. The amyloid aggregates may also block proteasomal activities and cause a marked disturbance in proteostasis. Beta-sheet-rich proteins jam the entry site to the catalytic core, thereby blocking the proteasome system [71-73]. Often the autophagy system seems impaired in these diseases with accumulation of autophagic vacuoles [74,76]. The toxic aggregates also disrupt permeability of cell membranes, impair mitochondrial function, increase reactive oxygen species, induce acute inflammation and disrupt proteostasis. The protein aggregates also expose hydrophobic portions which interact abnormally with other cellular proteins, which results in their sequestration and loss of normal function [61,77,78].

Epigallocatechin-3-gallate (EGCG) is a flavanol found in green tea leaves [79] EGCG has demonstrated neuroprotective, antioxidant, antibacterial and antitumor activity in vitro and in vivo [80,81] EGCG reduces the aggregation and toxicity of a wide range of proteins involved in proteinopathies. Some papers report that EGCG acts at an early stage of aggregation by binding with the proteins in a non-sequence specific manner [82]. Evidence suggests that it may bind to and stabilize unfolded conformations of Aβ and αs, thereby reducing fibrillation and re-directing the proteins from the aggregation cascade to off-pathway amorphous non-toxic aggregates.45 EGCG also binds to partially misfolded tau [83]. Through its multiple mechanisms of action on inhibiting amyloid aggregation suggests its potential use in preventive clinical trials on AD.

Curcumin is a biphenolic compound found in Curcuma longa, the Indian spice turmeric used in curry dishes, has strongly documented anti-inflammatory and antioxidant properties [84,85]. Based on its general activity inhibiting amyloid aggregation, Curcumin has shown beneficial effects in AD, PD, T2D and prion diseases [84,86,87] Clinical trials are underway for Curcumin for AD and T2D. Curcumin directly binds to Aβ and inhibits its aggregation in vitro [88] and in vivo [89]. Curcumin also disaggregates peptides from toxic aggregates.

Resveratrol is a natural phytoalexin stilbenoid polyphenolic compound found in grapes, berries, soybeans, peanuts and red wine. Resveratrol inhibits the aggregation of Aβ through selective transformation of the oligomers and shuttling them into off-pathway species which are unable to aggregate [90]. Resveratrol can bind multiple conformations of Aβ including Aβ42, Aβ40 and fibrillar Aβ [91]. Resveratrol is able to disaggregate Aβ from Aβ42 fibrils [92] In cell culture, resveratrol reduces the hyperphosphorylation of tau proteins [93]. In transgenic AD murine models, resveratrol has been shown to reduce amyloid plaque deposition without directly affecting the processing of APP [94,95].

In the transgenic murine AD models, resveratrol also:

1. Improves cognitive function [96,97],

2. Protects permeability of the blood-brain barrier [98],

3. Reduces acute inflammatory response through a decrease in microgliosis, and

4. Reduces the generation of reactive oxygen species (ROS) [99,100].

Botes and Sinskey have observed that Palm Fruit Bioactive, comprising a polyphenol-rich extract from the Elaeis guineensis, reduce the cytotoxicity of aggregated α-synuclein in a transgenic yeast rescue assay [101]. Other promising natural agents with potent anti-amyloid aggregation properties include: Apigenin, Fisetin, Kaempferol, Morin, Quercetin, Myricetin, Brazilin, Gallic acid, Oleocanthal, oleuropein, oleuropein aglycone, Orcein, Rosmarinic acid, Tanshinones, and Tannic acid. These natural compounds have been undergoing extensive investigation for their potential in preventing or reducing the proteinopathies, but a more detailed discussion of them is beyond the scope of this mini review.

Conclusion

The clinical trials with these natural compounds over the past decade have been disappointing but this may be the result of attempting to overcome irreversible and irreparable damage to the brain. We must consider implementing a diet rich in these natural anti-amyloid compounds early in life to prevent the neurotoxicity of these amyloid aggregates and thus prevent the inception and progression of these devastating neurodegenerative conditions. The answer may be in the prevention rather than the cure of these conditions.

Read More About this Article: https://biomedgrid.com/fulltext/volume3/natural-products-for-the-therapy-of-proteinopathies-underlying-the-neurodegenerative-conditions.000675.php

For more about: Journals on Biomedical Science :Biomed Grid

[moleculardepot]

Fisetin Inhibits Cell Proliferation through the Induction of G0/G1 Phase Arrest and Caspase-3-Mediated Apoptosis in Mouse Leukemia Cells. A new interesting article has been published in Am J Chin Med. 2019 May 16:1-23. doi: 10.1142/S0192415X19500447.

[healthtimetaylor]

Fisetin may represent a potential therapeutic strategy for human oral squamous cell carcinoma.

PMID:  Drug Des Devel Ther. 2020 ;14:773-782. Epub 2020 Feb 25. PMID: 32158195 Abstract Title:  Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways. Abstract:  Objective: Human oral squamous cell carcinoma (OSCC) is a major cause of mortality and morbidity worldwide. There is an urgent need to identify bioactive molecules and potential target genes that could inhibit carcinogenesis for OSCC therapy. Fisetin (3,7,3',4'-tetrahydroxyflavone), a naturally occurring flavonoid, has been previously shown to have anti-proliferative activities in OSCC; however, its molecular mechanism is unknown.Methods: Colony formation, cell viability, Boyden chamber, wound healing, and tumor xenograft assays were used to detect the impact of fisetin on OSCC cells in vitro and in vivo. Western blot analysis was used to examine the corresponding protein expression.Results: Fisetin treatment significantly inhibited proliferation and promoted apoptosis by repressing PAK4 expression. Moreover, fisetin treatment attenuated cell migration by blocking PAK4 signaling pathways. In addition, the tumor xenograft showed anti-tumor growth effects of fisetin exposure in vivo.Conclusion: Fisetin may represent a potential therapeutic strategy for human OSCC by targeting PAK4 signaling pathways.

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[jakehglover]

What Are the Benefits of Ground Cherries?

If there were a short list of fruits surrounded by confusing, misleading and downright incorrect nomenclature, ground cherries would be on it. There are several reasons for that: They have a long history and are well-traveled over hundreds of years, as they were discovered and propagated in multiple areas of the world.

They're also similar in appearance to the fruit of other plants, so this small, yellow-orange, husk-covered fruit with a store of tiny yellow seeds inside has a plethora of names.

They've been called "uniquely sweet; a mixture of pineapple, strawberry and green grapes — sweet, tart and vaguely tropical."1 Smithsonian may have the best description of ground cherries: They're said to taste "like a cherry tomato injected with mango and pineapple juice, and (look) like an orange pearl encased in a miniature paper lantern."

Equally at home in tropical, subtropical and temperate climates, they're sometimes called cape gooseberries, but the botanical names are slightly different. Because of their early history in Central and South America, they're sometimes referred to as Aztec berry, Inca berry, Peruvian groundcherry and Peruvian cherry.

They've taken on such monikers as aguaymanto in Peru, uvilla in Ecuador and uchuva in Colombia. In Madagascar they're called pok pok; in Hawaii, they're known as poha; and in Egypt, they're harankash.

According to Healthy Steps, ground cherries are not only related to the tomatillo (Physalis philadelphica) and Chinese lantern (Physalis alkekengi), they're also members of the nightshade family of plants. But in spite of the label, they're related to neither gooseberries nor cherries.

If all that is confusing, this might help: The botanical name for ground cherries, the variety native to North America, is Physalis pruinosa, while cape gooseberries, aka Physalis peruviana, are thought to have originated in South America. As Gracelinks observes:

"The two are very, very similar in both appearance and flavor, and in reality, the two names (ground cherries and cape gooseberries) are used interchangeably to refer to the fruit, which is generally yellow-orange, about the size of a large marble and enclosed in a papery husk …

Cape gooseberries, although native to South America, got their name from the Cape of Good Hope. They were introduced to South Africa in the early 19th century, and quickly became popular there.

From South Africa, the fruit was introduced to Australia and New Zealand. As with the early American pioneer settlers, early European colonists in Australia valued the fruit because it was one of the few fresh fruits available at the time."2

Ground Cherries Can Also Be Good for You

Their appearance as well as their flavor helps differentiate ground cherries from other fruits. Ground cherries (with yet again another descriptive name of "husk cherry") are said to make desserts brighter and add a sweet component to robust meals of meat or vegetables.

In her article referring to ground cherries as "misunderstood neighbors," Liz Granger mentions 70 varieties of Physalis fruits worldwide, and colorfully describes their many culinary aspects:

"Bite into this golden relative of the tomatillo, this berry thing, and taste its jammy insides — the nutty watermelon, the mellow sugar, the dulcet vinegar finish … They do sweet; they do savory. Native Americans turned ground cherries into a relish.

A Native American Zuni recipe combines them with onions, chili paste and coriander. The Omaha and other tribes enjoyed them fresh. Homesteaders preferred them with sugar. In sod homes and log cabins, pioneer ladies made ground cherry pie and ground cherry jam."3

But while one might think much of the nutritional value of this fruit must lie in its store of vitamins and minerals, in this case it's actually the phytochemicals. Like the sulforaphane in broccoli and the fisetin found in strawberries, it's in the polyphenols that you'll find the true power of the little-known ground cherry.

For instance, the oil from the fruit is rich in fatty acids, natural antioxidants, carotenoids, phytosterols and such chemical compounds as kaempferol, quercetin and withanolides, which have been found to possess antimicrobial, antitumor, anti-inflammatory and insect repellant properties, as well as hepatoprotective and immunomodulatory activity; glycosides also show anticancer activity.

Another study notes that a specific withanolide compound inhibits the growth of colon cancer cultures, induces cell cycle arrest at low concentrations and apoptosis at higher concentrations, and may have some effect on the prevalence of colon cancer, as well as having growth inhibiting effects on breast cancer cells.4

What Makes Ground Cherries Nutritionally Beneficial?

According to Fruits Info,5 ground cherries contain more vitamin C than oranges. It's important to note that the riper the fruit is, the higher the concentration of beta carotene. The journal International Journal of Food Nutrition and Safety notes that ground cherries (or more specifically, South American-derived cape gooseberries), have been popular as a traditional herb for blood purification and for treating cancer, leukemia, hepatitis and other ailments.

Vitamins and minerals are also plentiful. The five most prominent vitamins are A, C, thiamin, riboflavin and niacin, while significant minerals include calcium, iron, phosphorus and potassium. Then there's protein, which Nutrition Data6 reports is 2.7 grams or 5 percent of the dietary reference intake (DRI) per 1-cup serving. Lose Weight With Us also weighs in:

"Not only is vitamin A good for our eyesight, (it's) believed to inhibit cancer and lower cholesterol. Vitamin C protects us against colds and flu and is thought to lower our blood pressure and protect us from Parkinson's disease.

Niacin or vitamin B3 is well-known for increasing the level of HDL (high density lipoprotein) in our bodies, which in turn is thought to reduce the incidence of heart disease. This fruit also contains pectin, which helps regulate blood sugar."7

Additionally, water and ethanol extracts of P. peruviana, as well as other fruits, were tested to determine phenolic and antioxidant activity, and high levels of radical scavenging activity were found, which positively influenced high blood sugar and hypertension linked to Type 2 diabetes.8 As the International Journal of Food Nutrition and Safety observes:

"P. peruviana have been widely used in folk medicine as anticancer, antimycobacterial, antileukemic, antipyretic, immunomodulatory, and for treating diseases such as malaria, asthma, hepatitis, dermatitis, diuretic and rheumatism …

The plant is diuretic and juice of its leaves is given in worm and bowel complaints, while heated leaves are applied as a poultice (and) an extract of the leaves shows antibiotic activity against Staphylococcus."9

Propagating, Harvesting and Delicious Experimentation With Ground Cherries

Granger quotes Kathleen Cue, a horticulture associate from the University of Nebraska's Lincoln Extension office, who says early settlers found ground cherries invaluable because unlike many fruits like apples, pears and cherries, they didn't — and still don't — require five years to begin producing fruit; instead, they are easy for home gardeners to "morph from seed to food."

Treated like tomato plants, the seeds can be started indoors six weeks before the last frost before being transplanted into areas of full sun and, similarly, many "volunteer" by reseeding themselves.

It doesn't take long for ground cherry branches, which are faintly purple in color covered with fine hairs, to vine and spread. Under favorable conditions they may reach 6 feet in height, but they also do well when staked.

Although the period of harvest is relatively short, taking place somewhere between midsummer and early fall, the ease of the harvest helps explain how these fruits got their name, as they simply drop to the ground when they're ripe. The fruits continue to ripen, though, so collecting them early is best for flavor and texture.

First, the fruit turns from pale green to an amber or gold color, and indicates ripeness when the husk becomes papery and straw-colored. If they're still green in color, they're not ready yet and will taste bitter. When purchasing ground cherries, note that the outer covering should be intact, which helps them continue to ripen. They can be kept for as long as six months in a well-ventilated storage area, Fruits Info10 notes.

As for making use of your ground cherries in culinary endeavors, both sweet and savory recipes aren't difficult to find, but you don't need to go to a lot of trouble; simply adding them to tossed salads is said to be tasty with goat cheese. A sweet treat might involve adapting a healthy version of this tart recipe from My Three Loves,11 which uses "husk cherries" and plums with slices of ginger, orange and/or lemon zest, stevia (instead of sugar), nutmeg, cinnamon and vanilla.

Smithsonian.com12 lists five quite novel ways to prepare them, such as chopping them into a salsa verde concoction with diced red onion and jalapeno, cilantro, lime and sea salt. Or, use them in combination with a relative such as tomatoes. Making a caprese salad is as simple as slicing them onto a platter and adding fresh mozzarella, chiffonaded basil, seasonings and a splash of rice vinegar.

The Kitchn13 passes along the recipe for a tasty salad vinaigrette from a site called Rawmazing.14 Combine the following in your blender or food processor, but note that the salad itself incorporates a cup of ground cherries mixed with cubed jicama, pumpkin seeds and lettuce:

Ingredients

1 cup ground cherries

2 tablespoons red wine vinegar

3/4 to 1 tablespoon liquid stevia

1/4 cup organic virgin olive oil

3 tablespoons finely chopped shallots

Himalayan salt and pepper to taste

Caveats for Buying Ground Cherries: Go for Non-GMO

For whatever reason, ground cherries, although native to the continent, are relatively unfamiliar to many people in the U.S., which explains why you're not likely to find them at your local supermarket. You may, however acquire them at farmers markets and heartland fruit and veggie booths.

They're generally sold in their husks. Inside, the fruits are often covered with a fine, slightly sticky coating that should be washed off before eating. But once you try them, it's altogether possible you'll be hooked.

It must be noted that as a nightshade plant alongside relatives like potatoes, tomatoes, bell peppers and eggplant, they may prove to be hard to tolerate for some people.

The unripe fruits of some varieties, particularly the Chinese lantern plant, Granger cautions, have been reported as potentially toxic if too many are ingested. The wisest course with the leaves, stems and husks of nightshades is that they be discarded because they contain the poisonous compound solanine.

But there's something else to consider. Ground cherries may be prolific all over North America, growing in forests and hedgerows, but they're not exempt from efforts to use chemicals such as pesticides and herbicides in their growth. For that reason, search out sources for ground cherries that are free from harmful residue and sprays, which can be dangerous for anyone who ingests them.

Researchers using the gene-editing technology known as CRISPR-Cas9 (clustered regularly interspaced short palindrome repeat), say that while most produce took hundreds of generations to become what they are today, they've been able to circumvent that.

Now, with CRISPR-Cas9, they can "whittle down the domestication process" to a few years, and their first experiment involves ground cherries, which "has everything it takes to become the next strawberry" that's "more suitable for agriculture."

Plant biotechnology expert and one of the developers to make the plants more productive and larger, Joyce Van Eck, says: "With some improvements, maybe it could become a specialty fruit crop."15

But if you're more interested in adding non-GM (genetically modified) ground cherries to your nutritional and culinary repertoire, Seed Savers Exchange is a nonprofit dedicated to the preservation and sharing of heirloom seeds. Granger suggests Aunt Molly's Physalis pruinosa,16 an organic ground cherry variety featured in the organization's current catalog. Planet Natural17 offers heirloom varieties, as does Heirloom Seeds.18

from HealthyLife via Jake Glover on Inoreader http://articles.mercola.com/sites/articles/archive/2018/10/29/ground-cherries.aspx

[serinakemp]

Enthusiasm for Senolytic Therapies

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I think it is entirely appropriate to greet the advent of senolytics with enthusiasm. These treatments are the first legitimate rejuvenation therapies to successfully target one of the root causes of aging, the accumulation of lingering senescent cells in old tissues. The first human trial data is approaching publication, but even before it arrives, the evidence to date strongly suggests that meaningful levels of rejuvenation can be achieved in old people at a very low cost. The first senolytic drugs (such as dasatinib and navitoclax) and plant extracts (such as fisetin and piperlongumine) cost very little, and remove only some senescent cells, no more than half in some tissues, and far fewer than that in others. Nonetheless, in mouse studies they reliably reduce chronic inflammation, reverse the progression of numerous conditions ranging from arthritis to Alzheimer's disease, and extend healthy life span even when applied a limited number of times in very late life.

As we get older, more and more of our the cells in our bodies become dysfunctional and enter into a state known as senescence. These senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are known as the senescence-associated secretory phenotype (SASP). Dr. Judith Campisi from the Buck Institute for Research on Aging, along with her research team, identified that senescent cells secreted the various harmful chemicals that characterize the SASP in 2008, which was when interest in senescent cells really began.

The SASP is a real problem: it increases inflammation, harms tissue repair and function, causes the immune system to malfunction, and raises the risk of developing age-related diseases such as cancer. Even worse, the SASP also encourages nearby healthy cells to become senescent, so even a very small number of senescent cells can cause big problems. Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis or are cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and the senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.

With these experiments, the biotechnology industry had initial proof that targeting one of the aging processes directly could improve...

[Read More ...]

Read more about N.O. Supplements and Heart fitness.

from Nitric Oxide and Mens Health https://ift.tt/2yFB8oN via IFTTT

[cancersfakianakis1]

Cancers, Vol. 10, Pages 346: The “Yin and Yang” of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers

Cancers, Vol. 10, Pages 346: The “Yin and Yang” of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers

Cancers doi: 10.3390/cancers10100346

Authors: Elizabeth Varghese Samson Mathews Samuel Mariam Abotaleb Sohaila Cheema Ravinder Mamtani Dietrich Büsselberg

Among the different types of breast cancers, triple-negative breast cancers (TNBCs) are highly aggressive, do not respond to conventional hormonal/human epidermal growth factor receptor 2 (HER2)-targeted interventions due to the lack of the respective receptor targets, have chances of early recurrence, metastasize, tend to be more invasive in nature, and develop drug resistance. The global burden of TNBCs is increasing regardless of the number of cytotoxic drugs being introduced into the market each year as they have only moderate efficacy and/or unforeseen side effects. Therefore, the demand for more efficient therapeutic interventions, with reduced side effects, for the treatment of TNBCs is rising. While some plant metabolites/derivatives actually induce the risk of cancers, many plant-derived active principles have gained attention as efficient anticancer agents against TNBCs, with fewer adverse side effects. Here we discuss the possible oncogenic molecular pathways in TNBCs and how the purified plant-derived natural compounds specifically target and modulate the genes and/or proteins involved in these aberrant pathways to exhibit their anticancer potential. We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/β-catenin, Notch, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects.

https://ift.tt/2MRzzJs

[ghaw2007]

9 Cucumber Benefits

9 Cucumber Benefits

1. Good Source of Cancer-Fighting Antioxidants 

Several bioactive compounds have been isolated from the nutritious cucumber, including cucurbitacins, glucosides, lignans, apigenin and flavanols like firestin. These are known to have strong cancer-fighting abilities since they can protect DNA and cells from damage due to oxidative stress. Fisetin is specifically tied to brain health and preservation of cognitive function, while cucurbitacins are known to have cancerous tumor-reducing effects.

Researchers from the University of Valencia in Spain have found that cucurbitacins antioxidants, a type of triterpene compound, can induce cancerous cell death (a process known as apoptosis). The most significant mechanisms with regard to the apoptotic effects of cucurbitacins are their ability to modify activities via nuclear factors or genes and to activate anti-tumor proteins.

This is precisely the reason why genes don’t determine your destiny: Eating plenty of high-antioxidant foods can greatly lower your risk of cancer even if it unfortunately does run in your family, making cucumbers a natural cancer treatment.

2. High in Nutrients but Low in Calories

Cucumbers are one of the vegetables with the highest water content, which means they offer valuable vitamins and minerals, yet they’re super low in calories — with only about 16 calories per cup. Since they’re about 95 percent water, they do a good job of taking up room in your stomach and visually adding volume to meals without weighing you down.

This means you can eat more and feel satiated while still sticking to an overall healthy, low-calorie or low-carb weight loss plan. Plus, cucumber nutrition can help quench thirst and prevent the desire to snack due to dehydration.

3. Helps Detoxify the Body

Cucumbers support the digestive tract, including helping to cleanse the liver, which is our main detoxifying organ, by removing accumulated toxins and waste materials from the blood and gut. They’re also a natural diuretic food, which means they can help the body produce more urine to carry out toxins and waste.

In the process, they’re great for reducing bloating and uncomfortable water retention — one reason to fill up on cucumbers after a night of salty food or alcohol.

4. Hydrates and Soothes Skin

Fresh cucumber juice has been used to naturally nourish damaged, dry or sensitive skin for centuries. According to some studies, cucumber slices or seeds applied directly to the skin gives a soothing and cooling effect against skin irritations and reduces swelling and redness. It’s even been used to naturally treat acne, scars and other blemishes.

Cucumbers also have the power to relax and alleviate pain, blotchiness and swelling following a sunburn, making for a great natural sunburn remedy. The fruit is considered a “refrigerant, haemostatic and tonic, useful in treating hyperdipsia or thermoplegia.” In other words, cucumbers help stop bleeding, reduce heat buildup associated with inflammation, quench your thirst, relieve dehydration and fight “sunstroke” all at the same time!

5. Helps Improve Heart Health 

Lignans found in cucumbers have well-documented immune-boosting, anti-inflammatory effects that are beneficial for fighting cardiovascular disease. Studies investigating the effects of consuming ligans from plant foods (including from high sources like flaxseeds or sesame seeds) have found beneficial associations with C-reactive protein levels, a lowering effect on total and low-density lipoprotein (LDL) cholesterol, and improved blood pressure levels.

Cucumbers also provide important minerals that help maintain a healthy heart, including potassium and magnesium. Potassium is linked to healthier blood pressure levels since it helps control fluids in the body, therefore low potassium intake from fruits and veggies is often correlated with poorer heart health. Magnesium-rich foods are also beneficial for blood pressure in addition to general nerve functioning, heartbeat regulation, fluid balance, better blood sugar stability and higher energy expenditure.

6. Improves Digestion and Relieves Constipation

The seeds of a cucumber are known for having a healing, heat-reducing effect on the body, and they’re often used to prevent and naturally relieve constipation in traditional forms of medicine like Ayurveda. Many people suffer from magnesium deficiency without even knowing it, but cucumbers’ source of magnesium and other electrolytes can help hydrate the gut and digestive lining, which keeps you more “regular.”

Since they’re a great vegetable for juicing or making smoothies, you can try combining cucumbers with other hydrating foods — like melon, lime, avocado, celery and fennel – to create a natural anti-bloating drink.

7. Helps Alkalize the Blood 

Cucumber nutrition includes being one of the top alkaline foods that help balance the body’s pH level and counteract the effects of an acidic diet. Limiting consumption of acid-forming foods — such as fried foods, sugar and refined carbohydrates, and eating more alkaline-forming foods instead — is beneficial for protecting your body from diseases that thrive in an acidic entrainment.

According to a report published in the Journal of Environmental Public Health, “Life on earth depends on appropriate pH levels in and around living organisms and cells. Human life requires a tightly controlled pH level in the serum of about 7. It is generally accepted that agricultural humans today have a diet poor in magnesium and potassium as well as … This results in a diet that may induce metabolic acidosis which is mismatched to the genetically determined nutritional requirements.”

A properly balanced pH level is also thought to decrease leptin levels, the main hormone connected to hunger and appetite control, as well as inflammation, the root of most diseases. Since the body is able to easily digest nutrients in liquid form, this is one reason why cucumbers are a popular ingredient in green alkalizing juices.

8. Supports Strong Bones

With 22 percent of your daily vitamin K in every cup of cucumbers, eating more is a good way to help maintain bone mineral density. Vitamin K (in the form of K2) is a fat-soluble vitamin that works with other essential nutrients like calcium and magnesium to preserve strong bones. In fact, vitamin k builds bones better than calcium.

Vitamin K also supports a healthy metabolism, nutrient absorption, aids in heart health, helps with blood clotting, supports neurological function and can help protect against cancer. Yet vitamin K deficiency is common among adults and children due to a diet low in green vegetables, a low-cholesterol diet, medication use and poor absorption of nutrients.

9. Helps Prevent or Treat Headaches 

Traditionally, cucumbers have been used as a natural headache remedy and somewhat of a pain reducer since they fight inflammation and swelling. Headaches or migraines can be triggered by many things, including dehydration, stress, fatigue, low blood sugar and nutritional deficiencies.

Many studies show that foods high in water and magnesium like cucumbers combat headaches by balancing fluids in the body and preventing dehydration.

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[lopezdorothy70-blog]

Fisetin sensitized human pancreatic cancer cells to gemcitabine-induced cytotoxicity

PMID:  Anticancer Res. 2018 Jun ;38(6):3527-3533. PMID: 29848706 Abstract Title:  Fisetin Enhances the Cytotoxicity of Gemcitabine by Down-regulating ERK-MYC in MiaPaca-2 Human Pancreatic Cancer Cells. Abstract:  BACKGROUND: Pancreatic cancer is a highly lethal malignancy with a poor prognosis. This study was set up to investigate the combined effect of gemcitabine and fisetin, a natural flavonoid from plants, on human pancreatic cancer cells. Meterials and Methods: Cytotoxic effect of fisetin in combination with gemcitabine on MiaPaca-2 cells was evaluated by the MTT assay, caspase 3/7 assay and propidium iodide/Annexin V. Extracellular signal-regulated kinase (ERK)-v-myc avian myelocytomatosis viral oncogene homolog (MYC) pathway was investigated by western blotting and quantitative real-time polymerase chain reaction.RESULTS: Combination treatment with fisetin and gemcitabine inhibited the proliferation of pancreatic cancer cells within 72 h and induced apoptosis, as indicated by activation of caspase 3/7. Fisetin down-regulated ERK at the protein and mRNA levels, and reduced ERK-induced MYC instability at the protein level.CONCLUSION: Fisetin sensitized human pancreatic cancer cells to gemcitabine-induced cytotoxicity through inhibition of ERK-MYC signaling. These results suggest that the combination of fisetin and gemcitabine could be developed as a novel potent therapeutic.

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[battybat-boss]

Fisetin alleviates oxidative stress after traumatic brain injury.

PMID:  Neurochem Int. 2018 May 22. Epub 2018 May 22. PMID: 29792955 Abstract Title:  Fisetin alleviates oxidative stress after traumatic brain injury via the Nrf2-ARE pathway. Abstract:  Fisetin, a natural flavonoid, has neuroprotection properties in many brain injury models. However, its role in traumatic brain injury (TBI) has not been fully explained. In the present study, we aimed to explore the neuroprotective effects of fisetin in a mouse model of TBI. We found that fisetin improved neurological function, reduced cerebral edema, attenuated brain lesion and ameliorated blood-brain barrier (BBB) disruption after TBI. Moreover, the up-regulation of malondialdehyde (MDA) and the activity of glutathione peroxidase (GPx) were reversed by fisetin treatment. Furthermore, administration of fisetin suppressed neuron cell death and apoptosis, increased the expression of B-cell lymphoma 2 (Bcl-2), while decreased the expression of Bcl-2-associated X protein (Bax) and caspase-3 after TBI. In addition, fisetin activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway following TBI. However, fisetin only failed to suppress oxidative stress in Nrf2mice. In conclusion, our data provided the first evidence that fisetin played a critical role in neuroprotection after TBI partly through the activation of the Nrf2-ARE pathway.

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[epigen-papers]

Fisetin Induces Apoptosis of HSC3 Human Oral Cancer Cells Through Endoplasmic Reticulum Stress and Dysfunction of Mitochondria-mediated Signaling Pathways.

Pubmed: http://dlvr.it/PzTTqS

[omgdowhat-blog]

New Anti-Aging Drugs Focusing on Toxic Cells

New Post has been published on http://www.dowhat.xyz/new-anti-aging-drugs-focusing-on-toxic-cells/

New Anti-Aging Drugs Focusing on Toxic Cells

Drugs that strip away the defenses of toxin-spewing cells could slow aging and improve quality of life.

That’s the conclusion of researchers from the Mayo Clinic in Minnesota.

Senescent cells — the term for cells that stop dividing but remain alive and metabolically active — can play a positive role in health by emitting toxins that kill cancer cells.

However, senescent cells can also accumulate over time. If they grow too numerous, senescent cells can damage healthy cells and contribute to a broad range of aging-related chronic conditions, including diabetes, cardiovascular disease, cancer, dementia, arthritis, osteoporosis, and frailty.

Then the issue becomes the fact that senescent cells have built-in protections that make them difficult to kill.

Such cells can survive for months in lab conditions that kill regular cells in hours.

Preventing the formation of senescent cells isn’t an option, since doing so would open the door to all kinds of opportunistic diseases, including cancer.

Instead, researchers have focused on ways to temporarily disarm already-formed cells in order to kill them off once their productive work has been completed.

Attacking the strongholds

New drugs now under development are meant to attack senescent cells at their strongest point — the half dozen or so “pro-survival networks” that help them resist apoptosis, or programmed cell death.

“We’re allowing senescent cells to kill themselves with the bad things they produce,” said Dr. James Kirkland, director of the Kogod Center on Aging at the Mayo Clinic.

A review article from Mayo researchers, published in this month’s issue of the Journal of the American Geriatrics Society, states that “senolytic” drugs, if proven safe and effective in humans, could prevent or delay a broad range of chronic conditions from inflammation to cellular dysfunction, that contribute to aging.

“The big risk factor is aging, so what we want to go after is aging itself,” Kirkland told Healthline.

In some cases, the body may even be able to repair aging-related damage.

“Senescent cells act like poison for stem cells, so when you clear senescent cells, you rehabilitate stem cell function,” said Kirkland.

“If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time,” the report suggested.

Making life healthier

This class of drugs was first reported in 2015 in animal studies led by Kirkland, and included Paul Robbins, PhD, and Dr. Laura Niedernhofer of the Scripps Research Institute, who coined the term “senolytics.”

The intent isn’t necessarily to extend life span, although that could someday be possible.

Rather, the drugs target “health span” — the number of years people live healthy, productive lives.

 “We want to add life to the years, rather than years to life,” Kirkland said.

The 2015 study, published in the journal Aging Cell, found that killing (or “clearing”) the senescent cells in old mice significantly improved quality of life.

“In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended health span,” said Niedernhofer at the time of the study’s release. “Remarkably, in some cases, these drugs did so with only a single course of treatment.”

New drugs being developed

Mayo researchers have already identified several senolytic drugs that target senescent cells.

A new study published in the journal Nature Communications detailed a screening platform for identifying more drugs targeting these cells, including a new class of drugs called HSP90 inhibitors.

The experimental anticancer drug Navitoclax; as well as dasatinib, a drug used to fight leukemia; quercetin, a plant polyphenol from the flavonoid group; and piperlongumine, a natural product derived from the fruit of the Asian Long pepper, are among the agents discovered in the past several years to have senolytic effects.

In March, Mayo researchers reported three more in the journal Aging: fisetin (another flavonoid and antioxidant), and two BCL-XL inhibitors — A1331852 and A1155463.

All were shown to kill senescent cells in vitro while leaving normal cells unharmed.

“We’ve moved rapidly in the last few years, and it’s increasingly looking like senolytic drugs, including the recently discovered HSP90 inhibitors, are having an impact on a huge range of diseases,” Kirkland said in a press statement. “We will need to continue to test whether there are more optimal drugs or drug combinations to broaden the range of senescent cell types targeted.”

Testing still needed

Kirkland told Healthline that human research trials of senolytic drugs are “imminent,” noting that some of the medications have already been approved by the U.S. Food and Drug Administration (FDA) for treatment of other health conditions.

If approved by the FDA, the drugs would likely be targeted initially at individuals with life-threatening conditions such as idiopathic pulmonary fibrosis, liver cirrhosis, advanced kidney disease, and diabetes.

Treatment would likely include a mix of drugs and lifestyle interventions, Kirkland said.

Despite the seemingly vast promise of senolytics, “We honestly don’t know yet whether these drugs work in people or not, and nobody should start taking these drug, until the clinical trials are done,” stressed Kirkland.

However, he said, “If proven safe, we could see this moving to less and less seriously ill populations, and maybe see people taking these drugs preventively.”

“That’s a long way down the road, though,” he said.

[sherristockman]

Strawberry Compound a Key to Good Memory Dr. Mercola By Dr. Mercola Ask several people what their favorite fruit is, and a good number of them will say strawberries. But aside from being luscious and one of the most fragrant, colorful essences of summer, this fruit contains a powerful compound that can make a remarkable difference in treating, improving and protecting against many disorders and diseases in your body. This somewhat obscure compound, fisetin, has been shown to decrease pain, prevent toxicity, maintain energy and improve your energy levels on a macro level, translating to more specific benefits in your overall health. Forbes noted: "Never heard of fisetin? That's because it was only identified a little more than a decade ago when scientists isolated plant flavonols with the ability to protect brain cells from degeneration. Like the similar flavonol quercetin, it's a sirtuin-activating compound that mimics many of the natural effects of calorie restriction, a well-studied anti-aging strategy."1 Also the coloring agent, fisetin is also a flavanol, also found in persimmons, apples, mangoes, grapes, cucumbers and onions, but strawberries contain the most by far, according to a 2013 study.2 A Japanese study reported that the highest concentration of fisetin was found in strawberries (160 μg/g, or microgram/gram) followed by apple (26.9 μg/g) and persimmon (10.5 μg/g).3 While fisetin has antioxidant properties, which can help curb cell damage caused by free radicals, one of the most dramatic ways it impacts your health is targeted toward your brain, as studies indicate it can help prevent Alzheimer's and other age-related neurodegenerative diseases. According to Forbes, Pamela Maher, senior staff scientist at the Cellular Neurobiology Laboratory at the Salk Cellular Neurobiology Laboratory, called fisetin a "novel neuroprotective and cognitione-enhancing molecule."4 She and her colleagues spent 10 years conducting studies on fisetin to find additional brain benefits as well as benefits for other areas of the body. According to the study5, some of the ways fisetin impacts your brain health is that it helps protect against damage due to injury and degeneration from aging, and also improves your memory while working with other compounds, activating nerve cells and increasing the defense systems throughout your brain and body. Fisetin Studies Related to Brain Aging One of Maher's studies in 2014 focused on memory loss in mice due to familial Alzheimer's, which is a type that accounts for only 3 percent of cases. The newest study examined possible fisetin advantages on sporadic Alzheimer's disease, the most common type associated with age.6 Scientists used mice that had been "genetically engineered to age prematurely, resulting in a mouse model of sporadic Alzheimer's disease," Medical News Today said: "When the prematurely aging mice were 3 months old, they were divided into two groups. One group was fed a dose of fisetin with their food every day for 7 months, until they reached the age of 10 months. The other group did not receive the compound. The team explains that at 10 months of age, the physical and cognitive states of the mice were the equivalent to those of 2-year-old mice. All rodents were subject to cognitive and behavioral tests throughout the study, and the researchers also assessed the mice for levels of markers linked to stress and inflammation."7 Assessment then revealed that the 10-month-old mice not given fisetin had more markers linked to stress and inflammation, and performed "significantly worse" in cognitive testing than those given fisetin. Maher termed the differences "striking." More specifically, two neurons, astrocytes and microglia, usually considered anti-inflammatory, were actually promoting inflammation in the brains of the no-fisetin mice. Those dosed with the compound were reported as having the behavior and cognitive function of 3-month-old mice — their actual age. Alzheimer's Prevention noted fisetin halted memory loss in mice typically prone to Alzheimer's within a year of their birth.8 Maher and company noted that while mice aren't people, there were enough similarities indicating fisetin's potential as a preventative, not just for Alzheimer's, but many age-related cognitive diseases, that they encouraged further rigorous studies. Fisetin Decreases Brain Damage From Stroke, Minimizes Damage From Injury Fisetin is not a new compound. Other clinical studies and examinations have revealed its incredible potential for several years, but its strength was usually attributed to its free radical-scavenging antioxidant properties (which are, of course, extremely important). However, SelfHacked notes several highly significant studies on how fisetin protects your brain: Mice treated with fisetin showed fewer behavioral abnormalities after a stroke than mice that weren't.9 Another study showed how the compound helps protect the parts of the brain starved of blood flow during a stroke.10 It was one of 10 flavonoids tested for protective effects against glutamate toxicity and found to be one of four that increased neuroprotective and anti-inflammatory effects. (Sulfuretin, butein, butin and eriodictyol were the other four.)11 In the case against brain injury induced by a head injury causing repeated seizures characterized by traumatic epilepsy, a study indicated that animal models experienced fewer episodes when they were treated with fisetin.12 Indicating its effectiveness in inhibiting inflammatory pathways, rats given high doses of fisetin showed far superior neurological function and less brain swelling after brain injury.13 Fisetin also increases SIRTI, an enzyme that can "'turn off' certain genes that promote aging, such as those involved in inflammation, fat synthesis and storage, and managing blood sugar levels. Fisetin's Protection Against Brain Degeneration • A 2004 study of Maher's revealed that as a flavonoid, fisetin protects nerve cells from oxidative stress by "multiple mechanisms."14 The upshot was that, among several flavonoids, fisetin was most effective at causing new brain growth. • Another involving scientists from Salk as well as from Australia, Germany and Austria showed one reason the compound had so many brain-boosting effects was due to its ability to cross the blood-brain barrier.15 (BrainFacts explains that "the brain is the only organ known to have its own security system, a network of blood vessels that allows the entry of essential nutrients while blocking other substances."16) • Supplementation with fisetin increases the strength of long-term memory pathways, which may influence memory disorders like Alzheimer's.17 It regulates several pathways, such as mitochondrial and antioxidant function, connected with age-related brain decay.18 Glutathione, a key cellular antioxidant with the ability to protect nerve cells, is increased by a mechanism that activates transcription factors, such as Nrf2. • Fisetin limits the buildup of harmful compounds in your brain like phosphorylated tau, which are implicated in Alzheimer's.19 It's also useful for decreasing inflammation in microglia, immune cells that can exert neurotoxic effects and which are often activated in neurogenerative disorders.20 • Fisetin also was found to slow progression of Huntington's disease, an ultimately fatal neurodegenerative disorder characterized by psychiatric, cognitive and motor symptoms in animal studies by activating the Ras-extracellular signal-regulated kinase (ERK) cascade.21 Neuroprotective Aspects of Fisetin Aluminum chloride, a neurotoxin, is a common ingredient in one of the products many Americans say they would never go without: antiperspirants. But fisetin has been shown to protect against the damaging effects of this common household ingredient.22 Fisetin was shown to lower elevated levels of ammonia in blood (hyperammonemia) with the potential to damage vital brain functions in hyperammonemic rats.23 Another brain protective aspect of fisetin, shown in mice, is its power to increase serotonin, which helps elevate your mood and energy, and noradrenaline, a hormone produced naturally by the body that functions as a neurotransmitter. One study explains the importance of noradrenaline "to maintain the cognitive processes such as attention, perception, and particularly the memory consolidation and retrieval. Disruption of these processes may result in symptoms of neuropsychiatric diseases and neurodegeneration."24 Mice given fisetin in another study revealed fewer symptoms of anxiety and depression brought on by pain.25 Further, the antidepressant effects of fisetin are shown to be enhanced by 5-Hydroxytryptophan (5-HTP), an amino acid precursor of serotonin, with additional benefits for anti-anxiety, sleep and weight loss, SelfHacked explains.26 More Ways Fisetin Supports and Protects Your Body It's easy to see how many vital roles fisetin plays in your body, for brain health and several aspects under a similar umbrella, such as mental health and inflammation, which translate in your body to more optimal health and well-being, including: The treatment of inflammatory bowel disease (IBD) and inflammatory responses caused by high blood sugar Suppression of mast cells, found in tissues, especially in your skin, respiratory and GI tracts Allergic reactions due to inhibiting inflammatory cytokine production Treatment for eczema in animals, reducing inflammatory cytokines, eosinophils (disease-fighting white blood cells), mast cells and T-cells (white blood cells involved in immunity) found in skin lesions27 Inhibits pathways needed for overactive cancer cells to grow and survive,28 inhibits their ability to invade healthy tissues, discourages proliferation and induces apoptosis of certain leukemias, including chronic myeloid leukemia (white blood cell cancer)29 Strawberries: One of the Most Popular Fruits in the US — And the Dirtiest Strawberries are one of the top fruit picks for many Americans, as stats show that combined with other berries such as raspberries, blueberries and cranberries, they come in fifth, according to the U.S. Department of Agriculture.30 California is the largest strawberry-growing state in the U.S., producing 1.5 million tons in 2015. Bananas come in first, followed by citrus fruits, apples and watermelon. Strawberries contain the highest concentrations of fisetin, but it would require eating 37 of them to get the optimal amount for actual benefits (or nine servings of other fisetin-containing fruits), so supplementation has been an ongoing endeavor for more than one company. Besides the above fruits, there are other fisetin-producing plants, including acacia trees, honey locust and the Japanese wax shrub. But according to the Environmental Working Group (EWG), strawberries are again the No. 1 fruit on the Dirty Dozen List of the most pesticide-laden crops, which means that as American eat their 8 pounds of this fruit per year, they're also ingesting dozens of varieties of pesticides, including chemicals known to cause cancer and reproductive damage, many of them banned in Europe. EWG notes: "What's worse, strawberry growers use jaw-dropping volumes of poisonous gases, some developed for chemical warfare but now banned by the Geneva Conventions, to sterilize their fields before planting, killing every pest, weed and other living thing in the soil … USDA (U.S. Department of Agriculture) tests found that strawberries were the fresh produce items most likely to be contaminated with pesticide residues, even after they are picked, rinsed in the field and washed before eating."31 How Can You Keep From Ingesting Toxins on Strawberries? Grow Your Own The only way to avoid ingesting the chemical concoctions doused on strawberries, EWG asserts, is to grow your own, organically, or buy organically grown strawberries, as the list of hazardous chemicals on conventionally grown varieties is long and harrowing, including such toxins as: Carbendazim, a hormone-disrupting fungicide Bifenthrin, an insecticide California regulators call a possible human carcinogen Malathion, toxic to the nervous system and a probable human carcinogen Unfortunately, as good as fisetin is for you, if you don't grow your own clean crop of strawberries or buy them from a source you know is organic, without any of the potentially neurologically system-poisoning sprays they're typically grown with, I would recommend passing them up until you can find a good source. Research shows that organic produce has about 180 times fewer pesticides on them than conventional produce. In lieu of that, if you know you're suffering because of a lifetime of eating tainted fruits and vegetables, you can eat fermented foods such as cauliflower and cabbage, and even make your own kimchi, as studies show it can actually break down the toxins and negate some of the damage to your system.